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Nandan PK, Sivaraman J. Elucidating Ras protein as a dual therapeutic target for inflammation and cancer: a review. Discov Oncol 2025; 16:1029. [PMID: 40483365 PMCID: PMC12145382 DOI: 10.1007/s12672-025-02783-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 05/22/2025] [Indexed: 06/11/2025] Open
Abstract
Cancer, one of the most dreadful diseases of the twenty-first century develops as a result of unregulated inflammatory responses and mutations of genes. In human cancers, among various mutated genes, the Ras gene is one of the most commonly mutated oncogenes. However, when it comes to inflammation, oncogenic Ras mutants can induce tumorigenesis without tumour suppression loss driven by inflammatory responses. Ras protein is a membrane-bound protein with inbuilt GTPase activity which is activated by a variety of extracellular stimuli, converting from an inactive form to an active form. Oncogenic Ras mutants is continuously activated in cancer, thereby enhancing aberrant downstream signalling that leads to tumorigenesis. So, to highlight the significance of Ras protein in cancer and inflammation, this review discussed the signalling pathway for the activation of Ras protein, the role of Ras in immunity and inflammation, downstream regulators of Ras protein and their inhibitors epigenetic regulation of Ras protein. Moreover, we have also done a database-based search using the Database of Cancer Mutant Protein Domains (DCMP) to find out the single nucleotide polymorphism (SNP) level of the Ras gene in different types of cancer. In terms of future perspective, this review discussed emerging strategies to target Ras protein.
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Affiliation(s)
- Parmar Keshri Nandan
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India
| | - Jayanthi Sivaraman
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, India.
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2
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Gallagher P, Rolfo C, Elez E, Taieb J, Houlden J, Collins L, Roberts C, André T, Lawler M, Di Nicolantonio F, Grayson M, Boyd R, Popovici V, Bardelli A, Carson R, Khawaja H, Laurent-Puig P, Salto-Tellez M, Hennessy BT, Maughan TS, Tabernero J, Adams R, Jones R, Peeters M, Middleton MR, Wilson RH, Van Schaeybroeck S. A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers. BJC REPORTS 2025; 3:17. [PMID: 40140597 PMCID: PMC11947101 DOI: 10.1038/s44276-025-00133-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/04/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. METHODS In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. RESULTS Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). CONCLUSIONS PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. EUDRACT-NUMBER 2014-000463-40.
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Affiliation(s)
- Peter Gallagher
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Christian Rolfo
- Department of Medical Oncology, University of Antwerp/Antwerp University Hospital, Wilrijk, Belgium
| | - Elena Elez
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
| | - Julien Taieb
- Department of GI Oncology Hôpital Européen Georges-Pompidou, Institut du cancer Paris Carpem, AP-HP, Université Paris Cité, Paris, France
| | - Jennifer Houlden
- Department of Oncology, Oncology Clinical Trials Office (OCTO), University of Oxford, Oxford, UK
| | - Linda Collins
- Department of Oncology, Oncology Clinical Trials Office (OCTO), University of Oxford, Oxford, UK
| | - Corran Roberts
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - Thierry André
- Department of Medical Oncology, Sorbonne Université, Hôpital Saint Antoine, Paris, France
| | - Mark Lawler
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | | | - Margaret Grayson
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
| | - Ruth Boyd
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
| | - Vlad Popovici
- RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Alberto Bardelli
- Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology, Milano, Italy
| | - Robbie Carson
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Hajrah Khawaja
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Pierre Laurent-Puig
- Centre de recherche des cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Manuel Salto-Tellez
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Bryan T Hennessy
- Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Tim S Maughan
- Department of Oncology, Old Road Campus Research Building Roosevelt Drive, University of Oxford, Oxford, UK
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton St, Liverpool, UK
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
| | - Richard Adams
- Cardiff University and Velindre University NHS Trust, Cardiff, UK
| | - Robert Jones
- Cardiff University and Velindre University NHS Trust, Cardiff, UK
| | - Marc Peeters
- Department of Medical Oncology, University of Antwerp/Antwerp University Hospital, Wilrijk, Belgium
| | - Mark R Middleton
- Department of Oncology, Old Road Campus Research Building Roosevelt Drive, University of Oxford, Oxford, UK
| | - Richard H Wilson
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Sandra Van Schaeybroeck
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
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Yildirim HC, Gunenc D, Almuradova E, Sutcuoglu O, Yalcin S. A Narrative Review of RAS Mutations in Early-Stage Colorectal Cancer: Mechanisms and Clinical Implications. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:408. [PMID: 40142219 PMCID: PMC11944112 DOI: 10.3390/medicina61030408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Revised: 02/19/2025] [Accepted: 02/22/2025] [Indexed: 03/28/2025]
Abstract
Colorectal cancer (CRC) is the third-most common cancer globally and a leading cause of cancer-related deaths. While the prognostic and predictive roles of RAS mutations in advanced CRC are well-established, their significance in early-stage CRC remains a topic of debate. Studies have been conducted for many years on clinical and pathological parameters that may be associated with RAS mutation, and there are inconsistent results in this regard. Currently, the only biomarker used in early-stage CRC is microsatellite status. KRAS mutations are detected in 40-50% of patients with colorectal cancer. RAS activating mutations cause loss of EGFR regulation by acting on the RAS/RAF/MAPK signaling pathways. In advanced colorectal cancer, these mechanisms cause a decrease in the effectiveness of EGFR inhibitors. However, studies on patients with early-stage colorectal cancer have inconsistent results. This review highlights the prognostic and clinical significance of KRAS mutations in early-stage CRC, particularly in MSS tumors. In the MSS group, KRAS mutations were associated with shorter TTR and OS compared to DWT patients. In contrast, in the MSI-H group, KRAS mutations showed no prognostic effect in TTR and OS. However. KRAS mutations were associated with shorter SAR in both MSI-H and MSS groups of patients. The findings underscore the need for routine molecular profiling, including KRAS and MSI status, to refine risk stratification and guide adjuvant therapy decisions. Further studies are warranted to explore targeted therapeutic approaches for KRAS-mutant CRC in the adjuvant setting.
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Affiliation(s)
- Hasan Cagri Yildirim
- Department of Medical Oncology, Nigde Training and Research Hospital, 51100 Nigde, Turkey
| | - Damla Gunenc
- Department of Medical Oncology, Ege University Faculty of Medicine, 35040 Izmir, Turkey;
| | | | - Osman Sutcuoglu
- Department of Medical Oncology, Etlik City Hospital, 06170 Ankara, Turkey;
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, 06230 Ankara, Turkey;
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Avădănei ER, Căruntu ID, Nucă I, Balan RA, Lozneanu L, Giusca SE, Pricope DL, Dascalu CG, Amalinei C. KRAS Mutation Status in Relation to Clinicopathological Characteristics of Romanian Colorectal Cancer Patients. Curr Issues Mol Biol 2025; 47:120. [PMID: 39996841 PMCID: PMC11854687 DOI: 10.3390/cimb47020120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/06/2025] [Accepted: 02/09/2025] [Indexed: 02/26/2025] Open
Abstract
Our study's aim was to evaluate the clinicopathological profile of colorectal cancer (CRC) patients from North-East Romania in relation to the Kirsten rat sarcoma viral oncogene homolog (KRAS). We designed a retrospective study on 108 CRC patients using the fully automated real-time PCR-based molecular testing system, IdyllaTMKRAS Mutation Test (Biocartis, Mechelen, Belgium). Of the patients, 64 (59.3%) were men and 62 (57.4%) were older than the group average, with left bowel location in 38 cases (35.2%), adenocarcinoma NOS in 102 cases (94.4%), mixed histological pattern in 65 cases (60.2%), T3 in 60 patients (55.6%), N2 in 46 patients (42.6%), and 7-12 tumour buds registered in 58 tumours (53.7%). A total of 54 tumour samples (50%) showed KRAS mutation. Statistical comparative analyses associated KRAS mutations with the histopathological pattern (p = 0.018), tumour grade (p = 0.030), depth of invasion (pT) (p < 0.001), lymph node involvement (pN) (p < 0.001), venous vascular invasion (p = 0.048), and tumour buds' number (p = 0.007). Our results demonstrate the relationship between KRAS mutation and clinicopathological features, with possible impact in clinical tumour stratification and therapeutic management.
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Affiliation(s)
- Elena-Roxana Avădănei
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
- Praxis Medical Investigation Laboratory, 35 Moara de Vant Street, 700376 Iasi, Romania;
| | - Irina-Draga Căruntu
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
- Romanian Medical Science Academy, 1 I.C. Bratianu Boulevard, 030171 Bucharest, Romania
| | - Irina Nucă
- Praxis Medical Investigation Laboratory, 35 Moara de Vant Street, 700376 Iasi, Romania;
- Department of Mother and Child Medicine-Genetics, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania
| | - Raluca Anca Balan
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
| | - Ludmila Lozneanu
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
- Department of Pathology, “Sf. Spiridon” Clinical Emergency County Hospital, 1 Independentei Street, 700111 Iasi, Romania
| | - Simona-Eliza Giusca
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
| | - Diana Lavinia Pricope
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
| | - Cristina Gena Dascalu
- Department of Preventive Medicine and Interdisciplinarity-Medical Informatics and Biostatistics, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania;
| | - Cornelia Amalinei
- Department of Morpho-Functional Sciences I-Histology, Pathology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Street, 700115 Iasi, Romania; (I.-D.C.); (R.A.B.); (L.L.); (S.-E.G.); (D.L.P.); (C.A.)
- Department of Histopathology, Institute of Legal Medicine, 4 Buna Vestire Street, 700455 Iasi, Romania
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Pappas L, Quintanilha JCF, Huang RSP, Parikh AR. Genomic alterations associated with early-stage disease and early recurrence in patients with colorectal cancer. Oncologist 2025; 30:oyae269. [PMID: 39531357 PMCID: PMC11883158 DOI: 10.1093/oncolo/oyae269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/28/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND The molecular characterization of early-stage (1-3) colorectal cancer (CRC) remains incomplete, as opposed to metastatic disease, where comprehensive genomic profiling (CGP) is routinely performed. This study aimed to characterize the genomics of stages 1-3 versus IV CRC, and the genomics of patients recurring within 1 year of diagnosis. PATIENTS AND METHODS Patients from a de-identified CRC clinico-genomic database who received Foundation Medicine testing (FoundationOne/FoundationOne CDx) during routine clinical care at approximately 280 US cancer clinics between March 2014 and June 2023 were included. Genomic alterations (GA) were compared by Fisher's exact test. RESULTS A total of 4702 patients were included; 1902 with stages 1-3 and 2800 with stage 4 disease. Among patients with stages 1-3 disease, 546 recurred within 1 year. Patients staged 1-3 had higher prevalence of microsatellite instability (MSI-H, 11.4% vs 4.5%, P < .001), tumor mutational burden (TMB) ≥ 10 Mut/Mb (14.6% vs 6.8%, P < .001), GA in RNF43 (11.2% vs 5.7%, P < .001), MSH6 (3.9% vs 1.7%, P < .001), MLH1 (2.3% vs 0.7%, P < .001), and MSH2 (1.5% vs 0.6%, P < .01) compared to those with stage 4 disease. Patients who recurred within 1 year had higher prevalence of MSI-H (13.2% vs 4.4%, P < .001), TMB ≥ 10 Mut/Mb (16.2% vs 6.9%, P < .001), BRAF V600E (17.2% vs 7.9%, P < .003), GA in RNF43 (13.7% vs 5.3%, P < .001), MSH6 (4.2% vs 1.6%, P = .035), and BRCA1/2 (6.2% vs 3.0%, P = .030). On recurrence, more patients received targeted therapy when CGP was performed before versus after first-line therapy (43% vs 19%, P < .001). CONCLUSIONS Early-stage CRC patients can have distinct genomic profiles and CGP in this population can help expand access to targeted therapies.
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Affiliation(s)
- Leontios Pappas
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | | | - Aparna R Parikh
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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Kwon JJ, Dilly J, Liu S, Kim E, Bian Y, Dharmaiah S, Tran TH, Kapner KS, Ly SH, Yang X, Rabara D, Waybright TJ, Giacomelli AO, Hong AL, Misek S, Wang B, Ravi A, Doench JG, Beroukhim R, Lemke CT, Haigis KM, Esposito D, Root DE, Nissley DV, Stephen AG, McCormick F, Simanshu DK, Hahn WC, Aguirre AJ. Comprehensive structure-function analysis reveals gain- and loss-of-function mechanisms impacting oncogenic KRAS activity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.618529. [PMID: 39484452 PMCID: PMC11526993 DOI: 10.1101/2024.10.22.618529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
To dissect variant-function relationships in the KRAS oncoprotein, we performed deep mutational scanning (DMS) screens for both wild-type and KRASG12D mutant alleles. We defined the spectrum of oncogenic potential for nearly all possible KRAS variants, identifying several novel transforming alleles and elucidating a model to describe the frequency of KRAS mutations in human cancer as a function of transforming potential, mutational probability, and tissue-specific mutational signatures. Biochemical and structural analyses of variants identified in a KRASG12D second-site suppressor DMS screen revealed that attenuation of oncogenic KRAS can be mediated by protein instability and conformational rigidity, resulting in reduced binding affinity to effector proteins, such as RAF and PI3-kinases, or reduced SOS-mediated nucleotide exchange activity. These studies define the landscape of single amino acid alterations that modulate the function of KRAS, providing a resource for the clinical interpretation of KRAS variants and elucidating mechanisms of oncogenic KRAS inactivation for therapeutic exploitation.
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Affiliation(s)
- Jason J. Kwon
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Julien Dilly
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Shengwu Liu
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Eejung Kim
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Yuemin Bian
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Srisathiyanarayanan Dharmaiah
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Timothy H. Tran
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Kevin S. Kapner
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
| | - Seav Huong Ly
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Xiaoping Yang
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Dana Rabara
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Timothy J. Waybright
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | | | - Andrew L. Hong
- Department of Pediatrics, Emory University School of Medicine and Children’s Healthcare of Atlanta, Atlanta, GA, USA
| | - Sean Misek
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Belinda Wang
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Arvind Ravi
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - John G. Doench
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Rameen Beroukhim
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | | | - Kevin M. Haigis
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Dominic Esposito
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - David E. Root
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Dwight V. Nissley
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Andrew G. Stephen
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Frank McCormick
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
- University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
| | - Dhirendra K. Simanshu
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - William C. Hahn
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Andrew J. Aguirre
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
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7
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Taieb J, Basile D, Seligmann J, Argiles G, André T, Gallois C, Goldberg RM, Yothers G, Sobrero A, Meyerhardt JA, Souglakos J, Labianca R, Iveson T, Church DN, Arnold D, Tie J, Gill S, Laurent-Puig P, Yoshino T, Lonardi S, Shi Q. Standardizing data collection in adjuvant colon cancer trials: A consensus project from the IDEA and ACCENT international consortia and national experts. Eur J Cancer 2024; 206:114118. [PMID: 38810317 DOI: 10.1016/j.ejca.2024.114118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/01/2024] [Accepted: 05/04/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND Despite contributions provided by the recent clinical trials, several issues and challenges still remain unsolved in adjuvant colon cancer (CC). Hence, further studies should be planned to better refine risk assessment as well as to establish the optimal treatment strategy in the adjuvant setting. However, it is necessary to request adequate, contemporary and relevant variables and report them homogeneously in order to bring maximal information when analyzing their prognostic value. MATERIAL AND METHODS The project was devised to gain a consensus from experts engaged in the planning, accrual and analyses of stage II and III CC clinical trials, to identify mandatory and recommended baseline variables in order to i) harmonize future data collection worldwide in clinical trials dedicated to adjuvant treatment of CC; ii) propose guidance for Case Report Forms to be used for clinical trials in this setting. A total of 72 questions related to variables that should be reported and how to report them in adjuvant clinical trials were approved and then voted to reach a final consensus from panelists. RESULTS Data items on patient-related factors, histopathological features, molecular profile, circulating biomarkers and blood analyses were analyzed and discussed by the whole expert panel. For each item, we report data supporting the acquired consensus and the relevant issues that were discussed. Nineteen items were deemed to be mandatory for resected stage III patients and 24 for resected stage II disease. In addition, 9 and 4 items were judged as recommended for stage III and II, respectively. CONCLUSION In our opinion, these 28 variables should be used and uniformly reported in more comprehensive CRFs as research groups design future clinical trials in the field of adjuvant colon cancer.
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Affiliation(s)
- Julien Taieb
- Institut du Cancer Paris CARPEM, Gastroenterology and Digestive Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, France.
| | - Debora Basile
- Division of Medical Oncology, San Giovanni di Dio Hospital, Crotone, Italy
| | | | | | - Thierry André
- Sorbonne Université and department of Medical Oncology, Hospital Saint Antoine and INSERM 938 and SIRIC CURAMUS, Paris, France
| | - Claire Gallois
- Institut du Cancer Paris CARPEM, Gastroenterology and Digestive Oncology Department, APHP.Centre - Université Paris Cité, Hôpital Européen G. Pompidou, France; Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, France
| | - Richard M Goldberg
- West Virginia University Cancer Institute and the Mary Babb Randolph Cancer Center, Morgantown, WV
| | - Greg Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Alberto Sobrero
- Department of Medical Oncology, IRCCS San Martino, Genoa, Italy
| | | | - John Souglakos
- Department of Medical Oncology, University General Hospital of Heraklion, 71110 Heraklion, Greece
| | | | - Tim Iveson
- University Hospital Southampton NHS Trust, Southampton, United Kingdom
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Department of Oncology and Hematology, AK Altona, Hamburg, Germany
| | - Jeanne Tie
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Parkville, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia; Division of Personalised Oncology, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
| | | | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, EPIGENETEC, 75006 Paris, France
| | | | - Sara Lonardi
- Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy
| | - Qian Shi
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN, USA
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8
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Choi Y, Kim N. Sex Difference of Colon Adenoma Pathway and Colorectal Carcinogenesis. World J Mens Health 2024; 42:256-282. [PMID: 37652658 PMCID: PMC10949019 DOI: 10.5534/wjmh.230085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/09/2023] [Indexed: 09/02/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common causes of cancer morbidity in both sexes but shows sex differences. First, sex-specific differences in tumor recurrence and survival rates have been reported. For example, the development of CRC is found about 1.5 times higher and 4-8 years earlier in males compared to females, suggesting the protective role of estrogen in the disease. Furthermore, female patients have a higher risk of developing right-sided (proximal) colon cancer than male patients, which is known to have more aggressive clinical character compared to left-sided (distal) colon cancer. That is, left and right CRCs show differences in carcinogenic mechanism, that the chromosomal instability pathway is more common in left colon cancer while the microsatellite instability and serrated pathways are more common in right colon cancer. It is thought that there are sex-based differences on the background of carcinogenesis of CRC. Sex differences of CRC have two aspects, sexual dimorphism (biological differences in hormones and genes) and gender differences (non-biological differences in societal attitudes and behavior). Recently, sex difference of colon adenoma pathway and sexual dimorphism in the biology of gene and protein expression, and in endocrine cellular signaling in the CRC carcinogenesis have been accumulated. In addition, behavioral patterns can lead to differences in exposure to risk factors such as drinking or smoking, diet and physical activity. Therefore, understanding sex/gender-related biological and sociocultural differences in CRC risk will help in providing strategies for screening, treatment and prevention protocols to reduce the mortality and improve the quality of life. In this review, sex/gender differences in colon adenoma pathway and various aspects such as clinicopathological, biological, molecular, and socio-cultural aspects of CRC were described.
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Affiliation(s)
- Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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9
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Grabski IN, Heymach JV, Kehl KL, Kopetz S, Lau KS, Riely GJ, Schrag D, Yaeger R, Irizarry RA, Haigis KM. Effects of KRAS Genetic Interactions on Outcomes in Cancers of the Lung, Pancreas, and Colorectum. Cancer Epidemiol Biomarkers Prev 2024; 33:158-169. [PMID: 37943166 PMCID: PMC10841605 DOI: 10.1158/1055-9965.epi-23-0262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 07/02/2023] [Accepted: 11/07/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND KRAS is among the most commonly mutated oncogenes in cancer, and previous studies have shown associations with survival in many cancer contexts. Evidence from both clinical observations and mouse experiments further suggests that these associations are allele- and tissue-specific. These findings motivate using clinical data to understand gene interactions and clinical covariates within different alleles and tissues. METHODS We analyze genomic and clinical data from the AACR Project GENIE Biopharma Collaborative for samples from lung, colorectal, and pancreatic cancers. For each of these cancer types, we report epidemiological associations for different KRAS alleles, apply principal component analysis (PCA) to discover groups of genes co-mutated with KRAS, and identify distinct clusters of patient profiles with implications for survival. RESULTS KRAS mutations were associated with inferior survival in lung, colon, and pancreas, although the specific mutations implicated varied by disease. Tissue- and allele-specific associations with smoking, sex, age, and race were found. Tissue-specific genetic interactions with KRAS were identified by PCA, which were clustered to produce five, four, and two patient profiles in lung, colon, and pancreas. Membership in these profiles was associated with survival in all three cancer types. CONCLUSIONS KRAS mutations have tissue- and allele-specific associations with inferior survival, clinical covariates, and genetic interactions. IMPACT Our results provide greater insight into the tissue- and allele-specific associations with KRAS mutations and identify clusters of patients that are associated with survival and clinical attributes from combinations of genetic interactions with KRAS mutations.
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Affiliation(s)
- Isabella N. Grabski
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - John V. Heymach
- Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kenneth L. Kehl
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ken S. Lau
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Gregory J. Riely
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Deborah Schrag
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rafael A. Irizarry
- Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Kevin M. Haigis
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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10
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Aljehani MA, Bien J, Lee JSH, Fisher GA, Lin AY. KRAS Sequence Variation as Prognostic Marker in Patients With Young- vs Late-Onset Colorectal Cancer. JAMA Netw Open 2023; 6:e2345801. [PMID: 38032636 PMCID: PMC10690478 DOI: 10.1001/jamanetworkopen.2023.45801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/05/2023] [Indexed: 12/01/2023] Open
Abstract
Importance The understanding of the association between KRAS sequence variation status and clinical outcomes in colorectal cancer (CRC) has evolved over time. Objective To characterize the association of age at onset, tumor sidedness, and KRAS sequence variation with survival among patients diagnosed with CRC. Design, Setting, and Participants This cross-sectional study used data extracted from the Surveillance, Epidemiology, and End Results database. Patients diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2015 were included and were classified as having young-onset (YO) cancer if diagnosed between ages 20 to 49 years and late-onset (LO) cancer if diagnosed at age 50 years or older. Data were analyzed from April 2021 through August 2023. Main Outcomes and Measures CRC cause-specific survival (CSS) was summarized using Fine and Gray cumulative incidence and Kaplan-Meier curves. Estimation of subdistribution hazard ratios (sHRs) for the association of KRAS status, age at onset, and tumor location with CRC CSS was conducted using the Fine and Gray competing risk model. Cox proportional hazards regression was used to estimate and compare HRs. Results Among 21 661 patients with KRAS sequence variation status (mean [SD] age at diagnosis, 62.50 [13.78] years; 9784 females [45.2%]), 3842 patients had YO CRC, including 1546 patients with KRAS variants, and 17 819 patients had LO CRC, including 7311 patients with KRAS variants. There was a significant difference in median CSS time between patients with variant vs wild-type KRAS (YO: 3.0 years [95% CI, 2.8-3.3 years] vs 3.5 years [95% CI, 3.3-3.9 years]; P = .02; LO: 2.5 years [95% CI, 2.4-2.7 years] vs 3.4 years [95% CI, 3.3-3.6 years]; P < .001). Tumors with variant compared with wild-type KRAS were associated with higher risk of CRC-related death (YO: sHR, 1.09 [95% CI, 1.01-1.18]; P = .03; LO: sHR, 1.06 [95% CI, 1.02-1.09]; P = .002). Among patients with YO cancer, mortality hazards increased by location, from right (sHR, 1.02 [95% CI, 0.88-1.17) to left (sHR, 1.15 [95% CI, 1.02-1.29) and rectum (sHR, 1.16 [95% CI, 0.99-1.36), but no trend by tumor location was seen for LO cancer. Conclusions and Relevance In this study of patients diagnosed with CRC, KRAS sequence variation was associated with increased mortality among patients with YO and LO tumors. In YO cancer, variant KRAS-associated mortality risk was higher in distal tumors than proximal tumors.
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Affiliation(s)
| | - Jeffrey Bien
- Stanford University School of Medicine, Stanford, California
| | - Jerry S. H. Lee
- Ellison Institute of Technology, Los Angeles, California
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles
- Department of Chemical Engineering and Material Sciences, Viterbi School of Engineering, University of Southern California, Los Angeles
- Department of Quantitative and Computational Biology, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles
| | | | - Albert Y. Lin
- Stanford University School of Medicine, Stanford, California
- Division of Oncology, Department of Medicine, VA Palo Alto Medical Center, Palo Alto, California
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11
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Taieb J, Sinicrope FA, Pederson L, Lonardi S, Alberts SR, George TJ, Yothers G, Van Cutsem E, Saltz L, Ogino S, Kerr R, Yoshino T, Goldberg RM, André T, Laurent-Puig P, Shi Q. Different prognostic values of KRAS exon 2 submutations and BRAF V600E mutation in microsatellite stable (MSS) and unstable (MSI) stage III colon cancer: an ACCENT/IDEA pooled analysis of seven trials. Ann Oncol 2023; 34:1025-1034. [PMID: 37619846 PMCID: PMC10938565 DOI: 10.1016/j.annonc.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/05/2023] [Accepted: 08/10/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis. PATIENTS AND METHODS We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations. RESULTS Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively [adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001]. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence. CONCLUSIONS Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.
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Affiliation(s)
- J Taieb
- Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Cité, AP-HP, SIRIC CARPEM, Paris, France; Department of Oncology, Mayo Clinic, Rochester, USA.
| | | | - L Pederson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
| | - S Lonardi
- Department of Oncology, Veneto Institute of Oncology IRCCS, Padua, Italy
| | - S R Alberts
- Department of Oncology, Mayo Clinic, Rochester, USA
| | - T J George
- Department of Oncology, University of Florida and the University of Florida Health Cancer Center, Gainesville, USA
| | - G Yothers
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, USA
| | - E Van Cutsem
- Department of Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - L Saltz
- Department of Oncology, Memorial Sloan Kettering Cancer Center, New York, USA
| | - S Ogino
- Department of Pathology, Brigham & Women's Hospital, Boston, USA
| | - R Kerr
- Department of Oncology, Oxford University, Oxford, UK
| | - T Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - R M Goldberg
- Department of Oncology, West Virginia University Cancer Institute, Morgantown, USA; Mary Babb Randolph Cancer Center, Morgantown, USA
| | - T André
- Sorbonne Université, Department of Medical Oncology, Hôpital Saint-Antoine, Paris, France
| | - P Laurent-Puig
- Institut du cancer Paris CARPEM, AP-HP, Université Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Department of Tumor and Cancer Genomic Medicine, Paris, France; Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team Personalized Medicine, Phamacogenomics and Therapeutic Optimization, Paris, France
| | - Q Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, USA
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12
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Bourakkadi Idrissi M, El Bouhaddouti H, Mouaqit O, Ousadden A, Ait Taleb K, Benjelloun EB. Left-Sided Colon Cancer and Right-Sided Colon Cancer: Are They the Same Cancer or Two Different Entities? Cureus 2023; 15:e37563. [PMID: 37193477 PMCID: PMC10183151 DOI: 10.7759/cureus.37563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2023] [Indexed: 05/18/2023] Open
Abstract
Background Colon cancer is one of the most common cancers in the world and one of the main causes of cancer-related deaths. In Morocco, it occupies the first place among digestive cancers. Right-sided and left-sided colon cancers have different embryological, epidemiological, pathological, genetic, and clinical characteristics. This distinction leads to differences in the evolution and prognosis of the disease. This study aimed to identify epidemiological factors and clinical and pathological characteristics that can influence perioperative and prognostic outcomes in patients with right-sided colon cancer compared to those with left-sided colon cancer. Methodology We conducted a retrospective cohort study over a period of nine years from January 2012 until December 2020. We included 277 patients divided into two groups, namely, right colon cancer (group 1) (n = 99) and left colon cancer (group 2) (n = 178). Results The average age of our series was 57.4 years, with extremes ranging from 19 to 89 years old (SD = ±13.6451 years). The average age in the right colon group was 55.97 (SD = ±13.341 years). The average age in the left colon group was 58.18 (SD = ±13.69 years). The male gender had a predominance, with a sex ratio of 1.3 for both groups. Among the patients in group 2, 65% showed lymph node involvement on the CT scan, whereas only 34% of patients in group 1 displayed the same condition. The recurrence rate in the right-sided colon cancer group was 22.2% compared to 24.9% in the left-sided group. The five-year overall survival was estimated for the right-sided and left-sided colon cancer groups at 87% and 96.5%, respectively. In patients with stage III and IV cancer, overall survival was better for those who underwent surgery for left-sided colon cancer compared to those who underwent surgery for right-sided colon cancer (p = 0.029). In the case of vascular emboli or involvement of the perineural sheath, there was no significant difference in overall survival (p = 0.446 and p = 0.655, respectively). The three-month survival without recurrence was almost identical in both groups (31% for right-sided colon cancers and 30.9% for left-sided colon cancers). Age over 61 years was a predictive factor of poor prognosis in recurrence-free survival (hazard ratio = 3.245; p = 0.023). Conclusions We identified factors that can influence perioperative outcomes and prognosis in patients with right-sided colon cancer compared to those with left-sided colon cancer. Our findings suggest that age and lymph node involvement along with other factors play a role in the overall survival and recurrence outcomes of these patients. Further research is necessary to explore these differences and develop personalized treatment plans for patients with colon cancer.
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Affiliation(s)
| | | | - Ouadii Mouaqit
- Department of Visceral Surgery, Hassan II University Hospital, Fez, MAR
| | | | - Khalid Ait Taleb
- Department of Visceral Surgery, Hassan II University Hospital, Fez, MAR
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13
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Yao W, Chen X, Fan B, Zeng L, Zhou Z, Mao Z, Shen Q. Multidisciplinary team diagnosis and treatment of pancreatic cancer: Current landscape and future prospects. Front Oncol 2023; 13:1077605. [PMID: 37007078 PMCID: PMC10050556 DOI: 10.3389/fonc.2023.1077605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 03/03/2023] [Indexed: 03/17/2023] Open
Abstract
The pathogenesis of pancreatic cancer has not been completely clear, there is no highly sensitive and specific detection method, so early diagnosis is very difficult. Despite the rapid development of tumor diagnosis and treatment, it is difficult to break through in the short term and the overall 5-year survival rate of pancreatic cancer is less than 8%. In the face of the increasing incidence of pancreatic cancer, in addition to strengthening basic research, exploring its etiology and pathogenesis, it is urgent to optimize the existing diagnosis and treatment methods through standard multidisciplinary team (MDT), and formulate personalized treatment plan to achieve the purpose of improving the curative effect. However, there are some problems in MDT, such as insufficient understanding and enthusiasm of some doctors, failure to operate MDT according to the system, lack of good communication between domestic and foreign peers, and lack of attention in personnel training and talent echelon construction. It is expected to protect the rights and interests of doctors in the future and ensure the continuous operation of MDT. To strengthen the research on the diagnosis and treatment of pancreatic cancer, MDT can try the Internet +MDT mode to improve the efficiency of MDT.
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Affiliation(s)
- Weirong Yao
- Department of Oncology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Xiaoliang Chen
- Department of Hepatobiliary Surgery, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Bin Fan
- Department of Radiology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Lin Zeng
- Department of Oncology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Zhiyong Zhou
- Department of Oncology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Zhifang Mao
- Department of Oncology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
| | - Qinglin Shen
- Department of Oncology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- Institute of Clinical Medicine, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, China
- *Correspondence: Qinglin Shen,
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14
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Khawaja H, Briggs R, Latimer CH, Rassel M, Griffin D, Hanson L, Bardelli A, Di Nicolantonio F, McDade SS, Scott CJ, Lambe S, Maurya M, Lindner AU, Prehn JH, Sousa J, Winnington C, LaBonte MJ, Ross S, Van Schaeybroeck S. Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer. Mol Cancer Ther 2023; 22:135-149. [PMID: 36279564 PMCID: PMC9808374 DOI: 10.1158/1535-7163.mct-22-0301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 07/26/2022] [Accepted: 10/13/2022] [Indexed: 01/04/2023]
Abstract
Novel covalent inhibitors of KRASG12C have shown limited response rates in patients with KRASG12C-mutant (MT) colorectal cancer. Thus, novel KRASG12C inhibitor combination strategies that can achieve deep and durable responses are needed. Small-molecule KRASG12C inhibitors AZ'1569 and AZ'8037 were used. To identify novel candidate combination strategies for AZ'1569, we performed RNA sequencing, siRNA, and high-throughput drug screening. Top hits were validated in a panel of KRASG12CMT colorectal cancer cells and in vivo. AZ'1569-resistant colorectal cancer cells were generated and characterized. We found that response to AZ'1569 was heterogeneous across the KRASG12CMT models. AZ'1569 was ineffective at inducing apoptosis when used as a single agent or combined with chemotherapy or agents targeting the EGFR/KRAS/AKT axis. Using a systems biology approach, we identified the antiapoptotic BH3-family member BCL2L1/Bcl-xL as a top hit mediating resistance to AZ'1569. Further analyses identified acute increases in the proapoptotic protein BIM following AZ'1569 treatment. ABT-263 (navitoclax), a pharmacologic Bcl-2 family inhibitor that blocks the ability of Bcl-xL to bind and inhibit BIM, led to dramatic and universal apoptosis when combined with AZ'1569. Furthermore, this combination also resulted in dramatically attenuated tumor growth in KRASG12CMT xenografts. Finally, AZ'1569-resistant cells showed amplification of KRASG12C, EphA2/c-MET activation, increased proinflammatory chemokine profile and cross-resistance to several targeted agents. Importantly, KRAS amplification and AZ'1569 resistance were reversible upon drug withdrawal, arguing strongly for the use of drug holidays in the case of KRAS amplification. Taken together, combinatorial targeting of Bcl-xL and KRASG12C is highly effective, suggesting a novel therapeutic strategy for patients with KRASG12CMT colorectal cancer.
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Affiliation(s)
- Hajrah Khawaja
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Rebecca Briggs
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Cheryl H. Latimer
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Mustasin Rassel
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Daryl Griffin
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | | | - Alberto Bardelli
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Frederica Di Nicolantonio
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy
| | - Simon S. McDade
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Christopher J. Scott
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Shauna Lambe
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Manisha Maurya
- Precision Medicine Centre of Excellence, Health Sciences Building, Queen's University Belfast, Belfast, United Kingdom
| | - Andreas U. Lindner
- Centre of Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Jochen H.M. Prehn
- Centre of Systems Medicine, Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Jose Sousa
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
- Personal Health Data Science Group, Sano. Centre for Computational Personalised Medicine, Krakow, Poland
| | - Chris Winnington
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | - Melissa J. LaBonte
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
| | | | - Sandra Van Schaeybroeck
- Drug Resistance Group, Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, United Kingdom
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15
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Burska AN, Ilyassova B, Dildabek A, Khamijan M, Begimbetova D, Molnár F, Sarbassov DD. Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside. Cells 2022; 11:3454. [PMID: 36359850 PMCID: PMC9657932 DOI: 10.3390/cells11213454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative "Trojan horse" agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC's non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.
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Affiliation(s)
- Agata N. Burska
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | | | - Aruzhan Dildabek
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Medina Khamijan
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Dinara Begimbetova
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
| | - Ferdinand Molnár
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Dos D. Sarbassov
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
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16
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Volovat SR, Augustin I, Zob D, Boboc D, Amurariti F, Volovat C, Stefanescu C, Stolniceanu CR, Ciocoiu M, Dumitras EA, Danciu M, Apostol DGC, Drug V, Shurbaji SA, Coca LG, Leon F, Iftene A, Herghelegiu PC. Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI. Cancers (Basel) 2022; 14:4834. [PMID: 36230757 PMCID: PMC9562853 DOI: 10.3390/cancers14194834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
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Affiliation(s)
- Simona-Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Iolanda Augustin
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Daniela Zob
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Florin Amurariti
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Constantin Volovat
- Department of Medical Oncology, “Euroclinic” Center of Oncology, 2 Vasile Conta Str., 700106 Iasi, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eduard Alexandru Dumitras
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Anesthesiology and Intensive Care, Regional Institute of Oncology, 700115 Iasi, Romania
| | - Mihai Danciu
- Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Vasile Drug
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Sinziana Al Shurbaji
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Lucia-Georgiana Coca
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Florin Leon
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| | - Adrian Iftene
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Paul-Corneliu Herghelegiu
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
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17
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Dias Carvalho P, Martins F, Mendonça S, Ribeiro A, Machado AL, Carvalho J, Oliveira MJ, Velho S. Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast‐secreted factors through the HGF/C‐MET axis. Int J Cancer 2022; 151:1810-1823. [DOI: 10.1002/ijc.34225] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 07/07/2022] [Accepted: 07/19/2022] [Indexed: 11/06/2022]
Affiliation(s)
- Patrícia Dias Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- ICBAS ‐ Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto Porto Portugal
| | - Flávia Martins
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Susana Mendonça
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
| | - Andreia Ribeiro
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Ana Luísa Machado
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
- Department of Pathology FMUP – Faculty of Medicine of the University of Porto Porto Portugal
- Ciências Químicas e das Biomoléculas, Centro de Investigação em Saúde e Ambiente, Escola Superior de Saúde do Porto, Instituto Politécnico do Porto Porto Portugal
| | - Joana Carvalho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
| | - Maria José Oliveira
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- INEB – Institute of Biomedical Engineering, University of Porto Porto Portugal
| | - Sérgia Velho
- i3S ‐ Instituto de Investigação e Inovação em Saúde, Universidade do Porto Portugal
- IPATIMUP – Instituto de Patologia e Imunologia Molecular da Universidade do Porto Porto Portugal
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18
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Pelullo M, Zema S, De Carolis M, Cialfi S, Giuli MV, Palermo R, Capalbo C, Giannini G, Screpanti I, Checquolo S, Bellavia D. 5FU/Oxaliplatin-Induced Jagged1 Cleavage Counteracts Apoptosis Induction in Colorectal Cancer: A Novel Mechanism of Intrinsic Drug Resistance. Front Oncol 2022; 12:918763. [PMID: 35847908 PMCID: PMC9283835 DOI: 10.3389/fonc.2022.918763] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 06/02/2022] [Indexed: 11/23/2022] Open
Abstract
Colorectal cancer (CRC) is characterized by early metastasis, resistance to anti-cancer therapy, and high mortality rate. Despite considerable progress in the development of new treatment options that improved survival benefits in patients with early-stage or advanced CRC, many patients relapse due to the activation of intrinsic or acquired chemoresistance mechanisms. Recently, we reported novel findings about the role of Jagged1 in CRC tumors with Kras signatures. We showed that Jagged1 is a novel proteolytic target of Kras signaling, which induces Jagged1 processing/activation resulting in Jag1-ICD release, which favors tumor development in vivo, through a non-canonical mechanism. Herein, we demonstrate that OXP and 5FU cause a strong accumulation of Jag1-ICD oncogene, through ERK1/2 activation, unveiling a surviving subpopulation with an enforced Jag1-ICD expression, presenting the ability to counteract OXP/5FU-induced apoptosis. Remarkably, we also clarify the clinical ineffectiveness of γ-secretase inhibitors (GSIs) in metastatic CRC (mCRC) patients. Indeed, we show that GSI compounds trigger Jag1-ICD release, which promotes cellular growth and EMT processes, functioning as tumor-promoting agents in CRC cells overexpressing Jagged1. We finally demonstrate that Jagged1 silencing in OXP- or 5FU-resistant subpopulations is enough to restore the sensitivity to chemotherapy, confirming that drug sensitivity/resistance is Jag1-ICD-dependent, suggesting Jagged1 as a molecular predictive marker for the outcome of chemotherapy.
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Affiliation(s)
- Maria Pelullo
- CLN2S - Center for Life Nano- & Neuro Science, Istituto Italiano di Tecnologia, Rome, Italy
| | - Sabrina Zema
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Mariangela De Carolis
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Samantha Cialfi
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Maria Valeria Giuli
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Rocco Palermo
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Carlo Capalbo
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Giuseppe Giannini
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Isabella Screpanti
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
| | - Saula Checquolo
- Department of Medico-Surgical Sciences and Biotechnology, Sapienza University, Latina, Italy
- *Correspondence: Saula Checquolo, ; Diana Bellavia,
| | - Diana Bellavia
- Laboratory of Molecular Pathology, Department of Molecular Medicine, Sapienza University, Rome, Italy
- *Correspondence: Saula Checquolo, ; Diana Bellavia,
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Drug Resistance in Colorectal Cancer: From Mechanism to Clinic. Cancers (Basel) 2022; 14:cancers14122928. [PMID: 35740594 PMCID: PMC9221177 DOI: 10.3390/cancers14122928] [Citation(s) in RCA: 52] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. The 5-year survival rate is 90% for patients with early CRC, 70% for patients with locally advanced CRC, and 15% for patients with metastatic CRC (mCRC). In fact, most CRC patients are at an advanced stage at the time of diagnosis. Although chemotherapy, molecularly targeted therapy and immunotherapy have significantly improved patient survival, some patients are initially insensitive to these drugs or initially sensitive but quickly become insensitive, and the emergence of such primary and secondary drug resistance is a significant clinical challenge. The most direct cause of resistance is the aberrant anti-tumor drug metabolism, transportation or target. With more in-depth research, it is found that cell death pathways, carcinogenic signals, compensation feedback loop signal pathways and tumor immune microenvironment also play essential roles in the drug resistance mechanism. Here, we assess the current major mechanisms of CRC resistance and describe potential therapeutic interventions.
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20
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Khan MZI, Tam MSY, Azam Z, Law HKW. Proteomic profiling of metabolic proteins as potential biomarkers of radioresponsiveness for colorectal cancer. J Proteomics 2022; 262:104600. [DOI: 10.1016/j.jprot.2022.104600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/25/2022] [Accepted: 05/01/2022] [Indexed: 12/24/2022]
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21
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Foppa C, Tamburello S, Maroli A, Carvello M, Poliani L, Laghi L, Malesci A, Montorsi M, Perea J, Spinelli A. Early age of onset is an independent predictor for worse disease-free survival in sporadic rectal cancer patients. A comparative analysis of 980 consecutive patients. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:857-863. [PMID: 34740480 DOI: 10.1016/j.ejso.2021.10.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 09/19/2021] [Accepted: 10/22/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND while interest on early-onset colorectal cancer (age ≤49) is on the rise, studies on early-onset rectal cancer (EORC) are limited. The aim of this study was to compare predictors for disease progression/recurrence between sporadic EORC and late-onset RC patients (LORC). METHODS 163 EORC and 830 LORC operated between January 1st, 2010 and April 30th, 2021 at a tertiary center were included. Demographics, tumor characteristics, microsatellite status, gene mutations (KRAS, BRAF, NRAS, PI3Kca) and oncologic outcomes were compared. A Cox proportional hazards regression analysis was performed to ascertain the effect of variables on recurrence/progression and death. Recurrence/Progression free survival (R/PFS) and cancer specific survival (CSS) were analyzed by the Kaplan-Meier estimator. RESULTS Mean age of EORC was 42.16, (46% aged 45-49). A majority of EORC patients had a family history for CRC (p = 0.01) and underwent total neoadjuvant treatment (p = 0.01). EORC patients showed a higher rate of low-grade tumor differentiation (p < 0.0001), stage III-IV (p = 0.001), microsatellite instability (p = 0.02), locoregional nodal (p = 0.001) and distant metastases (p < 0.0001). Accordingly, more EORC patients underwent adjuvant treatment (p < 0.0001). Mutations were mostly reported among LORC cases (p = 0.04), whereas EORC patients showed a worse R/PFS (p = 0.02), even at stage I (p = 0.04). CSS did not differ (p = 0.11) across groups. Multivariate analysis indicated age of onset (p = 0.04) was an independent predictor for progression/recurrence. CONCLUSIONS Age of onset was shown to be an independent unfavorable predictor. Delayed diagnosis could explain this effect in the more advanced stages, while the worse outcomes in stage I may suggest a more aggressive disease behavior.
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Affiliation(s)
- Caterina Foppa
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Sara Tamburello
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Annalisa Maroli
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Michele Carvello
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Laura Poliani
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Luigi Laghi
- IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy; Department of Medicine and Surgery, University of Parma, 43100, Parma, Italy
| | - Alberto Malesci
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - Marco Montorsi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy
| | - José Perea
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Fundación Jiménez Díaz University Hospital Health Research Institute, Madrid, Spain
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
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22
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Frias-Gomes C, Sousa AC, Rolim I, Henriques AR, Branco F, Janeiro A, Malveiro S, Dário AR, Oliveira MH, Borralho P, Teixeira JA, Faria A, Maio R, Fonseca I, Cravo M. Phenotype-Genotype Correlation in Colorectal Cancer: A Real-Life Study. GE PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2022; 29:13-21. [PMID: 35111960 PMCID: PMC8787526 DOI: 10.1159/000516009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 03/06/2021] [Indexed: 09/26/2023]
Abstract
BACKGROUND AND AIMS Colorectal cancer (CRC) is a heterogeneous disease with distinctive genetic pathways, such as chromosomal instability, microsatellite instability and methylator pathway. Our aim was to correlate clinical and genetic characteristics of CRC patients in order to understand clinical implications of tumour genotype. METHODS Single-institution retrospective cohort of patients who underwent curative surgery for CRC, from 2012 to 2014. RAS and BRAF mutations were evaluated with the real-time PCR technique Idylla®. Mismatch repair deficiency (dMMR) was characterized by absence of MLH1, MSH6, MSH2 and/or PMS2 expression, evaluated by tissue microarrays. Overall survival (OS) and disease-free survival (DFS) were assessed using survival analysis. RESULTS Overall, 242 patients were included (males 57.4%, age 69.3 ± 12.9 years; median follow-up 49 months). RAS-mutated tumours were associated with reduced DFS (p = 0.02) and OS (p = 0.045) in stage I-III CRC. BRAF-mutated tumours were more predominant in females and in the right colon, similarly to dMMR tumours. BRAF status did not influence OS (4 years)/DFS (3.5 years) in stage I-III disease. However, after relapse, length of survival was 3.5 months in BRAF-mutated tumours in contrast to 18.6 months in BRAF wild-type tumours (p = NS). No germline mutations in mismatch repair genes were so far identified in the patients with dMMR tumours. Molecular phenotype (RAS, BRAF and MMR) did not influence OS in metastatic patients. Our small sample size may be a limitation of the study. CONCLUSION In our cohort, RAS-mutated tumours were associated with worse DFS and OS in early-stage CRC, whereas the remaining molecular variables had no prognostic influence.
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Affiliation(s)
- Catarina Frias-Gomes
- Serviço de Gastrenterologia, Departamento de Cirurgia, Hospital Beatriz Ângelo, Loures, Portugal
| | | | - Inês Rolim
- Serviço de Anatomia Patológica, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal
- Instituto de Anatomia Patológica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Ana Raquel Henriques
- Instituto de Anatomia Patológica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Francisco Branco
- Serviço de Oncologia Médica, Departamento de Oncologia, Hospital Beatriz Ângelo, Loures, Portugal
| | - André Janeiro
- Genomed, Instituto de Medicina Molecular, Lisboa, Portugal
| | - Sara Malveiro
- Genomed, Instituto de Medicina Molecular, Lisboa, Portugal
| | - Ana Rita Dário
- Genomed, Instituto de Medicina Molecular, Lisboa, Portugal
| | | | - Paula Borralho
- Instituto de Anatomia Patológica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Serviço de Anatomia Patológica, Hospital CUF Descobertas, Lisboa, Portugal
| | - José Alberto Teixeira
- Serviço de Oncologia Médica, Departamento de Oncologia, Hospital Beatriz Ângelo, Loures, Portugal
| | - Ana Faria
- Serviço de Oncologia Médica, Departamento de Oncologia, Hospital Beatriz Ângelo, Loures, Portugal
| | - Rui Maio
- Serviço de Cirurgia Geral, Departamento de Cirurgia, Hospital Beatriz Ângelo, Loures, Portugal
| | - Isabel Fonseca
- Serviço de Anatomia Patológica, Instituto Português de Oncologia Francisco Gentil, Lisboa, Portugal
- Instituto de Anatomia Patológica, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Marília Cravo
- Serviço de Gastrenterologia, Departamento de Cirurgia, Hospital Beatriz Ângelo, Loures, Portugal
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23
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Chen K, Collins G, Wang H, Toh JWT. Pathological Features and Prognostication in Colorectal Cancer. Curr Oncol 2021; 28:5356-5383. [PMID: 34940086 PMCID: PMC8700531 DOI: 10.3390/curroncol28060447] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
The prognostication of colorectal cancer (CRC) has traditionally relied on staging as defined by the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM staging classifications. However, clinically, there appears to be differences in survival patterns independent of stage, suggesting a complex interaction of stage, pathological features, and biomarkers playing a role in guiding prognosis, risk stratification, and guiding neoadjuvant and adjuvant therapies. Histological features such as tumour budding, perineural invasion, apical lymph node involvement, lymph node yield, lymph node ratio, and molecular features such as MSI, KRAS, BRAF, and CDX2 may assist in prognostication and optimising adjuvant treatment. This study provides a comprehensive review of the pathological features and biomarkers that are important in the prognostication and treatment of CRC. We review the importance of pathological features and biomarkers that may be important in colorectal cancer based on the current evidence in the literature.
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Affiliation(s)
- Kabytto Chen
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - Geoffrey Collins
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - Henry Wang
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
| | - James Wei Tatt Toh
- Discipline of Surgery, Faculty of Medicine and Health, The University of Sydney, Westmead 2145, Australia; (G.C.); (H.W.)
- Division of Colorectal Surgery, Department of Surgery, Westmead Hospital, Westmead 2145, Australia
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Nussinov R, Tsai CJ, Jang H. Anticancer drug resistance: An update and perspective. Drug Resist Updat 2021; 59:100796. [PMID: 34953682 PMCID: PMC8810687 DOI: 10.1016/j.drup.2021.100796] [Citation(s) in RCA: 228] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/08/2021] [Accepted: 12/13/2021] [Indexed: 12/12/2022]
Abstract
Driver mutations promote initiation and progression of cancer. Pharmacological treatment can inhibit the action of the mutant protein; however, drug resistance almost invariably emerges. Multiple studies revealed that cancer drug resistance is based upon a plethora of distinct mechanisms. Drug resistance mutations can occur in the same protein or in different proteins; as well as in the same pathway or in parallel pathways, bypassing the intercepted signaling. The dilemma that the clinical oncologist is facing is that not all the genomic alterations as well as alterations in the tumor microenvironment that facilitate cancer cell proliferation are known, and neither are the alterations that are likely to promote metastasis. For example, the common KRasG12C driver mutation emerges in different cancers. Most occur in NSCLC, but some occur, albeit to a lower extent, in colorectal cancer and pancreatic ductal carcinoma. The responses to KRasG12C inhibitors are variable and fall into three categories, (i) new point mutations in KRas, or multiple copies of KRAS G12C which lead to higher expression level of the mutant protein; (ii) mutations in genes other than KRAS; (iii) original cancer transitioning to other cancer(s). Resistance to adagrasib, an experimental antitumor agent exerting its cytotoxic effect as a covalent inhibitor of the G12C KRas, indicated that half of the cases present multiple KRas mutations as well as allele amplification. Redundant or parallel pathways included MET amplification; emerging driver mutations in NRAS, BRAF, MAP2K1, and RET; gene fusion events in ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN tumor suppressors. In the current review we discuss the molecular mechanisms underlying drug resistance while focusing on those emerging to common targeted cancer drivers. We also address questions of why cancers with a common driver mutation are unlikely to evolve a common drug resistance mechanism, and whether one can predict the likely mechanisms that the tumor cell may develop. These vastly important and tantalizing questions in drug discovery, and broadly in precision medicine, are the focus of our present review. We end with our perspective, which calls for target combinations to be selected and prioritized with the help of the emerging massive compute power which enables artificial intelligence, and the increased gathering of data to overcome its insatiable needs.
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Affiliation(s)
- Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD, 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel.
| | - Chung-Jung Tsai
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD, 21702, USA
| | - Hyunbum Jang
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research in the Laboratory of Cancer Immunometabolism, National Cancer Institute, Frederick, MD, 21702, USA
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25
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Maderer A, Fiteni F, Tanis E, Mauer M, Schmitt T, Aust DE, Lutz MP, Roelofson F, Gog C, Weinmann A, Koehne CH, Moehler M, Thomaidis T. CXCR4 and hif-1α as prognostic molecular markers for stage 3 colon cancer patients: post hoc analysis of the randomized, multicenter phase 3 PETACC-2 trial dataset. Acta Oncol 2021; 60:1543-1547. [PMID: 34355650 DOI: 10.1080/0284186x.2021.1959057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Annett Maderer
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Frederic Fiteni
- Fellowship Programme Unit, EORTC Headquarters, Brussels, Belgium
| | - Erik Tanis
- Fellowship Programme Unit, EORTC Headquarters, Brussels, Belgium
| | - Murielle Mauer
- Statistics Department, EORTC Headquarters, Brussels, Belgium
| | - Thomas Schmitt
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Daniela E. Aust
- Molekulare/Prädiktive Diagnostik, Koordination UCC Tumor- und Normalgewebebank Institut für Pathologie, Dresden, Germany
| | | | | | - Christiane Gog
- Klinikum der JW Goethe, Universität Frankfurt am Main, Frankfurt, Germany
| | - Arndt Weinmann
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Claus H. Koehne
- Department of Oncology and Hematology, Klinikum Oldenburg, European Medical School Oldenburg/Groningen, Carl von Ossietzky University Oldenburg, Oldenburg, Germany
| | - Markus Moehler
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
| | - Thomas Thomaidis
- Department of Internal Medicine, Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg University of Mainz, Mainz, Germany
- Second Department of Gastroenterology, Hygeia Hospital, Athens, Greece
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26
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Zhou J, Ji Q, Li Q. Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:328. [PMID: 34663410 PMCID: PMC8522158 DOI: 10.1186/s13046-021-02130-2] [Citation(s) in RCA: 129] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 08/22/2021] [Indexed: 12/28/2022]
Abstract
Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). Cetuximab can prolong survival by 8.2 months in RAS wild-type (WT) mCRC patients. Unfortunately, resistance to targeted therapy impairs clinical use and efficiency. The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. Multiple therapeutic strategies have been investigated extensively to overcome resistance to anti-EGFR mAbs. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. For intrinsic mechanisms, therapies mainly cover the following: new EGFR-targeted inhibitors, a combination of multitargeted inhibitors, and metabolic regulators. In addition, new cytotoxic drugs and small molecule compounds increase the efficiency of cetuximab. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis. The directions include the modification or activation of immune cells and suppression of CAFs and anti-VEGFR agents. In this review, we focus on the mechanisms of resistance to anti-EGFR monoclonal antibodies (anti-EGFR mAbs) and discuss diverse approaches to reverse resistance to this therapy in hopes of identifying more mCRC treatment possibilities.
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Affiliation(s)
- Jing Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qi Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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27
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Di Giorgio A, Santullo F, Attalla El Halabieh M, Lodoli C, Abatini C, Calegari MA, Martini M, Rotolo S, Pacelli F. Clinical and Molecular Features in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinosis from Colorectal Cancer. J Gastrointest Surg 2021; 25:2649-2659. [PMID: 34244953 DOI: 10.1007/s11605-021-05073-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 06/04/2021] [Indexed: 01/31/2023]
Abstract
PURPOSE Careful patient selection plays a crucial role in avoiding overtreatment and further increases survival rates in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) with peritoneal metastases (PM). METHODS The clinical and molecular factors influencing survival in patients who had undergone CRS with HIPEC between January 2015 and December 2018 were analyzed. RESULTS Sixty-six patients underwent CRS with HIPEC during the study period. The median overall survival (OS) was 36 months, with a 3-year OS of 43%. Multivariate analysis revealed increased PCI (HR: 1.21; 95% CI: 1.02-1.41; p = 0.020), right-sided primary tumor (HR: 3.01; 95% CI: 1.27-7.13; p = 0.017), and BRAF V600E mutation (HR: 4.55; 95% CI: 1.21-17.21; p = 0.025) as independent predictors for worse OS. CONCLUSION In addition to confirming the prognostic role of PCI, our study extends the role of BRAF mutation and right primary tumor location as markers for worse prognosis.
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Affiliation(s)
- Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Francesco Santullo
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.
| | - Miriam Attalla El Halabieh
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Claudio Lodoli
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | - Carlo Abatini
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy
| | | | - Maurizio Martini
- Institute of Pathology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Stefano Rotolo
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy.,Surgery, Oncology, and Stomatology Unit, University of Palermo, Palermo, Italy
| | - Fabio Pacelli
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168, Rome, Italy
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28
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Chen K, Zhang Y, Qian L, Wang P. Emerging strategies to target RAS signaling in human cancer therapy. J Hematol Oncol 2021; 14:116. [PMID: 34301278 PMCID: PMC8299671 DOI: 10.1186/s13045-021-01127-w] [Citation(s) in RCA: 125] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023] Open
Abstract
RAS mutations (HRAS, NRAS, and KRAS) are among the most common oncogenes, and around 19% of patients with cancer harbor RAS mutations. Cells harboring RAS mutations tend to undergo malignant transformation and exhibit malignant phenotypes. The mutational status of RAS correlates with the clinicopathological features of patients, such as mucinous type and poor differentiation, as well as response to anti-EGFR therapies in certain types of human cancers. Although RAS protein had been considered as a potential target for tumors with RAS mutations, it was once referred to as a undruggable target due to the consecutive failure in the discovery of RAS protein inhibitors. However, recent studies on the structure, signaling, and function of RAS have shed light on the development of RAS-targeting drugs, especially with the approval of Lumakras (sotorasib, AMG510) in treatment of KRASG12C-mutant NSCLC patients. Therefore, here we fully review RAS mutations in human cancer and especially focus on emerging strategies that have been recently developed for RAS-targeting therapy.
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Affiliation(s)
- Kun Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Yalei Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Ling Qian
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Peng Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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29
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Lakatos G, Köhne CH, Bodoky G. Current therapy of advanced colorectal cancer according to RAS/RAF mutational status. Cancer Metastasis Rev 2021; 39:1143-1157. [PMID: 32648137 DOI: 10.1007/s10555-020-09913-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Colorectal cancer is a clinically and molecularly heterogeneous disease. Currently, extended RAS and BRAF mutation testing is obligatory in routine clinical practice before starting any treatment in the metastatic setting. Treatment decision making also includes assessment of the clinical condition of the patient, definition of the treatment goal, and consideration of the primary tumor site. Biological treatment is part of the first-line drug combination unless contraindicated. Mutational status is significantly associated with the outcome of patients and is strongly predictive for anti-EGFR-targeted therapy. The prognosis of RAS mutant CRC is clearly inferior to wild-type cases. RAS remains an elusive target, and specific treatment options are not yet available. Recently, promising results of a direct KRAS G12C inhibitor have been reported; however, further confirmation is needed. The biomarker landscape in mCRC is evolving; new promising markers are awaited with the chance of more precise targeted treatment.
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Affiliation(s)
- Gábor Lakatos
- Department of Oncology, South-Pest Hospital Centre - National Institute for Infectology and Haematology, Budapest, Hungary.
| | - Claus-Henning Köhne
- Klinikum Oldenburg, University Clinic of Oncology and Haematology, Oldenburg, Germany
| | - György Bodoky
- Department of Oncology, South-Pest Hospital Centre - National Institute for Infectology and Haematology, Budapest, Hungary
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30
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Prasanna T, Yip D. Adjuvant Therapies in Colon Cancer. COLORECTAL CANCER 2021. [DOI: 10.5772/intechopen.93874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Most of the patients with localized colon cancer undergo curative resection. However, significant number of patients will recur with metastatic disease, especially those with node positive cancer. Adjuvant chemotherapy has shown to improve cure rate and survival by eradicating micrometastases. The benefit of adjuvant therapy is well established in node-positive cancers, while their role in stage II cancer is not well defined. A number of molecular markers have been identified that are prognostic and/or predictive in colon cancer. Such molecular markers, and other clinicopathological features play an important role in selection of appropriate therapy and duration of treatment. Emerging evidence for the utility of genomic profiling or detection of circulating tumor DNA (ctDNA) are promising which may further facilitate decision making in the future. This chapter reviews the evolution of adjuvant therapy for resected colon cancer, the current evidence and the factors influence the choice of therapy.
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31
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Addeo A, Banna GL, Friedlaender A. KRAS G12C Mutations in NSCLC: From Target to Resistance. Cancers (Basel) 2021; 13:2541. [PMID: 34064232 PMCID: PMC8196854 DOI: 10.3390/cancers13112541] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/11/2022] Open
Abstract
Lung cancer represents the most common form of cancer, accounting for 1.8 million deaths globally in 2020. Over the last decade the treatment for advanced and metastatic non-small cell lung cancer have dramatically improved largely thanks to the emergence of two therapeutic breakthroughs: the discovery of immune checkpoint inhibitors and targeting of oncogenic driver alterations. While these therapies hold great promise, they face the same limitation as other inhibitors: the emergence of resistant mechanisms. One such alteration in non-small cell lung cancer is the Kirsten Rat Sarcoma (KRAS) oncogene. KRAS mutations are the most common oncogenic driver in NSCLC, representing roughly 20-25% of cases. The mutation is almost exclusively detected in adenocarcinoma and is found among smokers 90% of the time. Along with the development of new drugs that have been showing promising activity, resistance mechanisms have begun to be clarified. The aim of this review is to unwrap the biology of KRAS in NSCLC with a specific focus on primary and secondary resistance mechanisms and their possible clinical implications.
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Affiliation(s)
- Alfredo Addeo
- Swiss Cancer Center Leman, Oncology Department, Switzerland University of Geneva, University Hospital Geneva, 1205 Geneva, Switzerland;
| | | | - Alex Friedlaender
- Swiss Cancer Center Leman, Oncology Department, Switzerland University of Geneva, University Hospital Geneva, 1205 Geneva, Switzerland;
- Oncology Service, Clinique Générale Beaulieu, 1206 Geneva, Switzerland
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32
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El agy F, el Bardai S, El Otmani I, Benbrahim Z, Karim IMH, Mazaz K, Benjelloun EB, Ousadden A, El Abkari M, Ibrahimi SA, Chbani L. Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report. PLoS One 2021; 16:e0248522. [PMID: 33784337 PMCID: PMC8009361 DOI: 10.1371/journal.pone.0248522] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/27/2021] [Indexed: 12/12/2022] Open
Abstract
This study aimed to estimate the incidence of KRAS, NRAS, and BRAF mutations in the Moroccan population, and investigate the associations of KRAS and NRAS gene mutations with clinicopathological characteristics and their prognosis value. To achieve these objectives, we reviewed medical and pathology reports for 210 patients. RAS testing was investigated by Sanger sequencing and Pyrosequencing technology. BRAF (exon 15) status was analyzed by the Sanger method. The expression of MMR proteins was evaluated by Immunohistochemistry. KRAS and NRAS mutations were found in 36.7% and 2.9% of 210 patients, respectively. KRAS exon 2 mutations were identified in 76.5% of the cases. RAS-mutated colon cancers were significantly associated with female gender, presence of vascular invasion, classical adenocarcinoma, moderately differentiated tumors, advanced TNM stage III-IV, left colon site, higher incidence of distant metastases at the time of diagnostic, microsatellite stable phenotype, lower number of total lymph nodes, and higher means of positive lymph nodes and lymph node ratio. KRAS exon 2-mutated colon cancers, compared with KRAS wild-type colon cancers were associated with the same clinicopathological features of RAS-mutated colon cancers. NRAS-mutated patients were associated with lower total lymph node rate and the presence of positive lymph node. Rare RAS-mutated tumors, compared with wild-type tumors were more frequently moderately differentiated and associated with lower lymph node rate. We found that KRAS codon 13-mutated, tumors compared to codon 12-mutated tumors were significantly correlated with a higher death cases number, a lower rate of positive lymph, lower follow-up time, and poor overall survival. Our findings show that KRAS and NRAS mutations have distinct clinicopathological features. KRAS codon 13-mutated status was the worst predictor of prognosis at all stages in our population.
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Affiliation(s)
- Fatima El agy
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- * E-mail:
| | - Sanae el Bardai
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ihsane El Otmani
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Unit of Medical Genetics and Oncogenetics, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Zineb Benbrahim
- Department of Oncology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ibn Majdoub Hassani Karim
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Khalid Mazaz
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - El Bachir Benjelloun
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Abdelmalek Ousadden
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Mohammed El Abkari
- Department of Gastroenterology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Sidi Adil Ibrahimi
- Department of General Surgery, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Laila Chbani
- Faculty of Medicine and Pharmacy, Laboratory of Biomedical and Translational Research, Sidi Mohamed Ben Abdellah University, Fez, Morocco
- Laboratory of Anatomic Pathology and Molecular Pathology, University Hospital Hassan II, Sidi Mohamed Ben Abdellah University, Fez, Morocco
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33
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Targeting the DNA replication stress phenotype of KRAS mutant cancer cells. Sci Rep 2021; 11:3656. [PMID: 33574444 PMCID: PMC7878884 DOI: 10.1038/s41598-021-83142-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Accepted: 01/28/2021] [Indexed: 12/16/2022] Open
Abstract
Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.
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34
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Melloul S, Mosnier JF, Masliah-Planchon J, Lepage C, Le Malicot K, Gornet JM, Edeline J, Dansette D, Texereau P, Delattre O, Laurent Puig P, Taieb J, Emile JF. Loss of SMARCB1 expression in colon carcinoma. Cancer Biomark 2020; 27:399-406. [PMID: 32083567 DOI: 10.3233/cbm-190287] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
SMARCB1 is a tumor suppressor gene, which is part of SWI/SNF complex involved in transcriptional regulation. Recently, loss of SMARCB1 expression has been reported in gastrointestinal carcinomas. Our purpose was to evaluate the incidence and prognostic value of SMARCB1 loss in colon carcinoma (CC). Patients with stage III CC (n= 1695), and a second cohort of 23 patients with poorly differentiated CC were analyzed. Immunohistochemistry for SMARCB1 was performed on tissue microarrays, and cases with loss of expression were controlled on whole sections. Loss of SMARCB1 was compared with the clinico-pathological and molecular characteristics, and the prognostic value was evaluated. Loss of SMARCB1 was identified in 12 of 1695 (0.7%) patients with stage III CC. Whole section controls showed a complete loss in only one of these cases, corresponding to a medullary carcinoma. SMARCB1 loss was not associated with histological grade, tumor size nor survival. In the cohort of poorly differentiated CC, we detected 2/23 (8.7%) cases with loss of SMARCB1; one was rhabdoid while the other had medullary and mucinous histology. These 2 cases were deficient for MisMatched Repair (dMMR) and mutated for BRAF. SMARCB1 loss is rare in stage III CC, but appears more frequent in poorly differentiated CC.
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Affiliation(s)
- S Melloul
- Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne, France
| | - J-F Mosnier
- Department of Pathology, Hotel Dieu, Nantes, France
| | - J Masliah-Planchon
- Somatic Genetic Unit, Institut Curie, Paris, France.,Paris-Sciences-Lettres, Institut Curie Research Center, INSERMU830, Paris, France.,SIREDO, Institut Curie, Paris, France
| | - C Lepage
- François Mitterrand University Hospital, Dijon, France.,EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Besançon, France
| | - K Le Malicot
- EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche-Comté, Besançon, France.,Francophone Society of Digestive Cancer, Dijon, France
| | | | - J Edeline
- Eugène Marquis Center, Rennes, France
| | - D Dansette
- Department of Pathology, Hotel Dieu, Nantes, France
| | - P Texereau
- Layne Hospital Center, Mont-de-Marsan, France
| | - O Delattre
- Somatic Genetic Unit, Institut Curie, Paris, France.,Paris-Sciences-Lettres, Institut Curie Research Center, INSERMU830, Paris, France.,SIREDO, Institut Curie, Paris, France
| | - P Laurent Puig
- G. Pompidou European Hospital, APHP, Paris, France.,INSERM UMR-S1147, Paris, France
| | - J Taieb
- G. Pompidou European Hospital, APHP, Paris, France.,INSERM UMR-S1147, Paris, France
| | - J-F Emile
- Department of Pathology, Ambroise Paré Hospital, APHP, Boulogne, France.,EA4340-BCOH, Versailles SQY University, Paris-Saclay University, Boulogne, France
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35
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Loong HHF, Du N, Cheng C, Lin H, Guo J, Lin G, Li M, Jiang T, Shi Z, Cui Y, Jin X, Yao J, Xing Y, Yao M, Wang K, Mok TSK, Liu L. KRAS G12C mutations in Asia: a landscape analysis of 11,951 Chinese tumor samples. Transl Lung Cancer Res 2020; 9:1759-1769. [PMID: 33209599 PMCID: PMC7653137 DOI: 10.21037/tlcr-20-455] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Background Kirsten rat sarcoma vial oncogene (KRAS) is one of the most prevalent oncogenes in multiple cancer types, but the incidence is different between the Asian and non-Asian populations. The recent development of KRAS G12C targeting drug has shown great promise. It is thus important to understand the genomic landscape of KRAS G12C in a specific population. Methods Sequencing data of 11,951 tumor samples collected from 11/2016 to 7/2019 from multiple centres in China were analyzed for KRAS mutation status. Concomitant genomic aberrations were further analyzed in tumors with KRAS G12C mutations, which were sequenced with comprehensive cancer panel including over 450 cancer-related genes. Smoking status and its correlation with KRAS were analyzed in 2,235 lung cancer cases within this cohort. Results KRAS mutations were identified in 1978 (16.6%) patient samples. Specifically, KRAS G12C accounted for 14.5% (n=286) of all KRAS mutations. G12C was most commonly seen in lung cancer (4.3%), followed by colorectal cancer (2.5%) and biliary cancer (2.3%). Almost all patients (99.6%) with G12C mutations had concomitant genomic aberrations. These were most commonly associated with the RAS/RTK pathway including BRAF and PI3KCA mutations. Moreover, KRAS mutation was positively correlated with smoking status in lung adenocarcinomas. Conclusions The overall incidence of KRAS G12C mutations remains low in the Chinese population. The most common tumor types harboring KRAS G12C mutations are in patients suffering from lung, colorectal and biliary cancers.
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Affiliation(s)
- Herbert Ho-Fung Loong
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.,State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Nan Du
- Department of Oncology, First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China
| | | | | | - Jian Guo
- Division of Thoracic Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Gen Lin
- Department of Thoracic Oncology, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, China
| | - Mingjiang Li
- Division of Thoracic Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Tao Jiang
- Division of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhihua Shi
- Division of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yanzhi Cui
- Medical Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xianfeng Jin
- Division of Thoracic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | | | | | | | | | - Tony S K Mok
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China.,State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lunxu Liu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
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36
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Mukherji R, Marshall JL, Seeber A. Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives. Cancers (Basel) 2020; 12:E2001. [PMID: 32707813 PMCID: PMC7465976 DOI: 10.3390/cancers12082001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/17/2020] [Accepted: 07/18/2020] [Indexed: 02/08/2023] Open
Abstract
The selection of treatment according to genomic alterations is a standard approach in metastatic colorectal cancer but is only starting to have an impact in the earlier stages of the disease. The status if genes like KRAS, BRAF, and MMR has substantial survival implications, and concerted research efforts have revolutionized treatment towards precision oncology. In contrast, a genomic-based approach has not changed the adjuvant setting after curative tumor-resection in the daily routine so far. This review focuses on the current knowledge regarding prognostic and predictive genomic biomarkers in patients with locally advanced nonmetastasized colorectal cancer. Furthermore, we provide an outlook on future challenges for a personalized adjuvant treatment approach in patients with colorectal cancer.
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Affiliation(s)
- Reetu Mukherji
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - John L. Marshall
- Ruesch Center for The Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA;
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck A-6020, Austria;
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Prior IA, Hood FE, Hartley JL. The Frequency of Ras Mutations in Cancer. Cancer Res 2020; 80:2969-2974. [PMID: 32209560 PMCID: PMC7367715 DOI: 10.1158/0008-5472.can-19-3682] [Citation(s) in RCA: 653] [Impact Index Per Article: 130.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 02/13/2020] [Accepted: 03/19/2020] [Indexed: 02/06/2023]
Abstract
Ras is frequently mutated in cancer, however, there is a lack of consensus in the literature regarding the cancer mutation frequency of Ras, with quoted values varying from 10%-30%. This variability is at least in part due to the selective aggregation of data from different databases and the dominant influence of particular cancer types and particular Ras isoforms within these datasets. To provide a more definitive figure for Ras mutation frequency in cancer, we cross-referenced the data in all major publicly accessible cancer mutation databases to determine reliable mutation frequency values for each Ras isoform in all major cancer types. These percentages were then applied to current U.S. cancer incidence statistics to estimate the number of new patients each year that have Ras-mutant cancers. We find that approximately 19% of patients with cancer harbor Ras mutations, equivalent to approximately 3.4 million new cases per year worldwide. We discuss the Ras isoform and mutation-specific trends evident within the datasets that are relevant to current Ras-targeted therapies.
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Affiliation(s)
- Ian A Prior
- Division of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
| | - Fiona E Hood
- Division of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom
| | - James L Hartley
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland
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Taghizadeh H, Prager GW. Personalized Adjuvant Treatment of Colon Cancer. Visc Med 2020; 36:397-406. [PMID: 33178737 DOI: 10.1159/000508175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 04/23/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Colon cancer (CC) is one of the most frequent malignant diseases. Adjuvant chemotherapy is of utmost importance in the management of localized disease. With the emergence of precision medicine, treatment approaches are becoming increasingly personalized and complex. This review contributes to a broader understanding of the role and relevance of personalized adjuvant treatment strategies in colon carcinoma, and summarizes the current status in this disease entity. Methods We searched the websites ClinicalTrials.gov, PubMed, and ASCO (American Society of Medical Oncology) Meeting Library for clinical trials and retrospective analyses in the field of adjuvant treatment of CC with special attention to personalized approaches. Results Various factors, including gender, age, sidedness, stage, dMMR/MSI-H, mutations, molecular profile, CMS, immunoscore, minimal residual disease, type of adjuvant therapy, therapy duration, and the patient's wish play an important role in the adjuvant setting of CC and should be considered in treatment decision making. Conclusion Future molecular profiling ideally assessed and monitored by liquid biopsy might personalize decision making even more in the adjuvant setting of CC patients. Further research and clinical trials are needed to clarify relevant questions and to highlight important clinical aspects.
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Affiliation(s)
- Hossein Taghizadeh
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.,Comprehensive Cancer Center Vienna, Vienna, Austria
| | - Gerald W Prager
- Department of Medicine I, Clinical Division of Oncology, Medical University of Vienna, Vienna, Austria.,Comprehensive Cancer Center Vienna, Vienna, Austria
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Lee HS, Hwang DY, Han HS. Histology and its prognostic effect on KRAS-mutated colorectal carcinomas in Korea. Oncol Lett 2020; 20:655-666. [PMID: 32565990 PMCID: PMC7285809 DOI: 10.3892/ol.2020.11606] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 04/15/2020] [Indexed: 12/13/2022] Open
Abstract
KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Korea Clinical Laboratory, Seoul 05396, Republic of Korea
| | - Dae Yong Hwang
- Department of Surgery, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
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Nazemalhosseini-Mojarad E, Kishani Farahani R, Mehrizi M, Baghaei K, Yaghoob Taleghani M, Golmohammadi M, Peyravian N, Ashtari S, Pourhoseingholi MA, Asadzadeh Aghdaei H, Zali MR. Prognostic Value of BRAF and KRAS Mutation in Relation to Colorectal Cancer Survival in Iranian Patients: Correlated to Microsatellite Instability. J Gastrointest Cancer 2020; 51:53-62. [PMID: 30635874 DOI: 10.1007/s12029-019-00201-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE To evaluate the prognostic role of BRAF and KRAS mutations after adjustment for microsatellite instability (MSI) in Iranian colorectal cancer (CRC) patients. METHODS BRAF and KRAS mutations and MSI status were assessed in 258 Iranian subjects with CRC. Two hundred fifty-eight consecutive stages I-IV CRC patients, who underwent surgical resection of adenocarcinoma from 2012 to 2016, were enrolled in the research. Pyrosequencing and Cast-PCR methods were used to the detection of KRAS and BRAF mutations. Kaplan-Meier and Cox regression were employed to estimate hazard ratios (HR) for the association between BRAF and KRAS mutation and overall survival (OS). RESULTS KRAS and BRAF mutations were detected in 36 (14%) and 15 (5.8%) cases of 258 patients with CRC, respectively. BRAF mutations that all comprised V600E and KRAS mutations was found in codon 12 and 13 (80.6% and 19.4%), respectively. KRAS mutations were detected in 19 (15.4%) patients of 123 microsatellite stable (MSS) CRC and it is significantly associated with tumor location and metastasis. BRAF and KRAS mutant vs. wild type of BRAF and KRAS, 5-year OS was 73.3% vs. 82.3% and 83.3% vs. 81.5% (long-rank P > 0.05), respectively. KRAS mutant vs. KRAS-wild-type tumors in MSS/MSI-L status CRC patients, 5-year OS was 78.9% vs. 90.4% (long-rank p = 0.046). CONCLUSION The present study revealed that BRAF and KRAS mutations were not related to the worse overall survival, while KRAS mutation can be a prognostic factor for overall survival in sporadic microsatellite-stable (MSS) status in Iranian CRC patients.
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Affiliation(s)
- Ehsan Nazemalhosseini-Mojarad
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Roya Kishani Farahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Mehrizi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Erabi Ave, P.O. Box 1985717413, Tehran, Velenjak, Iran
| | - Mohammad Yaghoob Taleghani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mina Golmohammadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Noshad Peyravian
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Ashtari
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Erabi Ave, P.O. Box 1985717413, Tehran, Velenjak, Iran.
| | - Mohmad Amin Pourhoseingholi
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Erabi Ave, P.O. Box 1985717413, Tehran, Velenjak, Iran
| | - Hamid Asadzadeh Aghdaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Erabi Ave, P.O. Box 1985717413, Tehran, Velenjak, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Erabi Ave, P.O. Box 1985717413, Tehran, Velenjak, Iran
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Fu HT, Xu YY, Tian JJ, Fu JX, Nie SL, Tang YY, Chen P, Zong L. Long-term efficacy of capecitabine plus oxaliplatin chemotherapy on stage III colon cancer: A meta-analysis. World J Meta-Anal 2020; 8:27-40. [DOI: 10.13105/wjma.v8.i1.27] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 09/26/2019] [Accepted: 10/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Many clinical studies for the long-term survival or efficacy of capecitabine plus oxaliplatin (XELOX) in colon cancer have already been studied, but its clinical benefit is controversial.
AIM To evaluate the long-term efficacy of XELOX regimen in comparison with other adjuvant chemotherapy protocols in colon cancer.
METHODS By searching the PubMed, EMBASE and Cochrane databases, a total of 12 randomized controlled trials involving 6698 stage III colon cancer cases (XELOX protocol: n = 3298 cases; other adjuvant chemotherapy protocol: n = 3268 cases) were included. The parameter outcomes included the overall survival and the disease-free survival. The quality control of selected literature was based on the Jadad scale and the GRADE system.
RESULTS In comparison to other adjuvant chemotherapy regimen, XELOX regimen showed a better overall survival (odds ratio = 1.29, 95% confidence interval: 1.15-1.44, P < 0.0001) and a better disease-free survival (odds ratio = 1.32, 95% confidence interval: 1.18-1.46, P < 0.0001) for colon cancer patients, suggesting the XELOX regimen can be a good option for postoperative treatment of stage III colon cancer.
CONCLUSION The XELOX regimen can be a preferred option for adjuvant treatment of stage III colon cancer after surgery.
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Affiliation(s)
- Hong-Tao Fu
- Department of Clinical Medicine, University of South China, Hengyang 421000, Hunan Province, China
| | - Ying-Ying Xu
- Department of General Surgery, Yizheng People’s Hospital, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Jing-Jing Tian
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
| | - Jia-Xin Fu
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Shao-Ling Nie
- Department of Colorectal Surgery, Hunan Cancer Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Yan-Yan Tang
- Department of Colorectal Surgery, Hunan Cancer Hospital, Central South University, Changsha 410000, Hunan Province, China
| | - Ping Chen
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
| | - Liang Zong
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou University, Yangzhou 225000, Jiangsu Province, China
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Prognostic and Predictive Molecular Biomarkers for Colorectal Cancer: Updates and Challenges. Cancers (Basel) 2020; 12:cancers12020319. [PMID: 32019056 PMCID: PMC7072488 DOI: 10.3390/cancers12020319] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/20/2020] [Accepted: 01/22/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of death among cancer patients. This heterogeneous disease is characterized by alterations in multiple molecular pathways throughout its development. Mutations in RAS, along with the mismatch repair gene deficiency, are currently routinely tested in clinics. Such biomarkers provide information for patient risk stratification and for the choice of the best treatment options. Nevertheless, reliable and powerful prognostic markers that can identify “high-risk” CRC patients, who might benefit from adjuvant chemotherapy, in early stages, are currently missing. To bridge this gap, genomic information has increasingly gained interest as a potential method for determining the risk of recurrence. However, due to several limitations of gene-based signatures, these have not yet been clinically implemented. In this review, we describe the different molecular markers in clinical use for CRC, highlight new markers that might become indispensable over the next years, discuss recently developed gene expression-based tests and highlight the challenges in biomarker research.
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Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol 2020; 17:11-32. [PMID: 31289352 PMCID: PMC7577509 DOI: 10.1038/s41571-019-0241-1] [Citation(s) in RCA: 218] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2019] [Indexed: 12/16/2022]
Abstract
The number of molecularly stratified treatment options available to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of biomarkers to guide prognostication and treatment decision-making. The increase in both the number of biomarkers and their use has resulted in a progressively complex situation, evident both from the extensive interactions between biomarkers and from their sometimes complex associations with patient prognosis and treatment benefit. Current and emerging biomarkers also reflect the genomic complexity of CRC, and include a wide range of aberrations such as point mutations, amplifications, fusions and hypermutator phenotypes, in addition to global gene expression subtypes. In this Review, we provide an overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.
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Affiliation(s)
- Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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High IGF1R protein expression correlates with disease-free survival of patients with stage III colon cancer. Cell Oncol (Dordr) 2019; 43:237-247. [PMID: 31823290 DOI: 10.1007/s13402-019-00484-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2019] [Indexed: 10/25/2022] Open
Abstract
PURPOSE The aim of this study was to investigate the association between expression of insulin-like growth factor-1 receptor (IGF1R) and its ligand, IGF-II, and disease-free survival (DFS) in patients with stage III colon cancer (CC). METHODS In this retrospective study we included consecutive patients who underwent curative surgery for stage III CC. IGF1R and IGF-II/IGF2 status were evaluated in tumour samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Associations of markers with DFS were analysed using Cox proportional hazards models. RESULTS Hundred and fifty-one CC patients were included (median age, 66.6 years; female, 54.3%). Low levels of IGF1R and IGF-II protein expression were observed in 16.1% and 10.7% of the cases, respectively. No significant differences in clinicopathological characteristics between patients with tumours expressing low IGF1R or IGF-II protein levels and those with high levels were observed. A low IGF1R protein expression was found to be significantly associated with a shorter DFS (HR 3.32; 95% CI, 1.7-6.31; p = 0.0003), while no association was observed between IGF-II protein expression and DFS (HR 0.91; 95% CI, 0.28-2.96; p = 0.87). In a multivariate analysis, IGF1R protein status remained an independent prognostic factor for DFS (HR 2.73; 95% CI, 1.40-5.31; p = 0.003). Furthermore, we found that neither IGF1R nor IGF2 mRNA expression levels as measured by qRT-PCR correlated with the respective protein expression levels as assessed by immunohistochemistry. Neither of the mRNA expression levels was significantly associated with DFS. CONCLUSIONS From our data we conclude that low IGF1R protein expression represents a poor prognostic biomarker in stage III colon cancer.
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Smeby J, Sveen A, Merok MA, Danielsen SA, Eilertsen IA, Guren MG, Dienstmann R, Nesbakken A, Lothe RA. CMS-dependent prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer. Ann Oncol 2019. [PMID: 29518181 PMCID: PMC5961317 DOI: 10.1093/annonc/mdy085] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background The prognostic impact of KRAS and BRAFV600E mutations in primary colorectal cancer (CRC) varies with microsatellite instability (MSI) status. The gene expression-based consensus molecular subtypes (CMSs) of CRC define molecularly and clinically distinct subgroups, and represent a novel stratification framework in biomarker analysis. We investigated the prognostic value of these mutations within the CMS groups. Patients and methods Totally 1197 primary tumors from a Norwegian series of CRC stage I-IV were analyzed for MSI and mutation status in hotspots in KRAS (codons 12, 13 and 61) and BRAF (codon 600). A subset was analyzed for gene expression and confident CMS classification was obtained for 317 samples. This cohort was expanded with clinical and molecular data, including CMS classification, from 514 patients in the publically available dataset GSE39582. Gene expression signatures associated with KRAS and BRAFV600E mutations were used to evaluate differential impact of mutations on gene expression among the CMS groups. Results BRAFV600E and KRAS mutations were both associated with inferior 5-year overall survival (OS) exclusively in MSS tumors (BRAFV600E mutation versus KRAS/BRAF wild-type: Hazard ratio (HR) 2.85, P < 0.001; KRAS mutation versus KRAS/BRAF wild-type: HR 1.30, P = 0.013). BRAFV600E-mutated MSS tumors were strongly enriched and associated with metastatic disease in CMS1, leading to negative prognostic impact in this subtype (OS: BRAFV600E mutation versus wild-type: HR 7.73, P = 0.001). In contrast, the poor prognosis of KRAS mutations was limited to MSS tumors with CMS2/CMS3 epithelial-like gene expression profiles (OS: KRAS mutation versus wild-type: HR 1.51, P = 0.011). The subtype-specific prognostic associations were substantiated by differential effects of BRAFV600E and KRAS mutations on gene expression signatures according to the MSI status and CMS group. Conclusions BRAFV600E mutations are enriched and associated with metastatic disease in CMS1 MSS tumors, leading to poor prognosis in this subtype. KRAS mutations are associated with adverse outcome in epithelial (CMS2/CMS3) MSS tumors.
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Affiliation(s)
- J Smeby
- Department of Molecular Oncology, Institute for Cancer Research; Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Department of Oncology, Oslo University Hospital, Oslo; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo
| | - A Sveen
- Department of Molecular Oncology, Institute for Cancer Research; Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre
| | - M A Merok
- Department of Molecular Oncology, Institute for Cancer Research; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - S A Danielsen
- Department of Molecular Oncology, Institute for Cancer Research; Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre
| | - I A Eilertsen
- Department of Molecular Oncology, Institute for Cancer Research; Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre
| | - M G Guren
- Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Department of Oncology, Oslo University Hospital, Oslo
| | - R Dienstmann
- Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona; Vall d'Hebron University Hospital, Barcelona; Universitat Autonoma de Barcelona, Barcelona, Spain; Computational Oncology, Sage Bionetworks, Seattle, USA
| | - A Nesbakken
- Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo; Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - R A Lothe
- Department of Molecular Oncology, Institute for Cancer Research; Division of Cancer Medicine, K.G. Jebsen Colorectal Cancer Research Centre; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo.
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Peng M, Fang Z, Na N, Ouyang J. A versatile single-molecule counting-based platform by generation of fluorescent silver nanoclusters for sensitive detection of multiple nucleic acids. NANOSCALE 2019; 11:16606-16613. [PMID: 31460540 DOI: 10.1039/c9nr04608a] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
The good photostability and strong brightness of individual DNA-templated silver nanoclusters (DNA-AgNCs) have been confirmed by single-molecule imaging in this work and DNA-AgNCs as a new class of outstanding fluorophores are applied in the construction of single-molecule counting-based probes for the first time. Based on the fluorescent AgNC-generating molecular beacons (AgNC-MBs), we present a versatile method for simultaneous analysis of multiple nucleic acids. Distinct from previous designs in which a AgNC stabilizing sequence is incorporated into the stem of a hairpin DNA to form the AgNC-MB, we prepared a nicked MB in which the AgNC stabilizing sequence is hybridized with the longer stem of a single-stranded DNA (ssDNA) with a stem-loop structure. Our proposed AgNC-MB is activated by probe-target hybridization then releasing the AgNC stabilizing sequence via a toehold-mediated strand displacement reaction, the versatility of which has been greatly improved because bases in the target-binding region are not involved in the formation of DNA-AgNCs. As a proof of concept, the simultaneous detection of two breast cancer-related MicroRNAs (miR-21 and let-7a miRNA) has been achieved with total internal reflection fluorescence (TIRF)-based imaging and the detection sensitivity of our method has been demonstrated to be improved by at least two orders of magnitude compared with conventional AgNC-MBs. Furthermore, in the single-nucleotide mutation identification assay, the simultaneous detection strategy introduces a competitive reaction between the two probe-target hybridizations, resulting in the excellent discrimination ability of the AgNC-MB sensing platform and the mutant-type targets can be successfully detected at low abundance. The new AgNC-MB sensing platform demonstrated potential to make AgNCs an attractive alternative to conventional organic dyes for single-molecule studies.
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Affiliation(s)
- Manshu Peng
- State Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
| | - Zhuyin Fang
- State Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
| | - Na Na
- State Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
| | - Jin Ouyang
- State Key Laboratory of Theoretical and Computational Photochemistry, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
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Bruzzi M, Auclin E, Lo Dico R, Voron T, Karoui M, Espin E, Cianchi F, Weitz J, Buggenhout A, Malafosse R, Denimal F, Le Malicot K, Vernerey D, Douard R, Emile JF, Lepage C, Laurent-Puig P, Taieb J. Influence of Molecular Status on Recurrence Site in Patients Treated for a Stage III Colon Cancer: a Post Hoc Analysis of the PETACC-8 Trial. Ann Surg Oncol 2019; 26:3561-3567. [PMID: 31209667 DOI: 10.1245/s10434-019-07513-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Indexed: 01/13/2023]
Abstract
BACKGROUND Recurrence patterns in stage III colon cancer (CC) patients according to molecular markers remain unclear. The objective of the study was to assess recurrence patterns according to microsatellite instability (MSI), RAS and BRAFV600E status in stage III CC patients. METHODS All stage III CC patients from the PETACC-8 randomized trial tested for MSI, RAS and BRAFV600E status were included. The site and characteristics of recurrence were analyzed according to molecular status. Survival after recurrence (SAR) was analyzed. RESULTS A total of 1650 patients were included. Recurrence occurred in 434 patients (26.3%). Microsatellite stable (MSS) patients had a significantly higher recurrence rate (27.2% vs. 18.7%, P = 0.02) with a trend to more pulmonary recurrence (28.8% vs. 12.9%, P = 0.06) when compared to MSI patients. MSI patients experienced more regional lymph nodes compared to MSS (12.9% vs. 4%, P = 0.046). In the MSS population, the recurrence rate was significantly higher in RAS (32.2%) or BRAF (32.3%) patients when compared to double wild-type patients (19.9%) (p < 0.001); no preferential site of recurrence was observed according to RAS and BRAFV600E mutations. Finally, decreased SAR was observed in the case of peritoneal recurrence or more than two recurrence sites. CONCLUSIONS Microsatellite, RAS and BRAFV600E status influences recurrence rates in stage III CC patients. However, only microsatellite status seems to be associated with specific recurrence patterns. More than two recurrence sites and recurrence in the peritoneum were associated with poorer SAR.
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Affiliation(s)
- M Bruzzi
- Department of General and Digestive Surgery, Georges Pompidou European Hospital, AP-HP, Paris, France.
| | - E Auclin
- Department of Digestive Oncology, Georges Pompidou European Hospital, AP-HP, Paris, France.,Methodological and Quality of Life in Oncology Unit, EA 3181, University Hospital of Besançon, Besançon, France
| | - R Lo Dico
- Department of Digestive and Oncological Surgery, Lariboisière Hospital, AP-HP, Paris, France
| | - T Voron
- Department of Digestive and General Surgery, Saint Antoine Hospital, AP-HP, Sorbonne Université, Paris, France
| | - M Karoui
- Department of Digestive and Hepato-Pancreato-Biliary Surgery, Pitié-Salpêtrière University Hospital, AP-HP, Paris VI University Institute of Cancerology, Paris, France
| | - E Espin
- Department of General Surgery, Hospital Valle de Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - F Cianchi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - J Weitz
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus of the Technical University Dresden, Dresden, Germany
| | - A Buggenhout
- Department of Surgical Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - R Malafosse
- Department of Digestive Surgery, Ambroise-Paré Hospital, AP-HP, Boulogne, France
| | - F Denimal
- Department of Digestive Surgery, Centre Hospitalier Départemental Vendée, La Roche Sur Yon, France
| | - K Le Malicot
- Statistical Department, Fédération Francophone de Cancérologie Digestive, EPICAD, INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, Dijon, France
| | - D Vernerey
- Methodological and Quality of Life in Oncology Unit, EA 3181, University Hospital of Besançon, Besançon, France
| | - R Douard
- Department of General and Digestive Surgery, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - J F Emile
- Pathology Department, Ambroise-Paré Hospital, AP-HP, Boulogne, France
| | - C Lepage
- Hepato-Gastroenterology Department, Dijon University Hospital and EPICAD INSERM LNC-UMR 1231, University of Burgundy and Franche Comté, Dijon, France
| | - P Laurent-Puig
- Department of Biology, European Georges Pompidou Hospital, AP-HP, INSERM-UMR-S1147, Paris, France
| | - J Taieb
- Department of Digestive Oncology, Georges Pompidou European Hospital, AP-HP, Paris, France
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Wiesweg M, Kasper S, Worm K, Herold T, Reis H, Sara L, Metzenmacher M, Abendroth A, Darwiche K, Aigner C, Wedemeyer HH, Helfritz FA, Stuschke M, Schumacher B, Markus P, Paul A, Rahmann S, Schmid KW, Schuler M. Impact of RAS mutation subtype on clinical outcome—a cross-entity comparison of patients with advanced non-small cell lung cancer and colorectal cancer. Oncogene 2018; 38:2953-2966. [DOI: 10.1038/s41388-018-0634-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 09/21/2018] [Accepted: 11/21/2018] [Indexed: 12/21/2022]
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Sperlich A, Balmert A, Doll D, Bauer S, Franke F, Keller G, Wilhelm D, Mur A, Respondek M, Friess H, Nitsche U, Janssen KP. Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer. BMC Cancer 2018; 18:998. [PMID: 30340556 PMCID: PMC6194664 DOI: 10.1186/s12885-018-4940-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Accepted: 10/11/2018] [Indexed: 02/08/2023] Open
Abstract
Background Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. Methods Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox’s proportional hazard models and integrative two-step cluster analysis. Results Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU. Conclusions Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients. Electronic supplementary material The online version of this article (10.1186/s12885-018-4940-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Andreas Sperlich
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Alexander Balmert
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Dietrich Doll
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany.,Darmzentrum Vechta, St. Marienhospital, Marienstraße 6-8, 49377, Vechta, Germany
| | - Sabine Bauer
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Fabian Franke
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Gisela Keller
- Institute of Pathology, Technical University of Munich, Trogerstr. 18, 81675, Munich, Germany
| | - Dirk Wilhelm
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Anna Mur
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Michael Respondek
- St. Marienhospital, Praxis für Pathologie Vechta, Marienstr. 11, 49377, Vechta, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Ulrich Nitsche
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany
| | - Klaus-Peter Janssen
- Department of Surgery, Klinikum rechts der Isar, TUM, Ismaninger Str. 22, 81675, Munich, Germany.
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50
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Van Nieuwenhuysen E, Busschaert P, Neven P, Han SN, Moerman P, Liontos M, Papaspirou M, Kupryjanczyk J, Hogdall C, Hogdall E, Oaknin A, Garcia A, Mahner S, Trillsch F, Cibula D, Heitz F, Concin N, Speiser P, Salvesen H, Sehouli J, Lambrechts D, Vergote I. The genetic landscape of 87 ovarian germ cell tumors. Gynecol Oncol 2018; 151:61-68. [DOI: 10.1016/j.ygyno.2018.08.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/10/2018] [Accepted: 08/11/2018] [Indexed: 12/12/2022]
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