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Shida D, Kuchiba A, Shibata T, Hamaguchi T, Yamasaki S, Ito M, Kobatake T, Tonooka T, Masaki T, Shiozawa M, Takii Y, Uetake H, Okamura S, Ojima H, Kazama S, Takeyama H, Kanato K, Shimada Y, Murakami Y, Kanemitsu Y. Genomic landscape and its prognostic significance in stage III colorectal cancer: JCOG1506A1, an ancillary of JCOG0910. Cancer Sci 2023. [PMID: 37189003 PMCID: PMC10394152 DOI: 10.1111/cas.15834] [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: 12/12/2022] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Large-scale genomic sequencing of colorectal cancers has been reported mainly for Western populations. Differences by stage and ethnicity in the genomic landscape and their prognostic impact remain poorly understood. We investigated 534 Japanese stage III colorectal cancer samples from the Phase III trial, JCOG0910. Targeted-capture sequencing of 171 potentially colorectal cancer-associated genes was performed, and somatic single-nucleotide variants and insertion-deletions were determined. Hypermutated tumors were defined as tumors with MSIsensor score >7 and ultra-mutated tumors with POLE mutations. Genes with alterations associated with relapse-free survival were analyzed using multivariable Cox regression models. In all patients (184 right-sided, 350 left-sided), mutation frequencies were TP53, 75.3%; APC, 75.1%; KRAS, 43.6%; PIK3CA, 19.7%; FBXW7, 18.5%; SOX9, 11.8%; COL6A3, 8.2%; NOTCH3, 4.5%; NRAS, 4.1%; and RNF43, 3.7%. Thirty-one tumors were hypermutated (5.8%; 14.1% right-sided, 1.4% left-sided). Modest associations were observed: poorer relapse-free survival was seen with mutant KRAS (hazard ratio 1.66; p = 0.011) and mutant RNF43 (2.17; p = 0.055), whereas better relapse-free survival was seen with mutant COL6A3 (0.35; p = 0.040) and mutant NOTCH3 (0.18; p = 0.093). Relapse-free survival tended to be better for hypermutated tumors (0.53; p = 0.229). In conclusion, the overall spectrum of mutations in our Japanese stage III colorectal cancer cohort was similar to that in Western populations, but the frequencies of mutation for TP53, SOX9, and FBXW7 were higher, and the proportion of hypermutated tumors was lower. Multiple gene mutations appeared to impact relapse-free survival, suggesting that tumor genomic profiling can support precision medicine for colorectal cancer.
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Affiliation(s)
- Dai Shida
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Aya Kuchiba
- Biostatistics Division, Center for Research Administration and Support, National Cancer Center, Tokyo, Japan
- Graduate School of Health Innovation, Kanagawa University of Human Services, Kanagawa, Japan
| | - Tatsuhiro Shibata
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tetsuya Hamaguchi
- Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Satoshi Yamasaki
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masaaki Ito
- Department of Colorectal Surgery, National Cancer Center Hospital East, Chiba, Japan
| | - Takaya Kobatake
- Department of Gastroenterological Surgery, National Hospital Organization Shikoku Cancer Center, Ehime, Japan
| | - Toru Tonooka
- Department of Gastroenterological Surgery, Chiba Cancer Center, Chiba, Japan
| | - Tadahiko Masaki
- Department of Surgery, Kyorin University, Mitaka City, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Kanagawa, Japan
| | - Yasumasa Takii
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Hiroyuki Uetake
- Department of Specialized Surgeries, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shu Okamura
- Department of Surgery, Suita Municipal Hospital, Osaka, Japan
| | - Hitoshi Ojima
- Department of Gastroenterological Surgery, Gunma Prefectural Cancer Center, Gunma, Japan
| | - Shinsuke Kazama
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | | | - Keisuke Kanato
- Research Management Division, Clinical Research Support Office, National Cancer Center Hospital, Tokyo, Japan
| | - Yasuhiro Shimada
- Gastrointestinal Medical Oncology Division, Kochi Health Sciences Center, Kochi, Japan
| | - Yoshinori Murakami
- Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
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Ranganathan M, Sacca RE, Trottier M, Maio A, Kemel Y, Salo-Mullen E, Catchings A, Kane S, Wang C, Ravichandran V, Ptashkin R, Mehta N, Garcia-Aguilar J, Weiser MR, Donoghue MT, Berger MF, Mandelker D, Walsh MF, Carlo M, Liu YL, Cercek A, Yaeger R, Saltz L, Segal NH, Mendelsohn RB, Markowitz AJ, Offit K, Shia J, Stadler ZK, Latham A. Prevalence and Clinical Implications of Mismatch Repair-Proficient Colorectal Cancer in Patients With Lynch Syndrome. JCO Precis Oncol 2023; 7:e2200675. [PMID: 37262391 PMCID: PMC10309569 DOI: 10.1200/po.22.00675] [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: 12/06/2022] [Accepted: 04/06/2023] [Indexed: 06/03/2023] Open
Abstract
PURPOSE Lynch syndrome (LS)-associated colorectal cancer (CRC) is characterized by mismatch repair-deficiency (MMR-D) and/or microsatellite instability (MSI). However, with increasing utilization of germline testing, MMR-proficient (MMR-P) and/or microsatellite stable (MSS) CRC has also been observed. We sought to characterize MMR-P/MSS CRC among patients with LS. METHODS Patients with solid tumors with germline MMR pathogenic/likely pathogenic (P/LP) variants were identified on a prospective matched tumor-normal next-generation sequencing (NGS) protocol. CRCs were evaluated for MMR-D via immunohistochemical (IHC) staining and/or MSI via NGS. Clinical variables were correlated with MMR status using nonparametric tests. RESULTS Among 17,617 patients with solid tumors, 1.4% (n = 242) had LS. A total of 36% (86 of 242) of patients with LS had at least one CRC that underwent NGS profiling, amounting to 99 pooled CRCs assessed. A total of 10% (10 of 99) of CRCs were MMR-P, with 100% concordance between MSS status and retained MMR protein staining. A total of 89% (8 of 9) of patients in the MMR-P group had MSH6 or PMS2 variants, compared with 30% (23 of 77) in the MMR-D group (P = .001). A total of 46% (6 of 13) of PMS2+ patients had MMR-P CRC. The median age of onset was 58 and 43 years for MMR-P and MMR-D CRC, respectively (P = .07). Despite the later median age of onset, 40% (4 of 10) of MMR-P CRCs were diagnosed <50. A total of 60% (6 of 10) of MMR-P CRCs were metastatic compared with 13% (12 of 89) of MMR-D CRCs (P = .002). A total of 33% (3 of 9) of patients with MMR-P CRC did not meet LS testing criteria. CONCLUSION Patients with LS remained at risk for MMR-P CRC, which was more prevalent among patients with MSH6 and PMS2 variants. MMR-P CRC was later onset and more commonly metastatic compared with MMR-D CRC. Confirmation of tumor MMR/MSI status is critical for patient management and familial risk estimation.
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Affiliation(s)
- Megha Ranganathan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rosalba E. Sacca
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Magan Trottier
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anna Maio
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Yelena Kemel
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Erin Salo-Mullen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Amanda Catchings
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sarah Kane
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Chiyun Wang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Vignesh Ravichandran
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ryan Ptashkin
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nikita Mehta
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Martin R. Weiser
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Surgery, Weill Cornell Medical College, New York, NY
| | - Mark T.A. Donoghue
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael F. Berger
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Diana Mandelker
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael F. Walsh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Maria Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Ying L. Liu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Leonard Saltz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Neil H. Segal
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Robin B. Mendelsohn
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Arnold J. Markowitz
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Kenneth Offit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zsofia K. Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
| | - Alicia Latham
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
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Sei S, Ahadova A, Keskin DB, Bohaumilitzky L, Gebert J, von Knebel Doeberitz M, Lipkin SM, Kloor M. Lynch syndrome cancer vaccines: A roadmap for the development of precision immunoprevention strategies. Front Oncol 2023; 13:1147590. [PMID: 37035178 PMCID: PMC10073468 DOI: 10.3389/fonc.2023.1147590] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/09/2023] [Indexed: 04/11/2023] Open
Abstract
Hereditary cancer syndromes (HCS) account for 5~10% of all cancer diagnosis. Lynch syndrome (LS) is one of the most common HCS, caused by germline mutations in the DNA mismatch repair (MMR) genes. Even with prospective cancer surveillance, LS is associated with up to 50% lifetime risk of colorectal, endometrial, and other cancers. While significant progress has been made in the timely identification of germline pathogenic variant carriers and monitoring and early detection of precancerous lesions, cancer-risk reduction strategies are still centered around endoscopic or surgical removal of neoplastic lesions and susceptible organs. Safe and effective cancer prevention strategies are critically needed to improve the life quality and longevity of LS and other HCS carriers. The era of precision oncology driven by recent technological advances in tumor molecular profiling and a better understanding of genetic risk factors has transformed cancer prevention approaches for at-risk individuals, including LS carriers. MMR deficiency leads to the accumulation of insertion and deletion mutations in microsatellites (MS), which are particularly prone to DNA polymerase slippage during DNA replication. Mutations in coding MS give rise to frameshift peptides (FSP) that are recognized by the immune system as neoantigens. Due to clonal evolution, LS tumors share a set of recurrent and predictable FSP neoantigens in the same and in different LS patients. Cancer vaccines composed of commonly recurring FSP neoantigens selected through prediction algorithms have been clinically evaluated in LS carriers and proven safe and immunogenic. Preclinically analogous FSP vaccines have been shown to elicit FSP-directed immune responses and exert tumor-preventive efficacy in murine models of LS. While the immunopreventive efficacy of "off-the-shelf" vaccines consisting of commonly recurring FSP antigens is currently investigated in LS clinical trials, the feasibility and utility of personalized FSP vaccines with individual HLA-restricted epitopes are being explored for more precise targeting. Here, we discuss recent advances in precision cancer immunoprevention approaches, emerging enabling technologies, research gaps, and implementation barriers toward clinical translation of risk-tailored prevention strategies for LS carriers. We will also discuss the feasibility and practicality of next-generation cancer vaccines that are based on personalized immunogenic epitopes for precision cancer immunoprevention.
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Affiliation(s)
- Shizuko Sei
- Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD, United States
| | - Aysel Ahadova
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Derin B. Keskin
- Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA, United States
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
- Broad Institute of The Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, United States
- Department of Computer Science, Metropolitan College, Boston University, Boston, MA, United States
- Harvard Medical School, Boston, MA, United States
- Section for Bioinformatics, Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Lena Bohaumilitzky
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Johannes Gebert
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Steven M. Lipkin
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Matthias Kloor
- Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
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Sakamoto Y, Mima K, Ishimoto T, Ogata Y, Imai K, Miyamoto Y, Akiyama T, Daitoku N, Hiyoshi Y, Iwatsuki M, Baba Y, Iwagami S, Yamashita Y, Yoshida N, Komohara Y, Ogino S, Baba H. Relationship between Fusobacterium nucleatum and antitumor immunity in colorectal cancer liver metastasis. Cancer Sci 2021; 112:4470-4477. [PMID: 34464993 PMCID: PMC8586672 DOI: 10.1111/cas.15126] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 08/20/2021] [Accepted: 08/30/2021] [Indexed: 12/31/2022] Open
Abstract
Fusobacterium nucleatum has been detected in 8%-13% of human colorectal cancer, and shown to inhibit immune responses against primary colorectal tumors in animal models. Thus, we hypothesized that the presence of F. nucleatum might be associated with reduced T cell density in colorectal cancer liver metastases (CRLM). We quantified F. nucleatum DNA in 181 CRLM specimens using quantitative PCR assay. The densities of CD8+ T cells, CD33+ cells (marker for myeloid-derived suppressor cells [MDSCs]), and CD163+ cells (marker for tumor-associated macrophages [TAMs]) in CRLM tissue were determined by immunohistochemical staining. Fusobacterium nucleatum was detected in eight (4.4%) of 181 CRLM specimens. Compared with F. nucleatum-negative CRLM, F. nucleatum-positive CRLM showed significantly lower density of CD8+ T cells (P = .033) and higher density of MDSCs (P = .001). The association of F. nucleatum with the density of TAMs was not statistically significant (P = .70). The presence of F. nucleatum is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRLM tissue. Upon validation, our findings could provide insights to develop strategies that involve targeting microbiota and immune cells for the prevention and treatment of CRLM.
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Affiliation(s)
- Yuki Sakamoto
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Kosuke Mima
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
- Department of SurgeryNational Hospital Organization Kumamoto Medical CenterKumamotoJapan
| | - Takatsugu Ishimoto
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
- Gastrointestinal Cancer BiologyInternational Research Center for Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yoko Ogata
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Katsunori Imai
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yuji Miyamoto
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Takahiko Akiyama
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Nobuya Daitoku
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological SurgeryCancer Institute HospitalTokyoJapan
| | - Masaaki Iwatsuki
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yoshifumi Baba
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Shiro Iwagami
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Yo‐ichi Yamashita
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Naoya Yoshida
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
- Division of Translational Research and Advanced Treatment Against Gastrointestinal CancerKumamoto UniversityKumamotoJapan
| | - Yoshihiro Komohara
- Department of Cell PathologyGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
| | - Shuji Ogino
- Program in MPE Molecular Pathological EpidemiologyDepartment of PathologyBrigham and Women's Hospital and Harvard Medical SchoolBostonMassachusettsUSA
- Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
- Department of Oncologic PathologyDana‐Farber Cancer InstituteBostonMassachusettsUSA
- Broad Institute of MIT and HarvardCambridgeMassachusettsUSA
- Cancer Immunology and Cancer Epidemiology ProgramsDana‐Farber Harvard Cancer CenterBostonMassachusettsUSA
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
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Sensitive detection of microsatellite instability in tissues and liquid biopsies: Recent developments and updates. Comput Struct Biotechnol J 2021; 19:4931-4940. [PMID: 34527197 PMCID: PMC8433064 DOI: 10.1016/j.csbj.2021.08.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
Microsatellite instability (MSI), a phenotype displayed as deletions/insertions of repetitive genomic sequences, has drawn great attention due to its application in cancer including diagnosis, prognosis and immunotherapy response prediction. Several methods have been developed for the detection of MSI, facilitating the MSI classification of cancer patients. In view of recent interest in minimally-invasive detection of MSI via liquid biopsy samples, which requires methods with high sensitivity to identify small fractions of altered DNA in the presence of large amount of wild type copies, sensitive MSI detection approaches are emerging. Here we review the available MSI detection methods and their detection limits and focus on recently developed next-generation-sequencing based approaches and bioinformatics algorithms available for MSI analysis in various cancer types.
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Yu F, Leong KW, Makrigiorgos A, Adalsteinsson VA, Ladas I, Ng K, Mamon H, Makrigiorgos GM. NGS-based identification and tracing of microsatellite instability from minute amounts DNA using inter-Alu-PCR. Nucleic Acids Res 2021; 49:e24. [PMID: 33290560 PMCID: PMC7913684 DOI: 10.1093/nar/gkaa1175] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/13/2020] [Accepted: 11/20/2020] [Indexed: 12/20/2022] Open
Abstract
Sensitive detection of microsatellite instability (MSI) in tissue or liquid biopsies using next generation sequencing (NGS) has growing prognostic and predictive applications in cancer. However, the complexities of NGS make it cumbersome as compared to established multiplex-PCR detection of MSI. We present a new approach to detect MSI using inter-Alu-PCR followed by targeted NGS, that combines the practical advantages of multiplexed-PCR with the breadth of information provided by NGS. Inter-Alu-PCR employs poly-adenine repeats of variable length present in every Alu element and provides a massively-parallel, rapid approach to capture poly-A-rich genomic fractions within short 80–150bp amplicons generated from adjacent Alu-sequences. A custom-made software analysis tool, MSI-tracer, enables Alu-associated MSI detection from tissue biopsies or MSI-tracing at low-levels in circulating-DNA. MSI-associated indels at somatic-indel frequencies of 0.05–1.5% can be detected depending on the availability of matching normal tissue and the extent of instability. Due to the high Alu copy-number in human genomes, a single inter-Alu-PCR retrieves enough information for identification of MSI-associated-indels from ∼100 pg circulating-DNA, reducing current limits by ∼2-orders of magnitude and equivalent to circulating-DNA obtained from finger-sticks. The combined practical and informational advantages of inter-Alu-PCR make it a powerful tool for identifying tissue-MSI-status or tracing MSI-associated-indels in liquid biopsies.
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Affiliation(s)
- Fangyan Yu
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ka Wai Leong
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Alexander Makrigiorgos
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Ioannis Ladas
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medicine School, Boston, MA, USA
| | - Harvey Mamon
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - G Mike Makrigiorgos
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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7
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Wang XQ, Xu SW, Wang W, Piao SZ, Mao XL, Zhou XB, Wang Y, Wu WD, Ye LP, Li SW. Identification and Validation of a Novel DNA Damage and DNA Repair Related Genes Based Signature for Colon Cancer Prognosis. Front Genet 2021; 12:635863. [PMID: 33719345 PMCID: PMC7943631 DOI: 10.3389/fgene.2021.635863] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 02/01/2021] [Indexed: 12/14/2022] Open
Abstract
Backgrounds: Colorectal cancer (CRC) with high incidence, has the third highest mortality of tumors. DNA damage and repair influence a variety of tumors. However, the role of these genes in colon cancer prognosis has been less systematically investigated. Here, we aim to establish a corresponding prognostic signature providing new therapeutic opportunities for CRC. Method: After related genes were collected from GSEA, univariate Cox regression was performed to evaluate each gene's prognostic relevance through the TCGA-COAD dataset. Stepwise COX regression was used to establish a risk prediction model through the training sets randomly separated from the TCGA cohort and validated in the remaining testing sets and two GEO datasets (GSE17538 and GSE38832). A 12-DNA-damage-and-repair-related gene-based signature able to classify COAD patients into high and low-risk groups was developed. The predictive ability of the risk model or nomogram were evaluated by different bioinformatics- methods. Gene functional enrichment analysis was performed to analyze the co-expressed genes of the risk-based genes. Result: A 12-gene based prognostic signature established within 160 significant survival-related genes from DNA damage and repair related gene sets performed well with an AUC of ROC 0.80 for 5 years in the TCGA-CODA dataset. The signature includes CCNB3, ISY1, CDC25C, SMC1B, MC1R, LSP1P4, RIN2, TPM1, ELL3, POLG, CD36, and NEK4. Kaplan-Meier survival curves showed that the prognosis of the risk status owns more significant differences than T, M, N, and stage prognostic parameters. A nomogram was constructed by LASSO regression analysis with T, M, N, age, and risk as prognostic parameters. ROC curve, C-index, Calibration analysis, and Decision Curve Analysis showed the risk module and nomogram performed best in years 1, 3, and 5. KEGG, GO, and GSEA enrichment analyses suggest the risk involved in a variety of important biological processes and well-known cancer-related pathways. These differences may be the key factors affecting the final prognosis. Conclusion: The established gene signature for CRC prognosis provides a new molecular tool for clinical evaluation of prognosis, individualized diagnosis, and treatment. Therapies based on targeted DNA damage and repair mechanisms may formulate more sensitive and potential chemotherapy regimens, thereby expanding treatment options and potentially improving the clinical outcome of CRC patients.
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Affiliation(s)
- Xue-quan Wang
- Laboratory of Cellular and Molecular Radiation Oncology, Department of Radiation Oncology, Radiation Oncology Institute of Enze Medical Health Academy, Affiliated Taizhou Hospital of Wenzhou Medical University, Taizhou, China
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
| | - Shi-wen Xu
- Wenzhou Medical University, Wenzhou, China
| | - Wei Wang
- Wenzhou Medical University, Wenzhou, China
| | - Song-zhe Piao
- Department of Urology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xin-li Mao
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Xian-bin Zhou
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Yi Wang
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Wei-dan Wu
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Li-ping Ye
- Wenzhou Medical University, Wenzhou, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
| | - Shao-wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Linhai, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China
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8
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Eso Y, Seno H. Current status of treatment with immune checkpoint inhibitors for gastrointestinal, hepatobiliary, and pancreatic cancers. Therap Adv Gastroenterol 2020; 13:1756284820948773. [PMID: 32913444 PMCID: PMC7443993 DOI: 10.1177/1756284820948773] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 07/16/2020] [Indexed: 02/04/2023] Open
Abstract
The development of immune checkpoint inhibitors (ICIs) targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death protein ligand 1 (PD-L1) has revolutionized the treatment strategy in various types of cancers. In addition, recent studies have revealed that tumor microsatellite instability (MSI) status and tumor mutation burden (TMB) contribute significantly to the therapeutic response to anti-PD-1 monoclonal antibody (mAb), which led to an accelerated approval to pembrolizumab for the treatment of MSI-high or mismatch-repair-deficient solid tumors after conventional chemotherapies in 2017 and for the treatment of TMB-high solid tumors in 2020 by the United States Food and Drug Administration (FDA). In the field of gastrointestinal cancers, many clinical trials evaluating the safety and efficacy of various regimens such as ICI monotherapy, the combination of anti-CTLA-4 mAb and anti-PD-1/PD-L1 mAb, and combination of ICI and conventional chemotherapy or tyrosine kinase inhibitor have been reported or are in progress. This review summarizes MSI status and TMB in gastrointestinal, hepatobiliary, and pancreatic cancers, and provides the results of most relevant clinical trials evaluating ICIs. We also discuss the development of biomarkers required for improving the selection of patients with a high probability of benefiting from treatment with ICIs, and potential therapeutic strategies that could help to enhance anticancer responses of ICIs.
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Affiliation(s)
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology,
Graduate School of Medicine, Kyoto University, Kyoto, Japan
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9
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Genomic mutations and histopathologic biomarkers in Y 90 radioembolization for chemorefractory colorectal liver metastases. Oncotarget 2018; 9:32523-32533. [PMID: 30197760 PMCID: PMC6126695 DOI: 10.18632/oncotarget.25992] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 08/02/2018] [Indexed: 12/20/2022] Open
Abstract
Background To investigate mutational load and histologic biomarkers as prognostic factors in patients with chemorefractory colorectal liver metastases (CRLM) treated with Y-90 radioembolization therapy. Materials and Methods Single institution retrospective study of patients with CRLM who received Y-90 radioembolization after undergoing molecular testing was performed. Patient demographics, systemic therapy regimens, tumor characteristics and overall survival were analyzed between patients with differing histopathologic and genomic status. PIK3CA, KRAS, NRAS, AKT1, MEK1, MLH1, MSH2, MSH6 and PMS2 were analyzed. Kaplan-Meier survival estimation and multivariate Cox regression were analyzed. Results 23 patients underwent genomic analysis prior to Y-90. Eleven (47.8%) had mutations identified (MUT), and 12 were sequenced as wild type (WT) (52.2%). Median OS of 23 patients after Y-90 was 9.6 months (95% CI 6.67-16.23). Median OS from first Y-90 was significantly greater in WT patients (16.2 mo vs 6.5 mo; p =.0054). The survival difference between poorly differentiated tumors compared to all other histologic grades was significant (poor vs. well p=0.025, HR=26.8; poor vs. moderate p=.014, HR=23.07; poor vs. moderate/poor p=0.014, HR=23.68). When separated into 3 different groups (WT vs. MUT/moderate differentiation vs. MUT/poor differentiation) there was a difference in median OS observed (16.2 vs. 8.0 vs. 3.8 mos; p<.0001). Imaging response via RECIST criteria was significantly different between MUT and WT groups (p=0.02). Conclusions Mutational status and histopathologic grade may predict survival after Y-90 radioembolization therapy for CRLM.
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10
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Morales-Miranda A, Rosado ID, Núñez CC, Montero FC. Appendiceal carcinoma associated with microsatellite instability. Mol Clin Oncol 2018; 8:694-698. [PMID: 29725538 DOI: 10.3892/mco.2018.1596] [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: 11/14/2017] [Accepted: 03/02/2018] [Indexed: 11/05/2022] Open
Abstract
Approximately 15% of colorectal cancer (CRC) cases exhibit microsatellite instability (MSI), which appears to be associated with unique biological behavior. The present study presents a case of appendiceal carcinoma associated with MSI that responded well to adjuvant chemotherapy. Clinical, pathological and immunohistochemical (IHC) characteristics have been described. The 60-year-old male patient had suffered from recurrent lower abdominal pain associated with abdominal distention for 6 months; then, following an acute attack, he was subjected to laparoscopic appendectomy. The histopathological examination revealed moderately differentiated appendiceal adenocarcinoma with mucinous areas, without lymphovascular or perineural invasion. The IHC examination was positive for keratin-20 and caudal type homeobox 2, and negative for MutL Homolog 1, MutS Homolog (MSH) 2 and MSH-6. A postoperative colonoscopy revealed diverticulosis, without the presence of polyps or tumors. However, an abdominal axial computerized tomography scan revealed thickening of the distal portion of the appendix, increased density of the greater omentum, and metastases to the liver capsule, spleen and peritoneum. The treatment of choice was right hemicolectomy with peritoneal debulking, followed by 10 cycles of chemotherapy with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX regimen). After 5 years of follow-up, the patient remains in good condition, without clinical or radiological signs of recurrence. The good response to chemotherapy corresponds with the observations made in other colon cancers with MSI. Therefore, testing for MSI in appendiceal carcinomas may provide useful information on prognosis and predict response to chemotherapy.
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Affiliation(s)
- Angélica Morales-Miranda
- Department of Reproductive Biology, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City 14080, Mexico
| | - Ismael Domínguez Rosado
- Department of Surgery, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City 14080, Mexico
| | - Carlos Chan Núñez
- Department of Surgery, National Institute of Medical Sciences and Nutrition Salvador Zubirán, Mexico City 14080, Mexico
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11
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Analysis of somatic microsatellite indels identifies driver events in human tumors. Nat Biotechnol 2017; 35:951-959. [DOI: 10.1038/nbt.3966] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 08/18/2017] [Indexed: 01/03/2023]
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12
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Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. CRC develops as a consequence of genomic instability, characterized by various genetic and epigenetic alterations. Its molecular heterogeneity explains the large variability in patient prognosis and treatment response, emphasizing the need for development of accurate prognostic and predictive biomarkers. This article delineates the different pathways of colorectal carcinogenesis and its molecular subtype classification. With this review, we aim to provide a comprehensive overview of the current and future biomarkers guiding clinical decision-making and CRC treatment.
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Affiliation(s)
- Pieter-Jan Cuyle
- Department of Gastroenterology/Digestive Oncology, Imelda General Hospital, Bonheiden, Belgium
- Department of Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
| | - Hans Prenen
- Department of Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
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13
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A. Cienfuegos J, Baixauli J, Arredondo J, Pastor C, Martínez Ortega P, Zozaya G, Martí-Cruchaga P, Hernández Lizoáin JL. Clinico-pathological and oncological differences between right and left-sided colon cancer (stages I-III): analysis of 950 cases. REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS 2017; 110. [DOI: 10.17235/reed.2017.5034/2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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14
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Iyevleva AG, Imyanitov EN. Cytotoxic and targeted therapy for hereditary cancers. Hered Cancer Clin Pract 2016; 14:17. [PMID: 27555886 PMCID: PMC4994296 DOI: 10.1186/s13053-016-0057-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 06/27/2016] [Indexed: 12/21/2022] Open
Abstract
There is a number of drugs demonstrating specific activity towards hereditary cancers. For example, tumors in BRCA1/2 mutation carriers usually arise via somatic inactivation of the remaining BRCA allele, which makes them particularly sensitive to platinum-based drugs, PARP inhibitors (PARPi), mitomycin C, liposomal doxorubicin, etc. There are several molecular assays for BRCA-ness, which permit to reveal BRCA-like phenocopies among sporadic tumors and thus extend clinical indications for the use of BRCA-specific therapies. Retrospective data on high-dose chemotherapy deserve consideration given some unexpected instances of cure from metastatic disease among BRCA1/2-mutated patients. Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by high-level microsatellite instability (MSI-H), increased antigenicity and elevated expression of immunosuppressive molecules. Recent clinical trial demonstrated tumor responses in HNPCC patients treated by the immune checkpoint inhibitor pembrolizumab. There are successful clinical trials on the use of novel targeted agents for the treatment or rare cancer syndromes, e.g. RET inhibitors for hereditary medullary thyroid cancer, mTOR inhibitors for tumors arising in patients with tuberous sclerosis (TSC), and SMO inhibitors for basal-cell nevus syndrome. Germ-line mutation tests will be increasingly used in the future for the choice of the optimal therapy, therefore turnaround time for these laboratory procedures needs to be significantly reduced to ensure proper treatment planning.
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Affiliation(s)
- Aglaya G Iyevleva
- N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, 197758 Russia ; St. Petersburg Pediatric Medical University, St. Petersburg, 194100 Russia
| | - Evgeny N Imyanitov
- N.N. Petrov Institute of Oncology, Pesochny-2, St. Petersburg, 197758 Russia ; St. Petersburg Pediatric Medical University, St. Petersburg, 194100 Russia ; I.I. Mechnikov North-Western Medical University, St. Petersburg, 191015 Russia ; St. Petersburg State University, St. Petersburg, 199034 Russia
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15
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Stadler ZK, Battaglin F, Middha S, Hechtman JF, Tran C, Cercek A, Yaeger R, Segal NH, Varghese AM, Reidy-Lagunes DL, Kemeny NE, Salo-Mullen EE, Ashraf A, Weiser MR, Garcia-Aguilar J, Robson ME, Offit K, Arcila ME, Berger MF, Shia J, Solit DB, Saltz LB. Reliable Detection of Mismatch Repair Deficiency in Colorectal Cancers Using Mutational Load in Next-Generation Sequencing Panels. J Clin Oncol 2016; 34:2141-7. [PMID: 27022117 PMCID: PMC4962706 DOI: 10.1200/jco.2015.65.1067] [Citation(s) in RCA: 199] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. METHODS We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. RESULTS Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). CONCLUSION A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.
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Affiliation(s)
- Zsofia K Stadler
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Francesca Battaglin
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Sumit Middha
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Jaclyn F Hechtman
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Christina Tran
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Andrea Cercek
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Rona Yaeger
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Neil H Segal
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Anna M Varghese
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Diane L Reidy-Lagunes
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Nancy E Kemeny
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Erin E Salo-Mullen
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Asad Ashraf
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Martin R Weiser
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Julio Garcia-Aguilar
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Mark E Robson
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Kenneth Offit
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Maria E Arcila
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Michael F Berger
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Jinru Shia
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - David B Solit
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy
| | - Leonard B Saltz
- Zsofia K. Stadler, Francesca Battaglin, Sumit Middha, Jaclyn F. Hechtman, Christina Tran, Andrea Cercek, Rona Yaeger, Neil H. Segal, Anna M. Varghese, Diane L. Reidy-Lagunes, Nancy E. Kemeny, Erin E. Salo-Mullen, Asad Ashraf, Martin R. Weiser, Julio Garcia-Aguilar, Mark E. Robson, Kenneth Offit, Maria E. Arcila, Michael F. Berger, Jinru Shia, David B. Solit, and Leonard B. Saltz, Memorial Sloan Kettering Cancer Center, New York, NY; and Francesca Battaglin, Veneto Institute of Oncology, Padua, Italy.
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16
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Chen KH, Lin YL, Liau JY, Tsai JH, Tseng LH, Lin LI, Liang JT, Lin BR, Hung JS, Chang YL, Yeh KH, Cheng AL. BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer. Med Oncol 2016; 33:39. [PMID: 27034263 DOI: 10.1007/s12032-016-0756-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 12/19/2022]
Abstract
The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.
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Affiliation(s)
- Kuo-Hsing Chen
- Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan.,National Taiwan University Cancer Center, Taipei, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yu-Lin Lin
- Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jau-Yu Liau
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Huei Tsai
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Li-Hui Tseng
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Liang-In Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Jin-Tung Liang
- Division of Colorectal Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Been-Ren Lin
- Division of Colorectal Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ji-Shiang Hung
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Yih-Leong Chang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.,Department and Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan. .,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan. .,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan
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17
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Urganci N, Genc DB, Kose G, Onal Z, Vidin OO. Colorectal Cancer due to Constitutional Mismatch Repair Deficiency Mimicking Neurofibromatosis I. Pediatrics 2015; 136:e1047-50. [PMID: 26391938 DOI: 10.1542/peds.2015-1426] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/08/2015] [Indexed: 11/24/2022] Open
Abstract
Colorectal carcinoma (CRC) is an extremely rare tumor of childhood that can be associated with cancer predisposition syndromes. A patient with CRC related to constitutional mismatch repair deficiency (CMMRD) syndrome with features of neurofibromatosis type 1 (NF-1) is presented here. A 13-year-old boy was admitted for a 4-month history of diarrhea and rectal bleeding. The patient had extensive café au lait spots, freckling, and Lisch nodules. He fulfilled the NF-1 diagnostic criteria. Colonoscopy showed numerous polyps and a colorectal mass lesion, of which a biopsy revealed adenocarcinoma, an uncommon pathology associated with NF-1. High microsatellite instability and homozygous mutation of PMS2 gene in tumor tissue and blood lymphocytes, respectively, confirmed the diagnosis of CMMRD. Unfortunately, because family history related to CMMRD was negative, the parents denied the diagnosis and refused the therapy, and the patient was lost to follow-up. CMMRD is a rare cancer predisposition syndrome with phenotypical features resembling NF-1. The disease may be suspected in the setting of NF-1 features and CRC, high-grade brain tumors, or hematologic malignancies. Lack of family history related to CMMRD may be a major obstacle to convincing parents of the presence of an inherited disease in their progeny.
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Affiliation(s)
- Nafiye Urganci
- Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey; and
| | - Dildar Bahar Genc
- Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey; and
| | - Gulsen Kose
- Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey; and
| | - Zerrin Onal
- Bakirkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul, Turkey
| | - Ozge Ozdemir Vidin
- Sisli Hamidiye Etfal Training and Research Hospital, Istanbul, Turkey; and
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