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Lichtenstein AV. Rethinking the Evolutionary Origin, Function, and Treatment of Cancer. BIOCHEMISTRY. BIOKHIMIIA 2025; 90:19-31. [PMID: 40058971 DOI: 10.1134/s0006297924603575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 09/29/2024] [Accepted: 12/08/2024] [Indexed: 05/13/2025]
Abstract
Despite remarkable progress in basic oncology, practical results remain unsatisfactory. This discrepancy is partly due to the exclusive focus on processes within the cancer cell, which results in a lack of recognition of cancer as a systemic disease. It is evident that a wise balance is needed between two alternative methodological approaches: reductionism, which would break down complex phenomena into smaller units to be studied separately, and holism, which emphasizes the study of complex systems as integrated wholes. A consistent holistic approach has so far led to the notion of cancer as a special organ, stimulating debate about its function and evolutionary significance. This article discusses the role of cancer as a mechanism of purifying selection of the gene pool, the correlation between hereditary and sporadic cancer, the cancer interactome, and the role of metastasis in a lethal outcome. It is also proposed that neutralizing the cancer interactome may be a novel treatment strategy.
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Affiliation(s)
- Anatoly V Lichtenstein
- N. N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of the Russian Federation, Moscow, 115478, Russia.
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Wang D, Song X, Zhu X, Yan L, Zhi X, Yan J, Liang H, Qiao J. Outcomes and the effect of PGT-M in women with hormone-related hereditary tumor syndrome. Front Oncol 2024; 14:1378019. [PMID: 38800375 PMCID: PMC11127562 DOI: 10.3389/fonc.2024.1378019] [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: 01/29/2024] [Accepted: 04/25/2024] [Indexed: 05/29/2024] Open
Abstract
Purpose To review the outcome of PGT-M in hormone-related hereditary tumor syndrome and evaluate the effect of ovarian induction on tumor growth in those patients. Methods Medical records of PGT-M were retrospectively analyzed in patients with hormone-related heritage tumors in our reproductive center. A total of eleven women with hereditary breast and ovarian cancer (HBOC) (including BRCA1/2 mutation carriers), and Lynch syndrome (including MMR gene mutation carriers) were included. Thirteen IVF/PGT-M cycles were performed. Eleven for PGT-M and two for fertility preservation. The ovulation protocol, numbers of oocytes retrieved and two pronuclei (2PN) zygotes, PGT-M results, and clinical outcomes were analyzed. Tumor progression was also estimated by comparing transvaginal ultrasound (TVS), MR, CT, or colonoscopy according to the follow-up requirements of different tumors. Results Eleven IVF/PGT-M cycles were performed with an antagonist protocol; Two cycles were performed with a mild stimulation protocol. The total dose of gonadotropin (Gn) was 1827 IU per patient (range from 1200 to 2625 IU). The median number of oocytes retrieved was 13 (range from 4 to 30), and the median number of 2PN zygotes was 8 (range from 2 to 16). A total of 32 embryos underwent PGT-M, and 9 (28.1%) embryos were suitable for transfer. Six transfer cycles were performed, and 5 cycles got clinical pregnancy (83%) with five newborns (83%). The follow-up examinations conducted 10-18 months after PGT-M/delivery revealed no new lesions or tumor progression. Conclusion PGT-M results can provide important information for improving the consultation of hormone-related heritage tumor patients regarding their fertility preservation and reproductive options. Ovarian induction for women with hormone-related hereditary tumor syndrome is not associated with tumor progression.
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Affiliation(s)
- Dingran Wang
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Xueling Song
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Xiaohui Zhu
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Liying Yan
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Xu Zhi
- Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Jie Yan
- Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
| | - Huamao Liang
- Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
| | - Jie Qiao
- Beijing Advanced Innovation Center for Genomics, Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Peking University Third Hospital, Beijing, China
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Norouzi M, Shafiei M, Abdollahi Z, Miar P, Galehdari H, Emami MH, Zeinalian M, Tabatabaiefar MA. WRN Germline Mutation Is the Likely Inherited Etiology of Various Cancer Types in One Iranian Family. Front Oncol 2021; 11:648649. [PMID: 34164337 PMCID: PMC8215443 DOI: 10.3389/fonc.2021.648649] [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: 01/01/2021] [Accepted: 05/05/2021] [Indexed: 11/15/2022] Open
Abstract
Background Familial cancers comprise a considerable distribution of colorectal cancers (CRCs), of which only about 5% occurs through well-established hereditary syndromes. It has been demonstrated that deleterious variants at the newly identified cancer-predisposing genes could describe the etiology of undefined familial cancers. Methods The present study aimed to identify the genetic etiology in a 32-year-old man with early onset familial CRC employing several molecular diagnostic techniques. DNA was extracted from tumoral and normal formalin-fixed-paraffin-embedded (FFPE) blocks, and microsatellite instability (MSI) was evaluated. Immunohistochemistry staining of MMR proteins was performed on tumoral FFPE blocks. Next-generation sequencing (NGS), multiplex ligation-dependent amplification (MLPA) assay, and Sanger sequencing were applied on the genomic DNA extracted from peripheral blood. Data analysis was performed using bioinformatics tools. Genetic variants interpretation was based on ACMG. Results MSI analysis indicated MSI-H phenotype, and IHC staining proved no expressions of MSH2 and MSH6 proteins. MLPA and NGS data showed no pathogenic variants in MMR genes. Further analysis of NGS data revealed a candidate WRN frameshift variant (p.R389Efs*3), which was validated with Sanger sequencing. The variant was interpreted as pathogenic since it met the criteria based on the ACMG guideline including very strong (PVS1), strong (PS3), and moderate (PM2). Conclusion WRN is a DNA helicase participating in DNA repair pathways to sustain genomic stability. WRN deficient function may contribute to CRC development that is valuable for further investigation as a candidate gene in hereditary cancer syndrome diagnosis.
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Affiliation(s)
- Mahnaz Norouzi
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohammad Shafiei
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Zeinab Abdollahi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Paniz Miar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Galehdari
- Department of Biology, Faculty of Sciences, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mohammad Hasan Emami
- Department of Gastroenterology, Poursina Hakim Digestive Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrdad Zeinalian
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
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Madsen T, Braun D, Peng G, Parmigiani G, Trippa L. Efficient computation of the joint probability of multiple inherited risk alleles from pedigree data. Genet Epidemiol 2018; 42:528-538. [PMID: 29943416 PMCID: PMC6129424 DOI: 10.1002/gepi.22130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/19/2018] [Accepted: 04/30/2018] [Indexed: 12/20/2022]
Abstract
The Elston-Stewart peeling algorithm enables estimation of an individual's probability of harboring germline risk alleles based on pedigree data, and serves as the computational backbone of important genetic counseling tools. However, it remains limited to the analysis of risk alleles at a small number of genetic loci because its computing time grows exponentially with the number of loci considered. We propose a novel, approximate version of this algorithm, dubbed the peeling and paring algorithm, which scales polynomially in the number of loci. This allows extending peeling-based models to include many genetic loci. The algorithm creates a trade-off between accuracy and speed, and allows the user to control this trade-off. We provide exact bounds on the approximation error and evaluate it in realistic simulations. Results show that the loss of accuracy due to the approximation is negligible in important applications. This algorithm will improve genetic counseling tools by increasing the number of pathogenic risk alleles that can be addressed. To illustrate we create an extended five genes version of BRCAPRO, a widely used model for estimating the carrier probabilities of BRCA1 and BRCA2 risk alleles and assess its computational properties.
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Affiliation(s)
- Thomas Madsen
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Danielle Braun
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Gang Peng
- Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut
| | - Giovanni Parmigiani
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Lorenzo Trippa
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
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Moufid FZ, Bouguenouch L, El Bouchikhi I, Chbani L, Iraqui Houssaini M, Sekal M, Belhassan K, Bennani B, Ouldim K. The First Molecular Screening of MLH1 and MSH2 Genes in Moroccan Colorectal Cancer Patients Shows a Relatively High Mutational Prevalence. Genet Test Mol Biomarkers 2018; 22:492-497. [PMID: 30044143 DOI: 10.1089/gtmb.2018.0067] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
INTRODUCTION Lynch syndrome (LS) is an autosomal dominant disorder characterized by early age of onset and increased risk of developing extracolonic tumors. Molecular diagnosis of LS requires identification of germline mutations in one of the Mismatch Repair (MMR) genes. AIM The objective of the study was to investigate the prevalence of MLH1/MSH2 mutation carriers among Moroccan patients with colorectal cancer (CRC) in a hospital-based cohort. METHODS In this study, 214 CRC patients from COLORECFez cohort were included. Patients whose tumors showed MMR deficiency (MMR-D) and wild-type BRAF were selected to undergo mutational analysis of the MLH1 and MSH2 genes using Sanger sequencing. RESULTS A total of 24 MMR-D tumors were identified (11.2%) among 214 CRC tested for MMR protein expression. The BRAF p.Val600Glu mutation was absent in all tumors deficient for MLH1 protein. Molecular screening showed germline MMR mutations (MLH1/MSH2) in four cases, two of which fulfilled Amsterdam criteria II and two met at least one of the revised Bethesda guidelines. The estimated frequency of MLH1/MSH2 mutations in Moroccan CRC patients was 1.87%. CONCLUSIONS The present study reports a relatively high incidence of MLH1/MSH2 (1.87%). These results confirm the contribution of MMR genes to CRC susceptibility in our population and provide evidence regarding the requirement of implementing a national screening program for LS in Morocco.
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Affiliation(s)
- Fatima Zahra Moufid
- 1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco .,2 Microbial Biotechnology Laboratory, Faculté des Sciences et Techniques, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
| | - Laila Bouguenouch
- 1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco .,3 Laboratory of Biomedical and Translational Research, Faculté 3de Médecine et de Pharmacie de Fès, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
| | - Ihssane El Bouchikhi
- 1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco .,2 Microbial Biotechnology Laboratory, Faculté des Sciences et Techniques, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
| | - Laila Chbani
- 3 Laboratory of Biomedical and Translational Research, Faculté 3de Médecine et de Pharmacie de Fès, Université Sidi Mohammed Ben Abdellah , Fez, Morocco .,4 Pathological Anatomy and Molecular Pathology Service, Hassan II University Hospital , Fez, Morocco
| | - Mohamed Iraqui Houssaini
- 2 Microbial Biotechnology Laboratory, Faculté des Sciences et Techniques, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
| | - Mohamed Sekal
- 4 Pathological Anatomy and Molecular Pathology Service, Hassan II University Hospital , Fez, Morocco
| | - Khadija Belhassan
- 1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco
| | - Bahia Bennani
- 5 Microbiology and Molecular Biology Laboratory, Microorganisms Team, Genomics and Oncogene Factors, Faculté de Médecine et de Pharmacie de Fès, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
| | - Karim Ouldim
- 1 Department of Medical Genetics and Oncogenetics, Centre Hospitalier Hassam II , Fez, Morocco .,3 Laboratory of Biomedical and Translational Research, Faculté 3de Médecine et de Pharmacie de Fès, Université Sidi Mohammed Ben Abdellah , Fez, Morocco
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Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials. Dis Colon Rectum 2018. [PMID: 29521828 DOI: 10.1097/dcr.0000000000001022] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.
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Maletzki C, Gladbach YS, Hamed M, Fuellen G, Semmler ML, Stenzel J, Linnebacher M. Cellular vaccination of MLH1 -/- mice - an immunotherapeutic proof of concept study. Oncoimmunology 2017; 7:e1408748. [PMID: 29399413 DOI: 10.1080/2162402x.2017.1408748] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 11/16/2017] [Accepted: 11/18/2017] [Indexed: 02/08/2023] Open
Abstract
Mismatch-repair deficiency (MMR-D) is closely linked to hypermutation and accordingly, high immunogenicity. MMR-D-related tumors thus constitute ideal vaccination targets for both therapeutic and prophylactic approaches. Herein, the prophylactic and therapeutic impact of a cellular vaccine on tumor growth and tumor-immune microenvironment was studied in a murine MLH1-/- knockout mouse model. Prophylactic application of the lysate (+/- CpG ODN 1826) delayed tumor development, accompanied by increased levels of circulating T cell numbers. Therapeutic application of the vaccine prolonged overall survival (median time: 11.5 (lysate) and 12 weeks (lysate + CpG ODN) vs. 3 weeks (control group), respectively) along with reduced tumor burden, as confirmed by PET/CT imaging and immune stimulation (increased CD3+CD8+ T - and NK cell numbers, reduced levels of TIM-3+ cells in both treatment groups). Coding microsatellite analysis of MMR-D-related target genes revealed increased mutational load upon vaccination (total mutation frequency within 28 genes: 28.6% vaccine groups vs. 14.9% control group, respectively). Reactive immune cells recognized autologous tumor cells, but also NK cells target YAC-1 in IFNγ ELISpot and, even more importantly, in functional kill assays. Assessment of tumor microenvironment revealed infiltration of CD8+ T-cells and granulocytes, but also upregulation of immune checkpoint molecules (LAG-3, PD-L1). The present study is the first reporting in vivo results on a therapeutic cellular MMR-D vaccine. Vaccination-induced prolonged survival was achieved in a clinically-relevant mouse model for MMR-D-related diseases by long-term impairment of tumor growth and this could be attributed to re-activated immune responses.
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Affiliation(s)
- Claudia Maletzki
- Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany
| | - Yvonne Saara Gladbach
- Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany
| | - Mohamed Hamed
- Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany
| | - Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research - IBIMA Rostock University Medical Center, Rostock, Germany
| | - Marie-Luise Semmler
- Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany
| | - Jan Stenzel
- Core Facility Multimodal Small Animal Imaging, Rostock University Medical Center, Rostock, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Rostock, Germany
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Cohn EG, Hamilton N, Larson EL, Williams JK. Self-reported race and ethnicity of US biobank participants compared to the US Census. J Community Genet 2017; 8:229-238. [PMID: 28623623 PMCID: PMC5496846 DOI: 10.1007/s12687-017-0308-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 05/11/2017] [Indexed: 12/17/2022] Open
Abstract
Precision medicine envisions a future of effective diagnosis, treatment, and prevention grounded in precise understandings of the genetic and environmental determinants of disease. Given that the original genome-wide association studies represented a predominately European White population, and that diversity in genomic studies must account for genetic variation both within and across racial categories, new research studies are at a heightened risk for inadequate representation. Currently biological samples are being made available for sequencing in biobanks across the USA, but the diversity of those samples is unknown. The aims of this study were to describe the types of recruitment and enrollment materials used by US biobanks and the diversity of the samples contained within their collection. Biobank websites and brochures were evaluated for reading level, health literacy, and factors known to encourage the recruitment of minorities, such as showing pictures of diverse populations. Biobank managers were surveyed by mail on the methods and materials used for enrollment, recruitment, consent, and the self-reported race/ethnicity of biobank participants. From 51 US biobanks (68% response rate), recruitment and enrollment materials were in English only, and most of the websites and brochures exceeded a fifth-grade reading level. When compared to the 2015 US Census, self-reported race/ethnicity of participants was not significantly different for Whites (61%) and blacks (13%). The percentages were significantly lower for Hispanics and Latinos (18 vs. 7%, p = 0.00) and Hawaiian/Pacific Islanders (0.2 vs. 0.01%; p = 0.01) and higher for Asians (13 vs. 5%, p = 0.01). Materials for recruitment predominantly in English may limit participation by underrepresented populations.
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Affiliation(s)
- Elizabeth Gross Cohn
- School of Nursing, Columbia University, New York, NY, USA.
- Adelphi University, Garden City, NY, USA.
| | - Nalo Hamilton
- School of Nursing, University of California, Los Angeles, Los Angeles, CA, USA
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Liccardo R, De Rosa M, Rossi GB, Carlomagno N, Izzo P, Duraturo F. Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome. Int J Mol Sci 2017; 18:ijms18050999. [PMID: 28481244 PMCID: PMC5454912 DOI: 10.3390/ijms18050999] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 04/21/2017] [Accepted: 05/02/2017] [Indexed: 12/23/2022] Open
Abstract
Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.
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Affiliation(s)
- Raffaella Liccardo
- Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy.
| | - Marina De Rosa
- Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy.
| | - Giovanni Battista Rossi
- Endoscopy Unit, Fondazione Pascale National Institute for Study and Care of Tumors, 80131 Naples, Italy.
| | - Nicola Carlomagno
- General Surgery Unit-Advanced Biomedical Science Department, Federico II University Medical School, 80131 Naples, Italy.
| | - Paola Izzo
- Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy.
- CEINGE-Biotecnologie Avanzate, 80145 Naples, Italy.
| | - Francesca Duraturo
- Department of Molecular Medicine and Medical Biotechnology, Federico II University Medical School, 80131 Naples, Italy.
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Halpern N, Goldberg Y, Kadouri L, Duvdevani M, Hamburger T, Peretz T, Hubert A. Clinical course and outcome of patients with high-level microsatellite instability cancers in a real-life setting: a retrospective analysis. Onco Targets Ther 2017; 10:1889-1896. [PMID: 28408840 PMCID: PMC5384685 DOI: 10.2147/ott.s126905] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND The prognostic and predictive significance of the high-level microsatellite instability (MSI-H) phenotype in various malignancies is unclear. We describe the characteristics, clinical course, and outcomes of patients with MSI-H malignancies treated in a real-life hospital setting. PATIENTS AND METHODS A retrospective analysis of MSI-H cancer patient files was conducted. We analyzed the genetic data, clinical characteristics, and oncological treatments, including chemotherapy and surgical interventions. RESULTS Clinical data of 73 MSI-H cancer patients were available. Mean age at diagnosis of first malignancy was 52.3 years. Eight patients (11%) had more than four malignancies each. Most patients (76%) had colorectal cancer (CRC). Seventeen patients (23%) had only extracolonic malignancies. Eighteen women (36%) had gynecological malignancy. Nine women (18%) had breast cancer. Mean follow-up was 8.5 years. Five-year overall survival and disease-free survival of all MSI-H cancer patients from first malignancy were 86% and 74.6%, respectively. Five-year overall survival rates of stage 2, 3, and 4 MSI-H CRC patients were 89.5%, 58.4%, and 22.9%, respectively. CONCLUSION Although the overall prognosis of MSI-H cancer patients is favorable, this advantage may not be maintained in advanced MSI-H CRC patients.
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Affiliation(s)
- Naama Halpern
- Institute of Oncology, The Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Yael Goldberg
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Luna Kadouri
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Morasha Duvdevani
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Tamar Hamburger
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Tamar Peretz
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
| | - Ayala Hubert
- Sharett Institute of Oncology, Hadassah Medical Center, Hebrew University, Jerusalem, Israel
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11
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Novel Implications in Molecular Diagnosis of Lynch Syndrome. Gastroenterol Res Pract 2017; 2017:2595098. [PMID: 28250766 PMCID: PMC5303590 DOI: 10.1155/2017/2595098] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 01/05/2017] [Indexed: 02/07/2023] Open
Abstract
About 10% of total colorectal cancers are associated with known Mendelian inheritance, as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). In these cancer types the clinical manifestations of disease are due to mutations in high-risk alleles, with a penetrance at least of 70%. The LS is associated with germline mutations in the DNA mismatch repair (MMR) genes. However, the mutation detection analysis of these genes does not always provide informative results for genetic counseling of LS patients. Very often, the molecular analysis reveals the presence of variants of unknown significance (VUSs) whose interpretation is not easy and requires the combination of different analytical strategies to get a proper assessment of their pathogenicity. In some cases, these VUSs may make a more substantial overall contribution to cancer risk than the well-assessed severe Mendelian variants. Moreover, it could also be possible that the simultaneous presence of these genetic variants in several MMR genes that behave as low risk alleles might contribute in a cooperative manner to increase the risk of hereditary cancer. In this paper, through a review of the recent literature, we have speculated a novel inheritance model in the Lynch syndrome; this could pave the way toward new diagnostic perspectives.
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12
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Shenoy S. Genetic risks and familial associations of small bowel carcinoma. World J Gastrointest Oncol 2016; 8:509-519. [PMID: 27326320 PMCID: PMC4909452 DOI: 10.4251/wjgo.v8.i6.509] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/02/2016] [Accepted: 03/14/2016] [Indexed: 02/05/2023] Open
Abstract
Adenocarcinoma of small intestines (SBA) is a relatively rare malignancy with poor outcomes due to delayed diagnosis. Fifty percent of patients have metastases on presentation and therefore early detection and treatment offers the best long term outcomes. Certain genetic polyposis syndromes and familial diseases are associated with increased risks for SBA. These include familial adenomatous polyposis (FAP), Lynch syndromes (LS), Juvenile polyposis syndrome, Peutz-Jeghers syndrome, Crohn's disease (CD) and celiac disease. Mutations in APC gene, Mismatch repair genes, STK11 gene, and SMAD4 gene have been implicated for the genetic diseases respectively. While there are no specific inherited genetic mutations for CD, genome-wide association studies have established over 140 loci associated with CD. CpG island mutations with defects in mismatch repair genes have been identified in celiac disease. Significant diagnostic advances have occurred in the past decade and intuitively, it would seem beneficial to use these advanced modalities for surveillance of these patients. At present it is debatable and no clear data exists to support this approach except for established guidelines to diagnose duodenal polyps in FAP, and LS. Here we discuss the genetic alterations, cancer risks, signaling mechanisms and briefly touch the surveillance modalities available for these genetic and clinical syndromes. English language articles from PubMed/Medline and Embase was searched were collected using the phrases "small-bowel adenocarcinoma, genetics, surveillance, familial adenomatous polyposis, lynch syndromes, Peutz-Jeghers syndrome, juvenile polyposis syndrome, CD and celiac disease". Figures, tables and schematic diagram to illustrate pathways are included in the review.
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Granato T, Manganaro L, Petri L, Porpora MG, Viggiani V, Angeloni A, Anastasi E. Low 25-OH vitamin D levels at time of diagnosis and recurrence of ovarian cancer. Tumour Biol 2015; 37:2177-81. [PMID: 26349750 DOI: 10.1007/s13277-015-4055-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Accepted: 09/02/2015] [Indexed: 10/23/2022] Open
Abstract
The objective of this study was to evaluate the correlation between 25-OH vitamin D and ovarian cancer as a diagnostic marker or recurrence disease marker. We studied the following: (1) 61 women without gynecologic diseases, (2) 45 women affected by benign ovarian disease, (3) 46 women with recent diagnosis of ovarian cancer, (4) 26 follow-up women with recurrent ovarian cancer, and (5) 32 follow-up women with stable ovarian cancer. The 25-OH vitamin D was quantified with LUMIPULSE® G 25-OH vitamin D on LUMIPULSE® G 1200 (Fujirebio, Japan). As a threshold value, identified by ROC curve analysis, 20.2 ng/mL (sensitivity 73.3 %, specificity 84 %) was chosen corresponding to the limit between sufficient and insufficient 25-OH vitamin D according to the WHO. Low 25-OH vitamin D levels were observed in 26 % of women without gynecologic diseases, in 80 % of women with recent diagnosis of ovarian cancer and in 24 % women affected by benign ovarian diseases (p < 0.001). The follow-up study showed an insufficient level of 25-OH vitamin D in 73 % women with recurrent ovarian cancer and in 47 % women with stable ovarian cancer (p < 0.0003). This study showed that patients with ovarian cancer are often insufficient in 25-OH vitamin D compared to women with benign ovarian diseases. The women with recurrent ovarian cancer presented more often low levels compared to women with stable ovarian cancer. This study suggests that 25-OH vitamin D, due to its antiproliferative properties, can be a good marker for ovarian cancer also.
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Affiliation(s)
- Teresa Granato
- CNR-IBPM, National Research Council, Viale Regina Elena 324, 00161, Rome, Italy
| | - Lucia Manganaro
- Department of Radiological, Oncological, and Pathological Sciences, "Sapienza" University of Rome, Rome, Italy
| | - Luca Petri
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Maria Grazia Porpora
- Department of Gynecology, Obstetrics and Urology, "Sapienza" University of Rome, Rome, Italy
| | - Valentina Viggiani
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Antonio Angeloni
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy
| | - Emanuela Anastasi
- Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.
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Bruno W, Fornarini G, Ghiorzo P. Signs and genetics of rare cancer syndromes with gastroenterological features. World J Gastroenterol 2015; 21:8985-8993. [PMID: 26290627 PMCID: PMC4533032 DOI: 10.3748/wjg.v21.i30.8985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/26/2015] [Accepted: 07/15/2015] [Indexed: 02/07/2023] Open
Abstract
Although the genetic bases of most hereditary cancer syndromes are known, and genetic tests are available for them, the incidence of the most rare of these syndromes is likely underestimated, partially because the clinical expression is neither fully understood nor easily diagnosed due to the variable and complex expressivity. The clinical features of a small pool of rare cancer syndromes include gastroenterological signs, though not necessarily tumors, that could require the intervention of a gastroenterologist during any of the phases of the clinical management. Herein we will attempt to spread the knowledge on these rare syndromes by summarizing the phenotype and genetic basis, and revising the peculiar gastroenterological signs whose underlying role in these rare hereditary cancer syndromes is often neglected. Close collaboration between geneticists and gastroenterologists could facilitate both the early identification of patients or relatives at-risk and the planning of multidisciplinary and tailored management of these subjects.
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Dashti SG, Chau R, Ouakrim DA, Buchanan DD, Clendenning M, Young JP, Winship IM, Arnold J, Ahnen DJ, Haile RW, Casey G, Gallinger S, Thibodeau SN, Lindor NM, Le Marchand L, Newcomb PA, Potter JD, Baron JA, Hopper JL, Jenkins MA, Win AK. Female Hormonal Factors and the Risk of Endometrial Cancer in Lynch Syndrome. JAMA 2015; 314:61-71. [PMID: 26151267 PMCID: PMC4688894 DOI: 10.1001/jama.2015.6789] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
IMPORTANCE Apart from hysterectomy, there is no consensus recommendation for reducing endometrial cancer risk for women with a mismatch repair gene mutation (Lynch syndrome). OBJECTIVE To investigate the association between hormonal factors and endometrial cancer risk in Lynch syndrome. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study included 1128 women with a mismatch repair gene mutation identified from the Colon Cancer Family Registry. Data were analyzed with a weighted cohort approach. Participants were recruited between 1997 and 2012 from centers across the United States, Australia, Canada, and New Zealand. EXPOSURES Age at menarche, first and last live birth, and menopause; number of live births; hormonal contraceptive use; and postmenopausal hormone use. MAIN OUTCOMES AND MEASURES Self-reported diagnosis of endometrial cancer. RESULTS Endometrial cancer was diagnosed in 133 women (incidence rate per 100 person-years, 0.29; 95% CI, 0.24 to 0.34). Endometrial cancer was diagnosed in 11% (n = 70) of women with age at menarche greater than or equal to 13 years compared with 12.6% (n = 57) of women with age at menarche less than 13 years (incidence rate per 100 person-years, 0.27 vs 0.31; rate difference, -0.04 [95% CI, -0.15 to 0.05]; hazard ratio per year, 0.85 [95% CI, 0.73 to 0.99]; P = .04). Endometrial cancer was diagnosed in 10.8% (n = 88) of parous women compared with 14.4% (n = 40) of nulliparous women (incidence rate per 100 person-years, 0.25 vs 0.43; rate difference, -0.18 [95% CI, -0.32 to -0.04]; hazard ratio, 0.21 [95% CI, 0.10 to 0.42]; P < .001). Endometrial cancer was diagnosed in 8.7% (n = 70) of women who used hormonal contraceptives greater than or equal to 1 year compared with 19.2% (n = 57) of women who used contraceptives less than 1 year (incidence rate per 100 person-years, 0.22 vs 0.45; rate difference, -0.23 [95% CI, -0.36 to -0.11]; hazard ratio, 0.39 [95% CI, 0.23 to 0.64]; P < .001). There was no statistically significant association between endometrial cancer and age at first and last live birth, age at menopause, and postmenopausal hormone use. CONCLUSIONS AND RELEVANCE For women with a mismatch repair gene mutation, some endogenous and exogenous hormonal factors were associated with a lower risk of endometrial cancer. These directions and strengths of associations were similar to those for the general population. If replicated, these findings suggest that women with a mismatch repair gene mutation may be counseled like the general population in regard to hormonal influences on endometrial cancer risk.
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Affiliation(s)
- Seyedeh Ghazaleh Dashti
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Rowena Chau
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Driss Ait Ouakrim
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Daniel D. Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark Clendenning
- Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Joanne P. Young
- Departments of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
- SAHMRI Colorectal Node, Basil Hetzel Institute for Translational Research, Woodville, South Australia, Australia
- School of Medicine, University of Adelaide, South Australia, Australia
| | - Ingrid M. Winship
- Department of Medicine, The University of Melbourne, Parkville, VIC 3010, Australia
- Genetic Medicine, The Royal Melbourne Hospital, Parkville, VIC 3010, Australia
| | - Julie Arnold
- New Zealand Familial Gastrointestinal Cancer Service, Auckland, New Zealand
| | - Dennis J. Ahnen
- Department of Medicine, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Robert W. Haile
- Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, California, USA
| | - Graham Casey
- Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, USA
| | - Steven Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Stephen N. Thibodeau
- Molecular Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Noralane M. Lindor
- Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, Arizona, USA
| | | | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, Washington, USA
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- School of Public Health, University of Washington, Seattle, Washington, USA
- Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - John A. Baron
- Department of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Department of Epidemiology and Institute of Health and Environment, School of Public Health, Seoul National University, Seoul, Korea
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Corresponding author: Aung Ko Win, PhD, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Level 3, 207 Bouverie Street, The University of Melbourne VIC 3010, Australia, Phone: +61 3 9035 8238 Fax: +61 3 9349 5815,
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Granato T, Porpora MG, Longo F, Angeloni A, Manganaro L, Anastasi E. HE4 in the differential diagnosis of ovarian masses. Clin Chim Acta 2015; 446:147-55. [PMID: 25892674 DOI: 10.1016/j.cca.2015.03.047] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 02/25/2015] [Accepted: 03/09/2015] [Indexed: 12/12/2022]
Abstract
Ovarian masses, a common finding among pre- and post-menopausal women, can be benign or malignant. Ovarian cancer is the leading cause of death from gynecologic malignancy among women living in industrialized countries. According to the current guidelines, measurement of CA125 tumor marker remains the gold standard in the management of ovarian cancer. Recently, HE4 has been proposed as emerging biomarker in the differential diagnosis of adnexal masses and in the early diagnosis of ovarian cancer. Discrimination of benign and malignant ovarian tumors is very important for correct patient referral to institutions specialized in care and management of ovarian cancer. Tumor markers CA125 and HE4 are currently incorporated into the "Risk of Ovarian Malignancy Algorithm" (ROMA) with menopausal status for discerning malignant from benign pelvic masses. The availability of a good biomarker such as HE4, closely associated with the differential and early diagnosis of ovarian cancer, could reduce medical costs related to more expensive diagnostic procedures. Finally, it is important to note that HE4 identifies platinum non-responders thus enabling a switch to second line chemotherapy and improved survival.
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Affiliation(s)
- Teresa Granato
- CNR-IBPM, National Research Council, Viale Regina Elena 324, 00161 Rome, Italy
| | - Maria Grazia Porpora
- Department of Gynaecology, Obstetrics and Urology, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy
| | - Flavia Longo
- Department of Molecular Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy
| | - Antonio Angeloni
- Department of Molecular Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy
| | - Lucia Manganaro
- Department of Radiology, "Sapienza", University of Rome, Viale Regina Elena 324, 00161 Roma, Italy
| | - Emanuela Anastasi
- Department of Molecular Medicine, "Sapienza" University of Rome, Policlinico Umberto I, Viale Regina Elena 324, 00161 Rome, Italy.
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Shia J. Evolving approach and clinical significance of detecting DNA mismatch repair deficiency in colorectal carcinoma. Semin Diagn Pathol 2015; 32:352-61. [PMID: 25716099 DOI: 10.1053/j.semdp.2015.02.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The last two decades have seen significant advancement in our understanding of colorectal tumors with DNA mismatch repair (MMR) deficiency. The ever-emerging revelations of new molecular and genetic alterations in various clinical conditions have necessitated constant refinement of disease terminology and classification. Thus, a case with the clinical condition of hereditary non-polyposis colorectal cancer as defined by the Amsterdam criteria may be one of Lynch syndrome characterized by a germline defect in one of the several MMR genes, one of the yet-to-be-defined "Lynch-like syndrome" if there is evidence of MMR deficiency in the tumor but no detectable germline MMR defect or tumor MLH1 promoter methylation, or "familial colorectal cancer type X" if there is no evidence of MMR deficiency. The detection of these conditions carries significant clinical implications. The detection tools and strategies are constantly evolving. The Bethesda guidelines symbolize a selective approach that uses clinical information and tumor histology as the basis to select high-risk individuals. Such a selective approach has subsequently been found to have limited sensitivity, and is thus gradually giving way to the alternative universal approach that tests all newly diagnosed colorectal cancers. Notably, the universal approach also has its own limitations; its cost-effectiveness in real practice, in particular, remains to be determined. Meanwhile, technological advances such as the next-generation sequencing are offering the promise of direct genetic testing for MMR deficiency at an affordable cost probably in the near future. This article reviews the up-to-date molecular definitions of the various conditions related to MMR deficiency, and discusses the tools and strategies that have been used in detecting these conditions. Special emphasis will be placed on the evolving nature and the clinical importance of the disease definitions and the detection strategies.
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Affiliation(s)
- Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, New York 10065.
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Chirurgie annexielle prophylactique des femmes à risque héréditaire : vers de nouvelles pistes ? ONCOLOGIE 2014. [DOI: 10.1007/s10269-014-2451-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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