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Pinto C, Pinheiro M, Peixoto A, Santos C, Veiga I, Rocha P, Pinto P, Lopes P, Baptista M, Henrique R, Teixeira MR. Co-occurrence of nonsense mutations in MSH6 and MSH2 in Lynch syndrome families evidencing that not all truncating mutations are equal. J Hum Genet 2015; 61:151-6. [DOI: 10.1038/jhg.2015.124] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 07/30/2015] [Accepted: 09/11/2015] [Indexed: 11/09/2022]
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Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer. Fam Cancer 2015; 13:109-19. [PMID: 24061861 DOI: 10.1007/s10689-013-9683-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Mismatch repair proficient hereditary non-polyposis colorectal cancer (MSS-HNPCC) encloses a heterogeneous group of families consisting of different unknown genetic syndromes and/or aggregations cases. The lack of information about the hereditability of cancer risk in these families makes it difficult to carry out an individualized Genetic Counseling. Therefore, deep description of such families becomes important for a better classification and search for underlying susceptibility causes. The aim of this study is to describe and compare the clinical, morphological features, tumor KRAS status and overall survival in MSS-HNPCC, Lynch and sporadic colorectal cancer. A total of 37 MSS-HNPCC families, 50 Lynch families and 612 sporadic CRC were included. Clinical and morphological data were evaluated by reviewing medical and pathology reports of 55, 69 and 102 tumors respectively. KRAS/BRAF status were detected by allele specific real-time PCR. Standardized incidence ratios (SIR) were calculated among 602 MSS-HNPCC relatives and 668 Lynch relatives. Main features distinguishing MSS-HNPCC were diagnosis age (55.1 ± 12.6), preferential distal location (76%), polyp detection (45%) and familial colorectal cancer incidence (SIR = 6.6). In addition, we found increased incidences rates for kidney, stomach and uterus tumors. KRAS mutation rates were similar in the study populations (48.8 ± 5.8) but higher than those described before by Sanger sequencing. MSS-HNPCC overall survival was similar to Lynch in B Dukes' stage tumors and between Lynch and sporadic in C stage tumors. Anatomical and morphological data of MSS-HNPCC are consistent with other described populations. Our studies disclose an increased HNPCC-extracolonic tumors incidence and improved overall survival in MSS-HNPCC families.
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Garre P, Martín L, Sanz J, Romero A, Tosar A, Bando I, Llovet P, Diaque P, García-Paredes B, Díaz-Rubio E, de la Hoya M, Caldés T. BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X. Clin Genet 2014; 87:582-7. [PMID: 24814045 DOI: 10.1111/cge.12427] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 05/09/2014] [Accepted: 05/09/2014] [Indexed: 01/19/2023]
Abstract
Familial colorectal cancer type X (FCCX) encompasses a group of families with dominant inheritance pattern of colorectal cancer (CRC) but no alteration in any known CRC susceptibility gene. Therefore, the explanation of their susceptibility is a priority to offer an accurate genetic counseling. We screened the 27 coding exons and exon-intron boundaries of BRCA2 in 48 FCCX probands. We identified 29 variants including a frameshift mutation. Deleterious variant c.3847_3848delGT p.(Val1283Lysfs*2) showed cosegregation with disease as well as loss of heterozygosity (LOH) in CRC tumor DNA. This is the first evidence of germline BRCA2 pathogenic mutation associated with CRC risk. Furthermore, missense variants c.502C>A p.(Pro168Thr), c.5744C>T p.(Thr1915Met) and c.7759C>T p.(Leu2587Phe) were proposed as candidate risk alleles based on cosegregation, LOH tumor analysis and in silico testing.
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Affiliation(s)
- P Garre
- Laboratorio de Oncología Molecular, Hospital Clínico San Carlos, IdISSC, Madrid, Spain
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Petersen SM, Dandanell M, Rasmussen LJ, Gerdes AM, Krogh LN, Bernstein I, Okkels H, Wikman F, Nielsen FC, Hansen TVO. Functional examination of MLH1, MSH2, and MSH6 intronic mutations identified in Danish colorectal cancer patients. BMC MEDICAL GENETICS 2013; 14:103. [PMID: 24090359 PMCID: PMC3850734 DOI: 10.1186/1471-2350-14-103] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 09/25/2013] [Indexed: 12/12/2022]
Abstract
Background Germ-line mutations in the DNA mismatch repair genes MLH1, MSH2, and MSH6 predispose to the development of colorectal cancer (Lynch syndrome or hereditary nonpolyposis colorectal cancer). These mutations include disease-causing frame-shift, nonsense, and splicing mutations as well as large genomic rearrangements. However, a large number of mutations, including missense, silent, and intronic variants, are classified as variants of unknown clinical significance. Methods Intronic MLH1, MSH2, or MSH6 variants were investigated using in silico prediction tools and mini-gene assay to asses the effect on splicing. Results We describe in silico and in vitro characterization of nine intronic MLH1, MSH2, or MSH6 mutations identified in Danish colorectal cancer patients, of which four mutations are novel. The analysis revealed aberrant splicing of five mutations (MLH1 c.588 + 5G > A, MLH1 c.677 + 3A > T, MLH1 c.1732-2A > T, MSH2 c.1276 + 1G > T, and MSH2 c.1662-2A > C), while four mutations had no effect on splicing compared to wild type (MLH1 c.117-34A > T, MLH1 c.1039-8 T > A, MSH2 c.2459-18delT, and MSH6 c.3439-16C > T). Conclusions In conclusion, we classify five MLH1/MSH2 mutations as pathogenic, whereas four MLH1/MSH2/MSH6 mutations are classified as neutral. This study supports the notion that in silico prediction tools and mini-gene assays are important for the classification of intronic variants, and thereby crucial for the genetic counseling of patients and their family members.
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Affiliation(s)
- Sanne M Petersen
- Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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Frequency and variability of genomic rearrangements on MSH2 in Spanish Lynch Syndrome families. PLoS One 2013; 8:e72195. [PMID: 24039744 PMCID: PMC3770653 DOI: 10.1371/journal.pone.0072195] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2013] [Accepted: 07/06/2013] [Indexed: 11/29/2022] Open
Abstract
Large genomic rearrangements (LGRs) in DNA-mismatch-repair (MMR) genes, particularly among MSH2 gene, are frequently involved in the etiology of Lynch syndrome (LS). The Multiplex Ligation and Probe Amplification assay (MLPA) is commonly used to identify such alterations. However, in most cases, the MLPA-identified alteration is not characterized at the molecular level, which might be important to identify recurrent alterations and to analyze the molecular mechanisms underlying these mutational events. Probands from a cohort of Lynch Syndrome families were screened for point mutation in MMR genes, subsequently the MLPA assay was used for LGR screening. The identified MLPA alteration was confirmed by cDNA, CGH-microarrays or massive parallel sequencing. In this study, we have delimited the region of 11 LGRs variants on MSH2 locus. Six of them were fully characterized the breakpoints and 9 of them were considered pathogenic. According to our data, LGR on MSH2 locus constituted the 10.8% (9 out of 83) of pathogenic germline alterations found in LS. The frequency of colorectal cancer (CRC) and endometrial cancer (EC) in LGR carriers was 55% and 11% respectively. Analysis of the breakpoint sequences revealed that in 3 cases, deletions appeared to originate from Alu-mediated recombination events. In the remaining cases, sequence alignment failed to detect microhomology around the breakpoints. The present study provides knowledge on the molecular characterization of MSH2 LGRs, which may have important implications in LS diagnosis and Genetic Counseling. In addition, our data suggests that nonhomologous events would be more frequently involved in the etiology of MSH2 LGRs than expected.
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Abstract
Muir-Torre syndrome (MTS), a phenotypic variant of the more common hereditary nonpolyposis colorectal cancer syndrome, or Lynch syndrome, is an autosomal dominantly inherited condition that combines at least one cutaneous sebaceous neoplasm and at least one visceral malignancy. Most patients (~90%) with MTS carry mutations in the MSH2 gene; less than 10% of the cases are associated with a mutation MLH1 gene, and only 3 MTS patients with a pathogenic MSH6 mutation have been previously documented. We report a family affected with MTS in which 3 members (father and 2 sons) were found to harbor a missense mutation c.2633T>C (p.V878A) in exon 4 of the MSH6 gene.
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Pérez-Cabornero L, Infante M, Velasco E, Lastra E, Miner C, Durán M. Evaluating the effect of unclassified variants identified in MMR genes using phenotypic features, bioinformatics prediction, and RNA assays. J Mol Diagn 2013; 15:380-90. [PMID: 23523604 DOI: 10.1016/j.jmoldx.2013.02.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2012] [Revised: 01/29/2013] [Accepted: 02/01/2013] [Indexed: 11/16/2022] Open
Abstract
Lynch syndrome is caused by mutations in one of the mismatch-repair system (MMR) genes. A major difficulty in diagnosis and management of Lynch syndrome is the existence of unclassified genetic variants (UVs) with unknown clinical significance, especially mutations with new descriptions and missense-type nucleotide substitutions. We evaluated the pathogenicity of 20 such mutations (6 in MLH1, 4 in MSH2, and 7 in MSH6) found in Spanish patients suspected of Lynch syndrome. The UVs were tested for evidence of MMR defect in tumor samples and were evaluated for co-occurrence with a pathogenic mutation, the cosegregation of the variant with the disease; where sufficient data were available, in silico resources at the protein level and mRNA analysis were used to assess the putative effect on the splicing mechanism. To evaluate the frequency of these UVs in the general population, a case--control study was also performed. Five variants were identified with similar frequencies in both cases and controls, suggesting a nonpathogenic effect in patients. In contrast, abnormal splicing mutations were detected in a high proportion of patients [3/20 (15%)]. In this study, we classified 15 of the 20 UVs: six variants with strong evidence of pathogenicity and nine variants that should be considered neutral variants. Clinical significance of the other five remains unknown.
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Affiliation(s)
- Lucia Pérez-Cabornero
- Cancer Genetics Laboratory, Institute of Biology and Molecular Genetics, University of Valladolid, Valladolid, Spain
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Adonizio C, Gazzillo M, Knezetic J, Snyder C, Lynch HT, Rybak C, Hall MJ, Lowstuter K, Eggington J, Morris GJ. Thirty-Nine-Year-Old With Familial Colon Cancer, and Variant of Undetermined Significance in MSH6. Semin Oncol 2012; 39:125-31. [DOI: 10.1053/j.seminoncol.2012.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Garre P, Briceño V, Xicola RM, Doyle BJ, de la Hoya M, Sanz J, Llovet P, Pescador P, Puente J, Díaz-Rubio E, Llor X, Caldés T. Analysis of the oxidative damage repair genes NUDT1, OGG1, and MUTYH in patients from mismatch repair proficient HNPCC families (MSS-HNPCC). Clin Cancer Res 2011; 17:1701-12. [PMID: 21355073 DOI: 10.1158/1078-0432.ccr-10-2491] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
PURPOSE Several studies have described molecular differences between microsatellite stable hereditary nonpolyposis colorectal cancer (MSS-HNPCC) and microsatellite unstable Lynch syndrome tumors (MSI-HNPCC). These differences highlight the possibility that other instability forms could explain cancer susceptibility in this group of families. The base excision repair (BER) pathway is the major DNA repair pathway for oxidative DNA damage. A defect in this pathway can result in DNA transversion mutations and a subsequent increased cancer risk. Mutations in MUTYH have been associated with increased colorectal cancer (CRC) risk while no association has been described for OGG1 or NUDT1. EXPERIMENTAL DESIGN We performed mutational screening of the three genes involved in defense against oxidative DNA damage in a set of 42 MSS-HNPCC families. RESULTS Eight rare variants and 5 frequent variants were found in MSS-HNPCC patients. All variants were previously described by other authors except variant c.285C>T in OGG1. Segregation studies were done and in silico programs were used to estimate the level of amino acid conservation, protein damage prediction, and possible splicing alterations. Variants OGG1 c.137G>A; MUTYH c.1187G>A were detected in Amsterdam I families and cosegregate with cancer. Analysis of OGG1 c.137G>A transcripts showed an inactivation of the splicing donor of exon 1. CONCLUSIONS Two rare variants (OGG1 c.137G>A; MUTYH c.1187G>A) and one common polymorphism (NUDT1 c.426C>T) were associated with CRC risk. We show that the BER pathway can play a significant role in a number of MSS-HNPCC colorectal cancers. More studies could be of interest in order to gain further understanding of yet unexplained CRC susceptibility cases.
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Affiliation(s)
- Pilar Garre
- Laboratorio de Oncología Molecular, Hospital Clinico San Carlos, Madrid, Spain
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Garre P, Pérez-Segura P, Díaz-Rubio E, Caldés T, de la Hoya M. Reassessing the TARBP2 mutation rate in hereditary nonpolyposis colorectal cancer. Nat Genet 2010; 42:817-8; author reply 818. [PMID: 20877318 DOI: 10.1038/ng1010-817] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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Giráldez MD, Balaguer F, Caldés T, Sanchez-de-Abajo A, Gómez-Fernández N, Ruiz-Ponte C, Muñoz J, Garre P, Gonzalo V, Moreira L, Ocaña T, Clofent J, Carracedo A, Andreu M, Jover R, Llor X, Castells A, Castellví-Bel S. Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer 2009; 8:525-31. [PMID: 19685280 DOI: 10.1007/s10689-009-9282-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2009] [Accepted: 08/03/2009] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3'UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.
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Affiliation(s)
- María Dolores Giráldez
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036 Catalonia, Barcelona, Spain
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Screening for germline mutations of MLH1, MSH2, MSH6 and PMS2 genes in Slovenian colorectal cancer patients: implications for a population specific detection strategy of Lynch syndrome. Fam Cancer 2009; 8:421-9. [DOI: 10.1007/s10689-009-9258-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 06/02/2009] [Indexed: 12/14/2022]
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Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG. Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer. Hum Mutat 2008; 29:367-74. [PMID: 18033691 DOI: 10.1002/humu.20635] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Identification of germline mutations in DNA mismatch repair genes in colorectal cancer probands without an extensive family history can be problematic when ascribing relevance to cancer causation. We undertook a structured assessment of the disease-causing potential of sequence variants identified in a prospective, population-based study of 932 colorectal cancer patients, diagnosed at <55 years of age. Patient samples were screened for germline mutations in MLH1, MSH2, and MSH6. Of 110 carriers, 74 (67%) had one of 33 rare variants of uncertain pathogenicity (12 MLH1, 11 MSH2, and 10 MSH6). Pathogenicity was assessed by determining segregation in families, allele frequency in large numbers of unaffected controls, effect on mRNA for putative splice-site mutations, effect on protein function by bioinformatic analysis and tumor microsatellite instability (MSI) status and DNA mismatch repair protein expression by immunohistochemistry. Because of the ambiguous nature of these variants and lack of concordance between functional assays and control allele frequency, we devised a scoring system to rank the degree of support for a pathogenic role. MLH1 c.200G>A p.G67E, MLH1 c.2041G>A p.A681T, and MSH2 c.2634+5G>C were categorized as pathogenic through assimilation of all available data, while 14 variants were categorized as benign (seven MLH1, three MSH2, and four MSH6). Interestingly, there is tentative evidence suggesting a possible protective effect of three variants (MLH1 c.2066A>G pQ689R, c.2146G>A p.V716M, and MSH2 c.965G>A p.G322D). These findings support a causal link with colorectal cancer for several DNA mismatch repair gene variants. However, the majority of missense changes are likely to be inconsequential polymorphisms.
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Affiliation(s)
- Rebecca A Barnetson
- University of Edinburgh Cancer Research Centre, School of Molecular and Clinical Medicine and Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Edinburgh, United Kingdom.
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Sánchez-de-Abajo A, de la Hoya M, van Puijenbroek M, Tosar A, López-Asenjo JA, Díaz-Rubio E, Morreau H, Caldes T. Molecular Analysis of Colorectal Cancer Tumors from Patients with Mismatch Repair–Proficient Hereditary Nonpolyposis Colorectal Cancer Suggests Novel Carcinogenic Pathways. Clin Cancer Res 2007; 13:5729-35. [PMID: 17908962 DOI: 10.1158/1078-0432.ccr-06-2996] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE A subset of colorectal cancers (CRC) arises in families that, despite fulfilling clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC), do not show evidence of a mismatch repair (MMR) deficiency. The main objective of this study was to characterize these tumors at the molecular level. EXPERIMENTAL DESIGN After comprehensive germ line mutation scanning, microsatellite analysis, and MMR protein expressions, we selected a well-defined cohort of 57 colorectal tumors with no evidence of MMR defects. In this group of tumors, we analyzed KRAS, BRAF, and APC somatic mutations, as well as methylguanine methyltransferase (MGMT) and beta-catenin expression. We correlated these alterations with clinicopathologic data and explored the relationship between KRAS G > A transitions and lack of MGMT expression. RESULTS The mutation profile at the RAS/RAF/MAPK pathway mimics sporadic microsatellite-stable CRCs. We found an average age of diagnosis 10 years older in KRAS-mutated patients (P = 0.001). In addition, we show that KRAS G > A transitions are actively selected by tumors, regardless of MGMT status. Similarities with HNPCC high-microsatellite instability tumors are observed when APC data are analyzed. The APC mutation rate was low and small insertions/deletions accounted for 70% of the alterations. In addition, we found a low frequency of beta-catenin nuclear staining. Finally, we did not find evidence of tumors arising in individuals from the same family sharing molecular features. CONCLUSIONS We show evidence that CRC tumors arising in HNPCC families without MMR alterations have distinctive molecular features. Overall, our work shows that systematic analysis of somatic alterations in a well-defined subset of CRCs is a good approach to provide new insights into the mechanisms of colorectal carcinogenesis.
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Suchy J, Kurzawski G, Jakubowska K, Rać ME, Safranow K, Kładny J, Rzepka-Górska I, Chosia M, Czeszyńska B, Oszurek O, Scott RJ, Lubiński J. Frequency and nature of hMSH6 germline mutations in Polish patients with colorectal, endometrial and ovarian cancers. Clin Genet 2006; 70:68-70. [PMID: 16813607 DOI: 10.1111/j.1399-0004.2006.00630.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Hampel H, Frankel W, Panescu J, Lockman J, Sotamaa K, Fix D, Comeras I, La Jeunesse J, Nakagawa H, Westman JA, Prior TW, Clendenning M, Penzone P, Lombardi J, Dunn P, Cohn DE, Copeland L, Eaton L, Fowler J, Lewandowski G, Vaccarello L, Bell J, Reid G, de la Chapelle A. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 2006; 66:7810-7. [PMID: 16885385 DOI: 10.1158/0008-5472.can-06-1114] [Citation(s) in RCA: 441] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation-positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable.
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Affiliation(s)
- Heather Hampel
- Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, 420 West 12th Avenue, Columbus, OH 43210, USA
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