BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X

[en] 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.

Disciplines :

Genetics & genetic processes

Author, co-author :

Garre, Pilar; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Martin Morales, Lorena ; Université de Liège - ULiège > GIGA Stem Cells - Cancer Signaling

Sanz, Julian; Hospital Clínico San Carlos > Anatomical Pathology

Romero, Atocha; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Tosar, Alicia; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Bando, Inmaculada; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Llovet, Patricia; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Diaque, Paula; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Garcia-Paredes, Beatriz; Hospital Clínico San Carlos > Medical Oncology

Diaz-Rubio, Eduardo; Hospital Clínico San Carlos > Medical Oncology

de la Hoya, Miguel; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Caldes, Trinidad; Hospital Clínico San Carlos > Medical Oncology > Molecular Oncology Laboratory

Language :

English

Title :

BRCA2 gene: a candidate for clinical testing in familial colorectal cancer type X

Publication date :

June 2015

Journal title :

Clinical Genetics

ISSN :

0009-9163

eISSN :

1399-0004

Publisher :

Wiley, Oxford, United Kingdom

Volume :

Issue :

Pages :

582-7

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 26 May 2021

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Bibliography

Vasen HF, Watson P, Mecklin JP et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999: 116: 1453-1456.
Garre P, Martin L, Bando I et al. Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer. Fam Cancer 2013: 13: 109-119.
Garre P, Briceno V, Xicola RM et al. 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: 1701-1712.
Palles C, Cazier JB, Howarth KM et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet 2013: 45: 136-144.
Lefevre JH, Bonilla C, Colas C et al. Role of rare variants in undetermined multiple adenomatous polyposis and early-onset colorectal cancer. J Hum Genet 2012: 57: 709-716.
Daley D, Lewis S, Platzer P et al. Identification of susceptibility genes for cancer in a genome-wide scan: results from the colon neoplasia sibling study. Am J Hum Genet 2008: 82: 723-736.
Phelan CM, Iqbal J, Lynch HT et al. Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br J Cancer 2014: 110: 530-534.
Caldes T, Godino J, Sanchez A et al. Immunohistochemistry and microsatellite instability testing for selecting MLH1, MSH2 and MSH6 mutation carriers in hereditary non-polyposis colorectal cancer. Oncol Rep 2004: 12: 621-629.
Caldes T, Godino J, de la Hoya M et al. Prevalence of germline mutations of MLH1 and MSH2 in hereditary nonpolyposis colorectal cancer families from Spain. Int J Cancer 2002: 98: 774-779.
Sanchez de Abajo A, de la Hoya M, Tosar A et al. Low prevalence of germline hMSH6 mutations in colorectal cancer families from Spain. World J Gastroenterol 2005: 11: 5770-5776.
Kote-Jarai Z, Leongamornlert D, Saunders E et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer 2011: 105: 1230-1234.
Osorio A, de la Hoya M, Rodriguez-Lopez R et al. Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. Int J Cancer 2002: 99: 305-309.
Willems AJ, Dawson SJ, Samaratunga H et al. Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res 2008: 14: 2953-2961.
Pettigrew CA, Wayte N, Wronski A et al. Colocalisation of predicted exonic splicing enhancers in BRCA2 with reported sequence variants. Breast Cancer Res Treat 2008: 110: 227-234.
Sliwinski T, Krupa R, Majsterek I et al. Polymorphisms of the BRCA2 and RAD51 genes in breast cancer. Breast Cancer Res Treat 2005: 94: 105-109.
Johnson N, Fletcher O, Palles C et al. Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet 2007: 16: 1051-1057.