Abstract
Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA samples from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependant Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.
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References
Smith P, McGuffog L, Easton DF et al (2006) A genome wide linkage search for breast cancer susceptibility genes. Genes Chromosomes Cancer 45:646–655
Watson P, Lynch HT (1993) Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71:677–85
Aarno M, Mcklin JP, Aaltonen LA et al (1995) Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64:430–433
Risinger JI, Barrett JC, Watson P et al (1996) Molecular genetic evidence of the occurrence of breast cancer as an integral tumour in patients with the hereditary non-polyposis colorectal carcinoma syndrome. Cancer 77:1836–1843
Southey MC, Young MA, Whitty J et al (2001) Molecular Pathologic analysis enhances the diagnosis and management of Muir-Torre syndrome and gives insight into its underlying molecular pathogenesis. Am J Surg Path 25:936–941
Muller A, Edmonston TB, Corao DA et al (2002) Exclusion of breast cancer as an integral tumour of hereditary nonpolyposi colorectal cancer. Cancer Res 62:1012–1019
de Leeuw WJ, Puijenbroek M, Tollenaar RAEM et al (2003) Correspondence re Muller et al. exclusion of breast cancer as an integral tumour of hereditary nonpolyposi colorectal cancer. Cancer Res 63:1148–1149
Scott RJ, McPhillips M, Meldrum CJ et al (2001) Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68:118–127
Vasen HFA, Morreau H, Nortier JWR (2001) Is breast cancer part of the tumour spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet 68:1533–1534
http://www.kconfab.org. Accessed Sept 2007
Hopper JL, Chenevix-Trench G, Jolley DJ et al (1999) Design and analysis issues in a population-based, case-control-family study of the genetic epidemiology of breast cancer and the Co-operative Family Registry for Breast Cancer Studies (CFRBCS). J Natl Cancer Inst Monogr 26:95–100
Hopper JL, Giles GG, McCredie MR, Boyle P (1994) Background rational and protocol for a case-control-family study of breast cancer. Breast 3:79–86
McCredie MR, Dite GS, Giles GG, Hopper JL (1998) Breast cancer in Australian women under the age of 40. Cancer Causes Control 9:189–198
Dite GS, Jenkins MA, Hocking JS et al (2002) Strong familial risks associated with early-onset breast cancer are only partially BRCA1- or BRCA2-related. JNCI 19:95,448–457, 2003
Chenevix-Trench G, Spurdle AB, Gatei M et al (2002) Dominant negative ATM mutations in breast cancer families. J Natl Cancer Inst 94, 205–215. Erratum in: J Natl Cancer Inst 2002 94, 952
Smith LD, Tesoriero AA, Ramus SJ et al (2007) BRCA1 promoter deletions in young women with breast cancer and a strong family history: a population-based study. Eur J Cancer 43:823–827
Mann GJ, Thorne H, Belleine RL et al (2006) Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res 8(1):R12. Epub 2006 Feb 13
Southey MC, Jenkins MA, Mead L et al (2005) Mismatch repair gene mutation testing, immunohistochemistry and microsatellite instability testing in a population-based series of unselected early-onset colorectal cancers. J Clin Oncol 23:6524–6532
Smith L, Tesoriero A, Mead L et al (2006) Genomic rearrangements in hMSH2 and hMLH1 in early-onset colorectal cancer: a population-based study. Clin Genet 70:250–252
Tesoriero AA, Wong EM, Jenkins MA et al (2005) Molecular characterization and cancer risk associated with BRCA1 and BRCA2 splice site variants identified in multiple-case breast cancer families. Hum Mutat 26:495
http://www.violin.genet.sickkids.on.ca/∼ali/splicesitefinder.html. Accessed Sept 2006
Wehner M, Buschhausen L, Lamberti C et al (1997) Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes. Hum Mutat 10:241–244
Wijnen J, Vasen H, Khan PM et al (1995) Seven new mutations in hMSH2, an HNPCC gene, identified by denaturing gradient-gel electrophoresis. Am J Hum Genet 56:1060–1066
Acknowledgments
The Australian Breast Cancer Family Registry was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia), and the US National Cancer Institute, National Institutes of Health, under Request for Application CA-95-003 as part of the Breast Cancer Family Registries (CFRs), and through cooperative agreements with the Fox Chase Cancer Center; Huntsman Cancer Institute, Columbia University; Northern California Cancer Center; Cancer Care Ontario; and The University of Melbourne. We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (funded by NHMRC grants 145684 and 288704) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. JLH is a Victorian Breast Cancer Research Consortium group leader.
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Wong, E.M., Tesoriero, A.A., Pupo, G.M. et al. Is MSH2 a breast cancer susceptibility gene?. Familial Cancer 7, 151–155 (2008). https://doi.org/10.1007/s10689-007-9162-8
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DOI: https://doi.org/10.1007/s10689-007-9162-8