Abstract
Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.
This is a preview of subscription content, log in via an institution to check access.
References
Boyd J, Rubin SC (1997) Hereditary ovarian cancer: molecular genetics and clinical implications. Gynecol Oncol 64:196–206
Claus EB, Schildkraut JM, Thompson WD, Risch NJ (1996) The genetic attributable risk of breast and ovarian cancer. Cancer 77:2318–2324
Zhang S, Royer R, Li S et al (2011) Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol 121:352–357
Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676–689
Frank TS, Deffenbaugh AM, Reid JE et al (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20:1480–1490
Barrow E, Alduaij W, Robinson L et al (2008) Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations. Clin Genet 74:233–242
Barrow E, Robinson L, Alduaij W et al (2009) Cumulative life incidence of extracolonic cancer in Lynch syndrome: a of 121 families with proven mutations. Clin Genet 75:141–149
Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR (2009) Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76:1–18
Lynch HT, Smyrk TC, Watson P et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary non polyposis colorectal cancer: an update review. Gastroenterology 104:1535–1549
Ligtenberg MJ, Kuiper RP, Chan TL et al (2009) Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3′ exons of TACSTD1. Nat Genet 41:112–117
Steinke V, Engel C, Büttner R, Schackert HK, Schmiegel WH, Propping P (2013) Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome. Dtsch Arztebl Int 110:32–38
Borg A, Isola J, Chen J et al (2000) Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma. Int J Cancer 85:796–800
Thiffault I, Hamel N, Pal T et al (2004) Germline truncating mutations in both MSH2 and BRCA2 in a single kindred. Br J Cancer 90:483–491
Kast K, Neuhann TM, Gorgens H et al (2012) Germline truncating-mutations in BRCA1 and MSH6 in a patient with early onset endometrial cancer. BMC Cancer 12:531
Pedroni M, Roncari B, Maffei S et al (2007) A mononucleotide markers panel to identify hMLh1/hMSH2 germline mutations. Dis Markers 23:179–187
Xicola RM, Llor X, Pons E et al (2007) Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst 99:244–252
Findeisen P, Kloor M, Merx S et al (2005) T25 repeat in the 3′untranslated region of the CASP2 gene: a sensitive and specific marker for microsatellite instability in colorectal cancer. Cancer Res 65:8072–8078
Ruffner H, Joazeiro CA, Hemmati D, Hunter T, Verma IM (2001) Cancer-predisposing mutations within the RING domain of BRCA1: loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity. Proc Natl Acad Sci USA 98:5134–5139
Kurzawski G, Suchy J, Kladny J et al (2002) Germline MSH2 and MLH1 mutation spectrum in HNPCC families from Poland and the Baltic States. J Med Genet 39:E65
Bonadona V, Bonaïti B, Olschwang S et al (2011) Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305:2304–2310
Vasen HF, Morreau H, Nortier JW (2001) Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet 68:1533–1535
Win AK, Young JP, Lindor NM et al (1012) Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. Clin Oncol 30:958–964
Jensen UB, Sunde L, Timshel S et al (2010) Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 120:777–782
Buerki N, Gautier L, Kovac M et al (2012) Evidence for breast cancer as an integral part of Lynch syndrome. Gene Chromosome Cancer 51:83–91
Acknowledgments
The study was supported by grants from the Italian Minister of University and Research, PRIN 2008 (2008RFCMH). The Authors thank AIRC (Associazione Italiana Ricerca Cancro) for financial support. We gratefully acknowledge our colleagues G Viale, M. Federico and L. Botticelli for their help in sample collection and clinical support.
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pedroni, M., Di Gregorio, C., Cortesi, L. et al. Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors. Tech Coloproctol 18, 285–289 (2014). https://doi.org/10.1007/s10151-013-1030-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10151-013-1030-y