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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.
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