title: Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors.
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.
authors.affiliation: Department of Diagnostic and Clinical Medicine and Public Health, University of Modena, Modena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pedroni
authors.forename: C
authors.initials: C
authors.lastname: Di Gregorio
authors.forename: L
authors.initials: L
authors.lastname: Cortesi
authors.forename: L
authors.initials: L
authors.lastname: Reggiani Bonetti
authors.forename: G
authors.initials: G
authors.lastname: Magnani
authors.forename: M L
authors.initials: ML
authors.lastname: Simone
authors.forename: V
authors.initials: V
authors.lastname: Medici
authors.forename: C
authors.initials: C
authors.lastname: Priore Oliva
authors.forename: M
authors.initials: M
authors.lastname: Marino
authors.forename: M
authors.initials: M
authors.lastname: Ponz de Leon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D017809:Fatal Outcome; D005260:Female; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D060787:Neoplasm Grading; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D010375:Pedigree
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1