Familial risk of endometrial cancer after exclusion of families that fulfilled Amsterdam, Japanese or Bethesda criteria for HNPCC

AbstractEndometrial cancer (EC) is the fifth most common cancer in women from developed countries, accounting for 4.8% of new cases and 2.1% of deaths. The genetic basis for the familial risk of endometrial cancer has not been completely defined. Mostly, hereditary EC is part of two syndromes as Lynch syndrome (LS) and Hereditary Breast and Ovarian Cancer syndrome (HBOC). LS is the prototypical hereditary cancer syndrome in EC and accounts for 2–6% of all endometrial cancers. This disease is caused by autosomal dominant mutations in DNA mismatch repair (MMR) genes. Patients carrying a germline mutation in one of the MMR genes have a cumulative lifetime risk to develop EC of 20–70%. HBOC is an autosomal dominantly inherited disease, which mostly predisposes to breast and ovarian cancers, but it can be also associated with other malignancies. HBOC results from germline mutations in BRCA1/2 genes. The aim of this study was to determine the mutational status of a cohort of 40 EC patients, 19 belonging to families with LS and 21 to HBOC. Mutation analysis of MLH1, MSH2, BRCA1 and BRCA2 genes showed pathogenic variants in 17/40 (42.5%) patients. Out of 19 patients belonging to LS families, 8 (42.1%) showed a pathogenic variant. Out of 21 patients belonging to HBOC families, 9 (42.8%) showed a pathogenic variant. 1/21 (4.8%) patient report 1 variant of unknown significance (UV), c.599 C > T (p.T200I), in BRCA2. Moreover, in 1/21 (4.8%) patient we identified a novel missense variant in BRCA2, c.9541A > T (p.Met3181Leu). Mutational analysis was extended to family members, both healthy and cancer affected, of mutated patients; all the tested relatives affected with cancer displayed the pathogenic variant. Our data suggest that patients with hereditary EC have a high percentage of mutations in the LS and HBOC main susceptibility genes; therefore, the surveillance for EC, already indicated in LS patients, should also be recommended for patients with HBOC.

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Correlation between clinical-pathological parameters and family history to detect mutations in MLH1, MSH2, and MSH6.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.4_suppl.391 ◽

2011 ◽

Vol 29 (4_suppl) ◽

pp. 391-391

Author(s):

C. Guillen-Ponce ◽

A. Castillejo ◽

V. M. Barbera ◽

C. Alenda ◽

M. Molina-Garrido ◽

...

Keyword(s):

Endometrial Cancer ◽

Family History ◽

Univariate Analysis ◽

Germline Mutations ◽

Clinical Feature ◽

Tumor Type ◽

Hereditary Nonpolyposis Colon Cancer ◽

Mmr Genes ◽

Bethesda Criteria ◽

Diagnosis Of Cancer

391 Background: The Amsterdam I/II and Bethesda criteria are used to select individuals for the study of mutations in hereditary nonpolyposis colon cancer (HNPCC). The aim of this study was to analyze whether specific clinical features and family history of individuals suspected of HNPCC were correlated with the detection of germline mutations in MLH1, MSH2 and MSH6. Methods: Between 2005-2008, the study of germline mutations in one or more of the genes MLH1, MSH2 or MSH6 was carried out on 124 individuals who fullfield the Amsterdam I/II criteria or Bethesda criteria with microsatellite instability (MSI) or loss of expression by immunohistochemistry (IHC) of any of the repair proteins of MMR genes. Subsequently, we applied univariate and multivariate analyses including clinicopathological characteristics and family history to see if they were related to the presence of germline mutations. The characteristics were: age, sex, age at diagnosis, whether they fulfilled the Amsterdam or Bethesda criteria, diagnosis of cancer, tumor type, presence of multiple tumors and age of first diagnosis of cancer in the family. Results: Out of 124 patients studied, 29 gene mutations were detected (detection rate 25%). Of all the parameters studied, only endometrial cancer increased the risk of mutation 7.3 times (confidence interval [CI] 95%, from 1.83 to 29.2) for colorectal cancer (p = 0.005). 20.7% of mutations in MMR genes were explained by the type of cancer (R square Nagelkerke = 0.207). In the multivariate analysis none of the variables predicted the presence of mutation. Conclusions: The most important clinical feature to predict the presence of a mutation in the genes MLH1, MSH2 and/or MSH6 in families with HNPCC is the diagnosis of endometrial cancer (univariate analysis). No significant financial relationships to disclose.

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