Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome

abstract:
Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: A meta-analysis and case report

 Highlights

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Germline BRCA1/2 mutations are more common in women with uterine serous carcinoma compared with the general population.

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The LOH and homologous recombination deficiency found in an USC of a BRCA1 germline carrier, support a causal relationship.

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Uterine serous carcinoma may be an overlooked component of BRCA1/2-associated hereditary breast and ovarian cancer syndrome.

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Screening for germline BRCA1/2 pathogenic mutations should be considered in women with uterine serous carcinoma.

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Background

Uterine serous carcinoma (USC) shows greater morphological, clinical and molecular similarities to high-grade ovarian tubal serous carcinoma than to other types of endometrial cancer. As high-grade ovarian tubal serous carcinoma is known to be associated with BRCA1/2 pathogenic germline mutations (PMs), we aimed to explore whether USC is also a constituent of hereditary breast and ovarian cancer syndrome.

Methods

Pubmed, EMBASE and Web of Science were searched in July 2016 for articles assessing the association between USC and germline BRCA1/2-PMs. Pooled analysis and comparisons were performed using a random effects logistic model, stratifying for ethnicity (Ashkenazi versus non-Ashkenazi). In addition, tumour tissue from an USC case with a hereditary BRCA1-PM was analysed for loss of heterozygosity at the BRCA1 locus and was functionally analysed for homologous recombination proficiency.

Results

The search yielded 1893 citations, 10 studies were included describing 345 USC patients. For Ashkenazi Jews, the pooled odds ratio of having a germline BRCA1/2-PM was increased in USC patients compared with the general Ashkenazi population: odds ratio 5.4 (95%confidence interval: 2.2–13.1). In the patient with USC, we identified the known germline BRCA1-PM in the tumour DNA. Furthermore, we showed both loss of heterozygosity of the wild-type allele and a deficiency of homologous recombination.

Conclusion

This study suggests that USC may be an overlooked component of BRCA1/2-associated hereditary breast and ovarian cancer syndrome. Screening for germline BRCA1/2-PMs should be considered in patients diagnosed with USC, especially in cases with a positive first-degree family history for breast and/or ovarian cancer.