br d Mayo Clinic Department
d Mayo Clinic, Department of Pathology, United States of America
e Mayo Clinic, Department of Biomedical Statistics and Informatics, United States of America
• Cancer predisposition gene mutations were found in 4–6% of patients with EC.
• Frequency of LS mutations was similar in both type I and type II EC.
Objectives. To determine the incidence of germline cancer predisposition gene mutations in patients with en-dometrial cancer (EC) subtypes.
Methods. Germline DNA was extracted from whole blood collected from consenting patients undergoing pri-mary surgery for EC between 5/2005 and 11/2016. DNA samples were evaluated by product sequencing from a targeted multiplex PCR panel including 21 known/suspected cancer predisposition genes. Variants were classi-fied as pathogenic/likely pathogenic based on allele frequency (b0.003), effects on protein function, and ClinVar assertions.
Conclusions. BRCA1/2 and Lynch mutations were rare in this cohort of unselected patients with type I and II EC, including USC. However, the presence of predisposition gene mutations in 4.2% of EC type I, 5.3% of EC type II, and 6.7% of USC suggests that somatic mutation testing should be considered for all EC patients.
☆ Dr. Couch reports funding from the National Institute of Health. The other authors
have no conflicts of interest.
☆☆ The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of con-tributing groups can be found at http://gnomad.broadinstitute.org/about.
Corresponding author at: 2150 Pennsylvania Avenue NW, Washington, DC 20037, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, George Washington University School of Medicine and Health Sciences, United States of America.
E-mail address: [email protected] (B. Long). 1 These authors contributed equally.
Endometrial cancer (EC) is composed of type I and type II subgroups, with the type I subtype accounting for over 80% of EC and type II EC representing the remaining 10–20%. However, the more aggressive type II histologic subtype accounts for at least 40% of EC-related deaths [1,2]. To date, only six 1161002-05-6 included on clinical hereditary cancer panel tests have a proven association with EC (MLH1, MSH2, MSH6, PMS2, EPCAM, and PTEN) , with referrals for clinical panel testing generally limited to patients suspected of having Lynch syndrome (LS). Further-more, genetic predisposition to type II EC, and risk factors for the disease
are not well defined. Several small, retrospective studies have suggested a link between BRCA1 mutations and uterine serous cancer, while others have found no such risk. These studies are difficult to interpret, as many include only Ashkenazi Jewish populations or are confounded by ta-moxifen exposure [4–6]. However, a recent prospective study found an increased risk of serous/serous-like EC in a large cohort of BRCA1-positive women undergoing risk reducing salpingo-oophorectomy (RRSO) without hysterectomy. In this investigation, 4 out of 627 women with BRCA1 mutations developed serous/serous-like EC after 3781.0 woman-years of follow-up. The observed rate of serous/ serous-like EC was 22.2 times the expected rate and translated to a 2.6–4.7% risk of developing serous/serous-like EC through age 70 . However, these estimates were based on only four cases of serous-like EC, three of which were associated with a history of tamoxifen use. Al-though observed rates of serous/serous-like EC remained high when stratified for tamoxifen exposure, it is difficult to make recommenda-tions regarding risk-reducing hysterectomy in BRCA carriers based on limited sample sizes.
Sample size has also limited estimation of type II EC risk in patients with Lynch Syndrome (LS). In one investigation of 50 patients with se-rous or mixed serous endometrial cancer, no mismatch repair (MMR) defects were identified . In another study of 40 cases of MMR-deficient endometrial cancer, only 26% were grade 3, and most were of endometrioid subtype. Only 5 type II cases were identified, including 1 uterine serous cancer. Another study including 134 patients with USC identified an MMR mutation in a single case with primarily endometrioid histology and only 1% serous component . Given these limited data, the risk of type II EC in patients with LS is unknown.
In order to more accurately characterize mutations associated with EC, we performed germline testing in a large, prospectively collected co-hort of patients with all EC subtypes. The objective of this study was to determine the incidence of germline BRCA and hereditary breast and/or ovarian cancer gene mutations in all EC subtypes. These data may deter-mine the need for mutation screening in this population and help in-form practical recommendations regarding hysterectomy for BRCA-positive women undergoing prophylactic salpingo-oophorectomy.