Understanding Inherited Risk in Unselected Newly Diagnosed Patients With Endometrial Cancer

Abstract

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

Up-Front Multigene Panel Testing for Cancer Susceptibility in Patients With Newly Diagnosed Endometrial Cancer: A Multicenter Prospective Study

“…12 Mutations in cancer susceptibility genes (CSGs) other than those associated with LS are thought to play a smaller role in EC risk. 13 Although multigene panel testing (MGPT) studies performed for women with EC have identified PVs in other CSGs, [14][15][16] the true burden of PVs in other CSGs remains unknown. The modest number of cases investigated (381 in the study by Ring et al, 14 156 in Cadoo et al, 15 and 98 in Samadder et al 16 ), coupled with the fact that the cohorts overrepresent women with nonendometrioid, high-grade, and higher-stage tumors, limits our understanding of how frequent PVs in other CSGs are in the general EC population.…”

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

“…Although associations with specific genomic characteristics are unknown, CS was more likely to be present in those with EC and age at diagnosis <50, macrocephaly, and concurrent renal cell carcinoma [7]. This study and others highlight the low yield of germline testing in unselected EC patients [10], however certain clinical features such as those seen in this patient, including younger age of diagnosis, macrocephaly, and concurrent cancers, may warrant germline assessment.…”

“…Although many environmental risk factors for EC have been identified, an inherited predisposition is thought to be present in about 5% of women with this disease [9,10]. The most common inherited syndrome in EC is Lynch syndrome, which is associated with MMRdeficient (MMRd)/microsatellite instability-high (MSI-H) tumors, as well as colon cancers and other cancers exhibiting an MMRd/MSI-H phenotype [11].…”

“…As a result, universal MMR/MSI testing is recommended in EC to identify patients for Lynch syndrome testing and subsequent cancer prevention [12]. In a small subset of EC patients, germline mutations in CHEK2, POLD1/POLE, MUTYH, and other genes involved in DNA repair have been identified [8,10,13]. There are burgeoning data to suggest a mildly increased risk of serous-like EC, endometrioid EC, and p53-abnormal EC in those with germline BRCA1 mutations as well as an increased risk of serous-like EC in germline BRCA2 mutations when compared with expected incidence rates, although absolute risk by age 75 remains low (3.0%) for the germline BRCA1/2 population [14].…”

Rare deleterious germline variants and risk of lung cancer

“…Genetic ancestry analysis shows 90% TCGA-LCs were inferred as genetic European ancestry 83 . However, it is possible that a small portion of European ancestry TCGA-patients has AJ origin, given that 7% of ovarian cancer 84 and 24% of endometrial cancer 85 are of AJ heritage. It is of note that in our dataset, none of the variant allele carriers of the 25 candidates were found to have African-ancestry.…”