Endometrial cancer gene panels: clinical diagnostic vs research germline DNA testing

Abstract

Endometrial cancer is the most common gynecological cancer, but is nevertheless uncommon enough to have value as a signature cancer for some hereditary cancer syndromes. Commercial multigene testing panels include up to 13 different genes annotated for germline DNA testing of patients with endometrial cancer. Many other genes have been reported as relevant to familial endometrial cancer from directed genome-wide sequencing studies or multigene panel testing, or research. This review assesses the evidence supporting association with endometrial cancer risk for 32 genes implicated in hereditary endometrial cancer, and presents a summary of rare germline variants in these 32 genes detected by analysis of quasi-population-based endometrial cancer patients from The Cancer Genome Atlas project. This comprehensive investigation has led to the conclusion that convincing evidence currently exists to support clinical testing of only six of these genes for diagnosis of hereditary endometrial cancer. Testing of endometrial cancer patients for the remaining genes should be considered in the context of research studies, as a means to better establish the level of endometrial cancer risk, if any, associated with genetic variants that are deleterious to gene or protein function. It is acknowledged that clinical testing of endometrial cancer patients for several genes included on commercial panels may provide actionable findings in relation to risk of other cancers, but these should be considered secondary or incidental findings and not conclusive evidence for diagnosis of inherited endometrial cancer. In summary, this review and analysis provides a comprehensive report of current evidence to guide the selection of genes for clinical and research gene testing of germline DNA from endometrial cancer patients.

Endometrial cancer risk and survival by tumor MMR status

“…For this dataset, MMR deficiency was based on tumor MSI-H status: tumors were considered MMR-deficient if they were MSI-H, or MMR-proficient if they exhibited low/indeterminate MSI or were microsatellite stable (MSS). Our previous analysis of TCGA germline exome sequencing data [ 25 ] was used to exclude patients carrying a MMR gene variant of uncertain significance, and assign tumor status as germline or somatic MMR-deficient — with the caveat that pathogenic copy number variation was not detected by our previous sequence analysis. Analyses included patients stratified into 3 groups: 1) MMR-proficient — non-carrier of a germline MMR pathogenic variant and tumor profile was not MSI-H (n=246); 2) assumed somatic MMR-deficient — non-carrier of a germline MMR pathogenic variant and tumor MSI-H profile (n=115); and 3) germline MMR-deficient — carrier of a germline MMR pathogenic variant and tumor MSI-H profile (n=6).…”

Identification of nine new susceptibility loci for endometrial cancer

“…Risk of endometrial cancer is approximately double for women who have a first degree relative with endometrial cancer 2 , 3 . Rare high-risk pathogenic variants in mismatch-repair genes, PTEN , and DNA polymerase genes 4 explain a small proportion of endometrial cancers, and the eight previously published common endometrial cancer-associated single-nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) studies 5 – 8 together explain <5% of the familial relative risk (FRR).…”

Risk and prognostic factors for endometrial carcinoma after diagnosis of breast or Lynch‐associated cancers—A population‐based analysis

“…Genetic risk factors for EC have been supported by the fact that there is at least a twofold increased risk of EC among women with at least one first‐ or second‐degree relative with EC . Such genetic factors include high‐risk pathogenic variants in the DNA mismatch repair (MMR) genes causing Lynch Syndrome, and very rarely, germline loss‐of‐function variants in the PTEN tumor suppressor gene causing Cowden Syndrome . We have recently shown that carriage of a pathogenic variant in an MMR gene only partly accounts for risk of EC associated with reported family history, indicating that additional genetic risk factors remain to be identified.…”