BACKGROUND: Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression. METHODS: Next-generation sequencing was performed on archived endometrial biopsy specimens from a retrospective cohort of women with endometrial hyperplasia. Cases were considered to be either progressing if the patient subsequently developed EMC or resolving if the patient had a subsequent negative tissue sampling or no cancer during medium-term follow-up (32 patients: 15 progressing and 17 resolving). Somatic mutations in endometrial hyperplasia were assessed for enrichment in progressing cases versus resolving cases, with an emphasis on genes commonly mutated in EMC. RESULTS: Several mutations were more common in progressing hyperplasia than resolving hyperplasia, although significant overlap was observed between progressing and resolving cases. Mutations included those in PTEN, PIK3CA, and FGFR2, genes commonly mutated in EMC. Mutations in ARID1A and MYC were seen only in progressing hyperplasia, although these were uncommon; this limited diagnostic sensitivity. Progressing hyperplasia demonstrated an accumulation of mutations in oncogenic signaling pathways similarly to endometrial carcinoma. CONCLUSIONS: Because of mutational differences between progressing and nonprogressing hyperplasia, mutational analysis may predict the risk of progression from endometrial hyperplasia to EMC. Cancer 2020;126:2775-2783.

We present a case of unexplained familial breast cancer (BC) from six family members, including four affected and two unaffected women, for whom clinical genetic testing panels were inconclusive. Exome sequencing data revealed heterozygous and rare germline variants to be inherited in an autosomal dominant manner in the family, in addition to several unclassified mutations in DNA repair and cell cycle-regulating genes that were not included in the family’s clinical genetic testing. A rare MYC-N11S germline mutation with conflicting interpretations of pathogenicity in the literature, and predicted to be deleterious, was present in all affected individuals. Whole exome sequencing provided a more comprehensive picture of inherited BC in this family that was missed by cancer gene panels alone.