Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases.

The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.