MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.

OBJECTIVE: Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors. METHODS: We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years). RESULTS: Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation. CONCLUSIONS: A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.

Treatment Options for Germline BRCA-Mutated Metastatic Pancreatic Adenocarcinoma.

Pancreatic cancer is the fourth leading cause of death from cancer in both men and women. Pancreatic cancer is typically diagnosed at an advanced stage and has an overall 5-year survival of approximately 9.3%. The National Comprehensive Cancer Network recommends both germline testing (testing cells such as blood or skin that do not have cancer) as well as somatic testing (testing cells with cancer) for pathogenic variants that may increase the risk of pancreatic cancer. In December 2019, the U.S. Food & Drug Administration approved the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib for maintenance treatment of germline BRCA-mutated metastatic pancreatic adenocarcinoma in individuals who have completed at least 16 weeks of progression-free treatment with first-line platinum-based chemotherapy. This new therapy option has implications not only for treatment but also for the role of the oncology advanced practitioner as genetic testing becomes more prevalent in the care of patients with cancer.