Sequential tumor molecular profiling identifies likely germline variants.

PURPOSE: To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs).

METHODS: The coefficient of variance was calculated from variant allele frequency of next generation sequencing assays. Variants' likelihood of being germline was ranked on a 1-5 scale. Outcomes were examined in patients with such variants.

RESULTS: In a pilot set of 33 genes, 89% of grade 1, 77% of grade 2, 62% of grade 3, 52% of grade 4, and 21% of grade 5 variants were confirmed to be germline. Among those, 22% were pathogenic or likely pathogenic in genes recognized as conferring hereditary HM (HHM) risk, including BRCA1/2, CHEK2, CSF3R, and DDX41. To determine if this approach identified genes with known autosomal dominant inheritance, we analyzed sequential data from 1336 genes in 1135 HM patients. Among unique variants, 16% occurred in HHM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival two years following initial molecular testing (78% versus 88%, p=0.0037) and increased all-cause mortality compared to those without (HR 2.02, 95%CI 1.18-3.46, p=0.01).

CONCLUSION: Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared to those without.