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Updated: Jul 9, 2025
Comparative Lesions Analysis Through a Targeted Sequencing Approach
Published on: November 5, 2019
Sequential tumor molecular profiling identifies likely germline variants
Ira L Kraft1, Hatice Basdag2, Ashwin Koppayi3
1Section of Hematology/Oncology, Department of Pediatrics, The University of Chicago, Chicago, IL; Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL; Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
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 to 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 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 hereditary HM genes, and 15% were deleterious. Patients with grade 1/2 alleles had decreased survival 2 years after initial molecular testing (78% versus 88%, P = .0037) and increased all-cause mortality compared with those without (hazard ratio 2.02, 95% CI 1.18-3.46, P = .019).
Conclusion:
Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared with those without.
