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Comparative Lesions Analysis Through a Targeted Sequencing Approach
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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.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
|December 6, 2023
PubMed
Summary
This summary is machine-generated.

Identifying likely germline DNA variants from tumor profiling can predict patient outcomes. Hematopoietic malignancy patients with germline variants show poorer survival rates.

Keywords:
Clinical next-generation sequencingGermline cancer genomicsHereditary hematopoietic malignancySequential tumor profilingTumor molecular profiling

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Area of Science:

  • Genetics
  • Oncology
  • Bioinformatics

Background:

  • Germline DNA variants play a crucial role in hereditary cancer syndromes.
  • Distinguishing germline from somatic mutations is essential for accurate diagnosis and risk assessment in hematopoietic malignancies (HMs).
  • Sequential tumor profiling offers a potential avenue for identifying germline variants.

Purpose of the Study:

  • To develop and validate a method for identifying likely germline DNA variants using sequential tumor profiling data in patients with HMs.
  • To assess the clinical significance of identified germline variants in HM patients.

Main Methods:

  • Calculated coefficient of variance from variant allele frequency in next-generation sequencing data.
  • Ranked variant likelihood of being germline on a 1-5 scale.
  • Analyzed sequential data from 1336 genes in 1135 HM patients.

Main Results:

  • In a pilot study, 89% of grade 1 variants were confirmed germline; 22% of these were pathogenic in known hereditary HM risk genes.
  • Across 1135 HM patients, 16% of unique variants occurred in hereditary HM genes, with 15% being deleterious.
  • Patients with high-grade germline alleles (grade 1/2) exhibited decreased survival and increased mortality.

Conclusions:

  • Sequential tumor profiling can effectively predict germline variant status in HMs.
  • Patients with likely germline variants face inferior clinical outcomes compared to those without.