Sequential tumor molecular profiling identifies likely germline variants

Ira L. Kraft; Hatice Basdag; Ashwin Koppayi; Courtnee V. Rodgers; Caner Saygin; Yogameenakshi Haribabu; Pankhuri Wanjari; Nifang Niu; Soma Das; Jill L.O. de Jong; Jeremy Segal; Lucy A. Godley

doi:10.1016/j.gim.2023.101037

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Sequential tumor molecular profiling identifies likely germline variants

Journal article

Open access

Peer reviewed

Sequential tumor molecular profiling identifies likely germline variants

Ira L. Kraft, Hatice Basdag, Ashwin Koppayi, Courtnee V. Rodgers, Caner Saygin, Yogameenakshi Haribabu, Pankhuri Wanjari, Nifang Niu, Soma Das, Jill L.O. de Jong, …

Genetics in medicine, Vol.26(3), p.101037

03/01/2024

DOI: 10.1016/j.gim.2023.101037

PMCID: PMC11401608

PMID: 38054407

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Abstract

To identify likely germline DNA variants from sequential tumor profiling data from hematopoietic malignancies (HMs). 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. 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). Variant germline status may be predicted using sequential tumor profiling and patients with likely germline variants experience inferior outcomes compared with those without.

Clinical next-generation sequencing

Germline cancer genomics

Hereditary hematopoietic malignancy

Sequential tumor profiling

Tumor molecular profiling

Details

Title: Subtitle: Sequential tumor molecular profiling identifies likely germline variants
Creators: Ira L. Kraft - University of Chicago
Hatice Basdag - University of Chicago
Ashwin Koppayi - Northwestern University
Courtnee V. Rodgers - University of Chicago
Caner Saygin - University of Chicago
Yogameenakshi Haribabu - Northwestern University
Pankhuri Wanjari - University of Chicago
Nifang Niu - University of Chicago
Soma Das - University of Chicago
Jill L.O. de Jong - University of Chicago
Jeremy Segal - University of Chicago
Lucy A. Godley - Northwestern University
Resource Type: Journal article
Publication Details: Genetics in medicine, Vol.26(3), p.101037
Publisher: Elsevier Inc
DOI: 10.1016/j.gim.2023.101037
PMID: 38054407
PMCID: PMC11401608
ISSN: 1098-3600
eISSN: 1530-0366
Language: English
Date published: 03/01/2024
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9984701657002771

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