Tumor-Normal Sequencing Uncovers Secondary Germline Findings in Cancer Patients
This review examines the growing practice of paired tumor-normal sequencing, which simultaneously identifies somatic oncogenic drivers and incidental germline cancer predisposition variants. The approach detects hereditary cancer syndromes in patients who would not meet traditional genetic testing criteria, enabling cascade screening of at-risk family members. The paper discusses laboratory workflow implications, variant interpretation challenges, and the clinical utility of this dual-purpose sequencing strategy.
The original study
The emerging significance of secondary germline testing in cancer genomics.
- Authors
- Mandelker D, Zhang L
- Journal
- The Journal of pathology
- Type
- Journal Article, Review
- PMID
- 29293272
Original abstract
Many clinical laboratories now sequence the tumors from advanced cancer patients to identify oncogenic drivers and guide targeted therapies and clinical trials. One limitation of tumor sequencing is that it cannot distinguish between tumor-specific somatic (acquired) mutations and patients' germline (constitutional) variants. To definitively identify somatic variants, some clinical labs sequence both a normal sample from a patient and their tumor to subtract the germline variants from the somatic variants. Having a paired normal sample also allows for the identification of secondary germline mutations in cancer patients who may not meet the current clinical guidelines for genetic testing of cancer predisposition syndromes. Such simultaneous detection of somatic alterations and germline mutations during tumor-normal sequencing can guide therapeutic decision making for cancer patients and the identification and screening of at-risk family members. Here, we review the clinical workflow, advantages and disadvantages, and clinical utility of tumor-normal sequencing in the management of cancer patients. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.