Integrating Germline Analysis with Tumor Sequencing: Advancing Cancer Genomics
Cancer Genetics and Therapeutics
-
Primary Categories:
- Cancer
-
Secondary Categories:
- Cancer
Introduction:
Sequencing panels for tumors is standard practice in clinical oncology, aiding both in understanding the molecular mechanisms of tumor development and guiding potential treatments. Whole genome and transcriptome sequencing (WGTS) offers a comprehensive molecular profile of a patient's tumor compared to sequencing panels. By concurrently analyzing a matched germline comparator sample, somatic variants can be accurately differentiated from germline-derived ones, facilitating better interpretation of both somatic as well as germline findings. This approach also provides the opportunity to investigate clinically significant variants in hereditary cancer predisposition genes or the American College of Medical Genetics and Genomics (ACMG) recommendation of reporting secondary findings (SF) from genomic testing, with patient consent. Despite its advantages, paired tumor-germline testing is not universally adopted, particularly in targeted somatic panel testing.
Methods:
Informed consent was obtained from all participants for clinical WGTS testing. Germline variant reporting in normal samples focused on the most current ACMG SF list (v2.0, v3.1, v3.2) at the time of analysis and hereditary cancer predisposition genes identified by Maxwell et al. in 2016 (PMID: 27153395). Variants were classified according to ACMG and ClinGen Sequence Variant Interpretation Working Group guidelines. Result reporting was limited to pathogenic and likely pathogenic variants in the selected gene lists.
Results:
Between January 2021 and October 2024, clinical WGTS test was performed on 99 consented patients. The most frequent tumors tested were breast (n=14), kidney (n=13), blood/bone marrow (n=12), lung (n=8), colorectal (n=7), prostate (n=6), bladder (n=6), and ovary (n=5).
In addition to reporting clinically significant somatic variants, this study focused on reporting of the germline variants which were reported in 19 of the 99 individuals tested (~19%). Sixteen individuals (16/19) harbored P/LP variants in hereditary cancer predisposition genes, including CHEK2 (n=4), APC (n=3), BRCA2 (n=3), FANCA (n=2), and one each in FH, ATM, DICER1, MLH1, CEBPA, TP53, SDHC, and MSH6. Three individuals (3/19) had reportable variants in genes associated with cardiomyopathy (TTN, LMNA, and MYH7).
The clinical context, including tumor type, site, and personal or family history, supported hereditary cancer predisposition syndromes in 8 cases, where identified germline variants were consistent with the tested tumor. In the remaining 8 cases, the reported germline variants were unrelated to the tested tumor or site of the tumor. For these individuals, surveillance measures were initiated, and cascade testing was recommended for at-risk family members. These findings would have been missed without paired tumor-germline testing.
Conclusion:
Integrating germline analysis with tumor sequencing tests should become a standard practice in oncology. This approach not only enhances the interpretation of somatic variants but also identifies hereditary cancer risks and ACMG secondary findings, enabling preventative care and cascade testing for at-risk family members.
Sequencing panels for tumors is standard practice in clinical oncology, aiding both in understanding the molecular mechanisms of tumor development and guiding potential treatments. Whole genome and transcriptome sequencing (WGTS) offers a comprehensive molecular profile of a patient's tumor compared to sequencing panels. By concurrently analyzing a matched germline comparator sample, somatic variants can be accurately differentiated from germline-derived ones, facilitating better interpretation of both somatic as well as germline findings. This approach also provides the opportunity to investigate clinically significant variants in hereditary cancer predisposition genes or the American College of Medical Genetics and Genomics (ACMG) recommendation of reporting secondary findings (SF) from genomic testing, with patient consent. Despite its advantages, paired tumor-germline testing is not universally adopted, particularly in targeted somatic panel testing.
Methods:
Informed consent was obtained from all participants for clinical WGTS testing. Germline variant reporting in normal samples focused on the most current ACMG SF list (v2.0, v3.1, v3.2) at the time of analysis and hereditary cancer predisposition genes identified by Maxwell et al. in 2016 (PMID: 27153395). Variants were classified according to ACMG and ClinGen Sequence Variant Interpretation Working Group guidelines. Result reporting was limited to pathogenic and likely pathogenic variants in the selected gene lists.
Results:
Between January 2021 and October 2024, clinical WGTS test was performed on 99 consented patients. The most frequent tumors tested were breast (n=14), kidney (n=13), blood/bone marrow (n=12), lung (n=8), colorectal (n=7), prostate (n=6), bladder (n=6), and ovary (n=5).
In addition to reporting clinically significant somatic variants, this study focused on reporting of the germline variants which were reported in 19 of the 99 individuals tested (~19%). Sixteen individuals (16/19) harbored P/LP variants in hereditary cancer predisposition genes, including CHEK2 (n=4), APC (n=3), BRCA2 (n=3), FANCA (n=2), and one each in FH, ATM, DICER1, MLH1, CEBPA, TP53, SDHC, and MSH6. Three individuals (3/19) had reportable variants in genes associated with cardiomyopathy (TTN, LMNA, and MYH7).
The clinical context, including tumor type, site, and personal or family history, supported hereditary cancer predisposition syndromes in 8 cases, where identified germline variants were consistent with the tested tumor. In the remaining 8 cases, the reported germline variants were unrelated to the tested tumor or site of the tumor. For these individuals, surveillance measures were initiated, and cascade testing was recommended for at-risk family members. These findings would have been missed without paired tumor-germline testing.
Conclusion:
Integrating germline analysis with tumor sequencing tests should become a standard practice in oncology. This approach not only enhances the interpretation of somatic variants but also identifies hereditary cancer risks and ACMG secondary findings, enabling preventative care and cascade testing for at-risk family members.