Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 15;14(1):92.
doi: 10.1186/s13073-022-01101-2.

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

Ozge Ceyhan-Birsoy #  1 , Gowtham Jayakumaran #  1 , Yelena Kemel  2 , Maksym Misyura  1 , Umut Aypar  1 , Sowmya Jairam  1 , Ciyu Yang  1 , Yirong Li  1 , Nikita Mehta  1 , Anna Maio  3 , Angela Arnold  3 , Erin Salo-Mullen  3 , Margaret Sheehan  3 , Aijazuddin Syed  1 , Michael Walsh  3 , Maria Carlo  3 , Mark Robson  3 , Kenneth Offit  3 , Marc Ladanyi  1 , Jorge S Reis-Filho  1 , Zsofia K Stadler  3 , Liying Zhang  1   4 , Alicia Latham  3 , Ahmet Zehir  5   6 , Diana Mandelker  7
Affiliations

Diagnostic yield and clinical relevance of expanded genetic testing for cancer patients

Ozge Ceyhan-Birsoy et al. Genome Med. .

Abstract

Background: Genetic testing (GT) for hereditary cancer predisposition is traditionally performed on selected genes based on established guidelines for each cancer type. Recently, expanded GT (eGT) using large hereditary cancer gene panels uncovered hereditary predisposition in a greater proportion of patients than previously anticipated. We sought to define the diagnostic yield of eGT and its clinical relevance in a broad cancer patient population over a 5-year period.

Methods: A total of 17,523 cancer patients with a broad range of solid tumors, who received eGT at Memorial Sloan Kettering Cancer Center between July 2015 to April 2020, were included in the study. The patients were unselected for current GT criteria such as cancer type, age of onset, and/or family history of disease. The diagnostic yield of eGT was determined for each cancer type. For 9187 patients with five common cancer types frequently interrogated for hereditary predisposition (breast, colorectal, ovarian, pancreatic, and prostate cancer), the rate of pathogenic/likely pathogenic (P/LP) variants in genes that have been associated with each cancer type was analyzed. The clinical implications of additional findings in genes not known to be associated with a patients' cancer type were investigated.

Results: 16.7% of patients in a broad cancer cohort had P/LP variants in hereditary cancer predisposition genes identified by eGT. The diagnostic yield of eGT in patients with breast, colorectal, ovarian, pancreatic, and prostate cancer was 17.5%, 15.3%, 24.2%, 19.4%, and 15.9%, respectively. Additionally, 8% of the patients with five common cancers had P/LP variants in genes not known to be associated with the patient's current cancer type, with 0.8% of them having such a variant that confers a high risk for another cancer type. Analysis of clinical and family histories revealed that 74% of patients with variants in genes not associated with their current cancer type but which conferred a high risk for another cancer did not meet the current GT criteria for the genes harboring these variants. One or more variants of uncertain significance were identified in 57% of the patients.

Conclusions: Compared to targeted testing approaches, eGT can increase the yield of detection of hereditary cancer predisposition in patients with a range of tumors, allowing opportunities for enhanced surveillance and intervention. The benefits of performing eGT should be weighed against the added number of VUSs identified with this approach.

PubMed Disclaimer

Conflict of interest statement

J.S. Reis-Filho reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics, Paige.AI, and Eli Lilly; membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Paige.AI, and Personalis; membership of the Board of Directors of Grupo Oncoclinicas; and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Novartis, Genentech, and InVicro, outside the scope of this study. Z.K. Stadler’s immediate family member serves as a consultant in Ophthalmology for Alcon, Adverum Biotechnologies, Gyroscope Therapeutics Limited, Neurogene, and RegenexBio outside the submitted work. M.E. Robson reports grants from AstraZeneca, Merck, and Pfizer and personal fees from Change Healthcare outside the submitted work, as well as an uncompensated advisory for Artios Pharma, AstraZeneca, Daiichi Sankyo, Epic Sciences, Merck, Pfizer, Tempus Lab, and Zenith Pharma. L. Zhang reports receiving honoraria from Future Technology Research LLC, BGI, Illumina, and Roche Diagnostics Asia Pacific. L. Zhang’s family members hold a leadership position and ownership interests of Decipher Medicine. A. Zehir is currently an employee of AstraZeneca. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Distribution of pathogenic/likely pathogenic variants identified in eGT of 17,523 cancer patients across genes and cancer types. The distribution of P/LP variants identified in patients with each cancer type, grouped based on gene penetrance and inheritance pattern, is presented. The number of patients in each category is in parentheses. Specific variants that show different penetrance or inheritance pattern from typical variants in the gene were plotted separately: APC^: APC p.Ile1307Lys; CHEK2^: CHEK2 p.Ile157Thr; FH^: FH p.Lys477dup; and VHL^: VHL p.Arg200Trp. Percentage of high/moderate-penetrance (%H/M pen) variants identified in each cancer type and overall percentage of patients with P/LP variants (%Overall) are presented with 95% confidence intervals in parentheses
Fig. 2
Fig. 2
Rate of positive results identified in each gene in patients with five common cancer types. Percentage of patients with breast cancer (n = 2243), colorectal cancer (n = 2060), ovarian cancer (n = 1122), pancreatic cancer (n = 1648), and prostate cancer (n = 2114) who had P/LP variants in genes that have been associated with each cancer type. Error bars represent 95% confidence intervals
Fig. 3
Fig. 3
Pathogenic/likely pathogenic variants identified in genes not associated with the patient’s cancer type. Genes were grouped based on inheritance pattern, and autosomal dominant genes were further grouped based on penetrance as high, moderate, low, and uncertain. In three genes, only specific variants were targeted: HOXB13 p.Gly84Glu, MITF p.Glu318Lys, and YAP1 p.Arg331Trp. Certain variants were considered as having different penetrance or inheritance pattern from typical variants in the gene: APC p.Ile1307Lys and CHEK2 p.Ile157Thr as having uncertain penetrance; FH p.Lys477dup, VHL p.Arg200Trp, and EGFR loss-of-function variants as being AR. The percentage of carriers within each cancer type is presented in the upper panels. The number of P/LP variants identified in each gene and cancer type are presented in the lower panels
See this image and copyright information in PMC

References

    1. Robson ME, et al. American Society of Clinical Oncology Policy Statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2015;33(31):3660–3667. doi: 10.1200/JCO.2015.63.0996. - DOI - PubMed
    1. Stadler ZK, et al. Cancer genomics and inherited risk. J Clin Oncol. 2014;32(7):687–698. doi: 10.1200/JCO.2013.49.7271. - DOI - PMC - PubMed
    1. Mandelker D, Ceyhan-Birsoy O. Evolving significance of tumor-normal sequencing in cancer care. Trends Cancer. 2020;6(1):31–39. doi: 10.1016/j.trecan.2019.11.006. - DOI - PMC - PubMed
    1. Jonsson P, et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature. 2019;571(7766):576–579. doi: 10.1038/s41586-019-1382-1. - DOI - PMC - PubMed
    1. Le DT, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413. doi: 10.1126/science.aan6733. - DOI - PMC - PubMed

Publication types