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Gene-Based Confirmatory Germline Testing Following Tumor-Only Sequencing of Prostate Cancer
TAKE-HOME MESSAGE
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The authors performed an analysis of data from men with prostate cancer undergoing both tumor and germline sequencing to determine the conditions under which the identification of tumor variants should prompt confirmatory germline testing. Of the patients harboring pathogenic or likely pathogenic variants, germline testing was positive for at least one actionable variant in nearly one-fourth of the patients.
- Urologists should continue to focus on performing germline testing for men with advanced and high-risk prostate cancer, as many patients harbor actionable mutations. The urologic community should continue to provide resources to providers regarding this topic for improving the utilization of germline testing in the appropriate patient populations.
abstract
This abstract is available on the publisher's site.
Access this abstract now Full Text Available for ClinicalKey SubscribersBACKGROUND
Tumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.
OBJECTIVE
To determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.
DESIGN, SETTING, AND PARTICIPANTS
Men with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS
Tumor and germline profiles were analyzed for pathogenic and likely pathogenic ("pathogenic") variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability.
RESULTS AND LIMITATIONS
Of the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants.
CONCLUSIONS
Of patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing.
PATIENT SUMMARY
Patients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient's prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome.
Additional Info
Disclosure statements are available on the authors' profiles:
Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer
Eur Urol 2022 Sep 14;[EPub Ahead of Print], H Truong, K Breen, S Nandakumar, DD Sjoberg, Y Kemel, N Mehta, AT Lenis, PA Reisz, J Carruthers, N Benfante, V Joseph, A Khurram, A Gopalan, SW Fine, VE Reuter, AJ Vickers, O Birsoy, Y Liu, M Walsh, A Latham, D Mandelker, ZK Stadler, E Pietzak, B Ehdaie, KA Touijer, VP Laudone, SF Slovin, KA Autio, DC Danila, DE Rathkopf, JA Eastham, Y Chen, MJ Morris, K Offit, DB Solit, HI Scher, W Abida, ME Robson, MI CarloFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Genetic testing recommendations are becoming much more common for patients with urological malignancies, with a guideline that all men with advanced prostate cancer should undergo genetic counseling. Urological malignancies are not the only solid tumor diseases with these increased recommendations and referrals; therefore, the impact on the healthcare system, genetic counselors, and education regarding understanding germline testing is strained. This study presents a potential work around that could decrease the strain of genetic referral by using prostate cancer tumor (primary or metastatic site) profiling as an initial screen for the necessity of germline testing. Of all variants on tumor sequencing, the finding of actionable germline variant was 22%, proving that this population should be referred and screened for germline mutations with higher priority than just all individuals with advanced prostate cancer. Another example: DDR mutations found in prostate tumor sequencing could lead to a trigger for germline testing, and this was identified in up to 40% of the patients in this study, with the highest likelihood of identification of germline mutation in PALB2 (69%), MTIF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%). This study may allow for a more personalized approach for genetic counseling and germline testing referral in patients with advanced prostate cancer.
This is a study from the Memorial Sloan Kettering Cancer Center involving men who underwent tumor and germline sequencing for prostate cancer. A total of 1883 patients with prostate cancer were identified, and 58% had a somatic or germline pathogenic variant in one of the 60 examined genes. Of these patients, 22% had at least one germline variant.
Some of the variations were exclusively in the somatic genes analyzed, which included TP53, P10, and RB1. The somatic variants that had the highest probability of a germline co-mutation were PALB2, MITF, HOXB13, CHEK2, BRCA1, and BRCA2. The probability of a germline variant varied between 47% and 69%, with both of the BRCA genes demonstrating probabilities of approximately 50%.
These data indicate that a high percentage of patients will have germline or somatic alterations detected on next-generation sequencing. A number of these alterations are clinically actionable, and what is clinically actionable today may be different tomorrow, given the intense research effort focusing on targeted therapies. Men with advanced prostate cancer are recommended to undergo germline testing, and it is important to recognize that somatic genetic testing can add value in a substantial number of cases.