Synapse - Gene-based confirmatory germline testing following tumor-only sequencing of prostate cancer

Gene-based confirmatory germline testing following tumor-only sequencing of prostate cancer Journal Article

Authors:	Truong, H.; Breen, K.; Nandakumar, S.; Sjoberg, D. D.; Kemel, Y.; Mehta, N.; Lenis, A. T.; Reisz, P. A.; Carruthers, J.; Benfante, N.; Joseph, V.; Khurram, A.; Gopalan, A.; Fine, S. W.; Reuter, V. E.; Vickers, A. J.; Birsoy, O.; Liu, Y.; Walsh, M.; Latham, A.; Mandelker, D.; Stadler, Z. K.; Pietzak, E.; Ehdaie, B.; Touijer, K. A.; Laudone, V. P.; Slovin, S. F.; Autio, K. A.; Danila, D. C.; Rathkopf, D. E.; Eastham, J. A.; Chen, Y.; Morris, M. J.; Offit, K.; Solit, D. B.; Scher, H. I.; Abida, W.; Robson, M. E.; Carlo, M. I.
Article Title:	Gene-based confirmatory germline testing following tumor-only sequencing of prostate cancer
Abstract:	Background: 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. © 2022 European Association of Urology
Keywords:	adult; controlled study; middle aged; unclassified drug; major clinical study; sequence analysis; somatic mutation; genetics; clinical feature; advanced cancer; comparative study; dna repair; cancer susceptibility; genetic predisposition to disease; metastasis; protein; cohort analysis; genetic association; cancer screening; brca1 protein; brca2 protein; protein p53; carcinogenesis; prostate cancer; prostatic neoplasms; cancer center; heterozygosity; microsatellite instability; family history; prostate tumor; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; atm protein; genomics; checkpoint kinase 2; microphthalmia associated transcription factor; tumor suppressor protein; genetic predisposition; genetic screening; lynch syndrome; protein msh6; apc protein; germ-line mutation; genetic testing; penetrance; molecular pathology; clinical outcome; germline mutation; retinoblastoma binding protein 1; advanced prostate cancer; dna sequencing; humans; human; male; article; hereditary tumor syndrome; mutl protein homolog 1; dna mismatch repair protein msh2; germline testing; tumor mutational burden; tumor-only sequencing; dna damage repair genes; hoxb13 protein; familial renal cell carcinoma
Journal Title:	European Urology
Volume:	83
Issue:	1
ISSN:	0302-2838
Publisher:	Elsevier Science, Inc.
Date Published:	2023-01-01
Start Page:	29
End Page:	38
Language:	English
DOI:	10.1016/j.eururo.2022.08.028
PUBMED:	36115772
PROVIDER:	scopus
PMCID:	PMC10208030
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85138110715&doi=10.1016%2fj.eururo.2022.08.028&partnerID=40&md5=f746b5c348a59896c70e948c18a1a5f0
Notes:	Maria I. Carlo is the corresponding author for this article -- Export Date: 3 January 2023 -- Source: Scopus