TY - JOUR
T1 - Pathogenic germline DNA repair gene and HOXB13 mutations in men with metastatic prostate cancer
AU - Boyle, Julie L.
AU - Hahn, Andrew W.
AU - Kapron, Ashley L.
AU - Kohlmann, Wendy
AU - Greenberg, Samantha E.
AU - Parnell, Timothy J.
AU - Teerlink, Craig C.
AU - Maughan, Benjamin L.
AU - Feng, Bing Jian
AU - Cannon-Albright, Lisa
AU - Agarwal, Neeraj
AU - Cooney, Kathleen A.
N1 - Funding Information:
We thank the Genome Aggregation Database and all groups that provided exome and genome variant data to this resource; the TCGA Research Network, control data from which was used for metastatic prostate cancer minor allele frequency significance evaluations; Scott Tomlins, MD, PhD, for assisting with gene target selection; the University of Utah Center for Clinical and Translational Science (funded by National Institutes of Health Clinical and Translational Science Awards); the Pedigree and Population Resource; and the University of Utah Information Technology Services and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center, and Intermountain Health Care.
Funding Information:
Supported by National Institutes of Health Grant No. P30CA042014 awarded to the Huntsman Cancer Institute for the Genetic Counseling and High-Throughput Genomics and Bioinformatics Analysis Shared Resource and generous donors; by the Huntsman Cancer Foundation and Department of Defense Grant No. PC170413 (L.C.-A.); by the University of Utah, the Huntsman Cancer Institute, and Huntsman Cancer Institute Cancer Center Support Grant No. P30 CA42014 from the National Cancer Institute in partial support for all data sets within the Utah Population Database; and in part by AstraZeneca.
Publisher Copyright:
© 2020 by American Society of Clinical Oncology.
PY - 2019
Y1 - 2019
N2 - PURPOSE Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. PATIENTS AND METHODS To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/ LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. RESULTS All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations. CONCLUSION These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.
AB - PURPOSE Germline mutations in DNA repair (DR) genes and susceptibility genes CDKN2A and HOXB13 have previously been associated with prostate cancer (PC) incidence and/or progression. However, the role and prevalence of this class of mutations in metastatic PC (mPC) are not fully understood. PATIENTS AND METHODS To evaluate the frequency of pathogenic/likely pathogenic germline variants (PVs/ LPVs) in men with mPC, this study sequenced 38 DR genes, CDKN2A, and HOXB13 in a predominantly white cohort of 317 patients with mPC. A PC registry at the University of Utah was used for patient sample acquisition and retrospective clinical data collection. Deep target sequencing allowed for germline and copy number variant analyses. Validated PVs/LPVs were integrated with clinical and demographic data for statistical correlation analyses. RESULTS All pathogenic variants were found in men self-reported as white, with a carrier frequency of 8.5% (DR genes, 7.3%; CDKN2A/HOXB13, 1.2%). Consistent with previous reports, mutations were most frequently identified in the breast cancer susceptibility gene BRCA2. It was also found that 50% of identified PVs/LPVs were categorized as founder mutations with European origins. Correlation analyses did not support a trend toward more advanced or earlier-onset disease in comparisons between carriers and noncarriers of deleterious DR or HOXB13 G84E mutations. CONCLUSION These findings demonstrate a lower prevalence of germline PVs/LPVs in an unselected, predominantly white mPC cohort than previously reported, which may have implications for the design of clinical trials testing targeted therapies. Larger studies in broad and diverse populations are needed to more accurately define the prevalence of germline mutations in men with mPC.
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U2 - 10.1200/PO.19.00284
DO - 10.1200/PO.19.00284
M3 - Article
C2 - 32923906
AN - SCOPUS:85086475122
SN - 2473-4284
VL - 3
SP - 139
EP - 151
JO - JCO Precision Oncology
JF - JCO Precision Oncology
ER -