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Cited by 1,680BRCA gene mutations in cancerGenetic factors in colorectal cancerProstate Cancer Diagnosis and Treatment

Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer

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Pritchard, Colin C., Mateo, Joaquin, Walsh, Michael F., De Sarkar, Navonil, Abida, Wassim, Beltran, Himisha, Garofalo, Andrea, Gulati, Roman +35 more·2016·New England Journal of Medicine
DOI 10.1056/nejmoa1603144PMC PMC4986616
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Abstract

BACKGROUND: Inherited mutations in DNA-repair genes such as BRCA2 are associated with increased risks of lethal prostate cancer. Although the prevalence of germline mutations in DNA-repair genes among men with localized prostate cancer who are unselected for family predisposition is insufficient to warrant routine testing, the frequency of such mutations in patients with metastatic prostate cancer has not been established. METHODS: We recruited 692 men with documented metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis. We isolated germline DNA and used multiplex sequencing assays to assess mutations in 20 DNA-repair genes associated with autosomal dominant cancer-predisposition syndromes. RESULTS: A total of 84 germline DNA-repair gene mutations that were presumed to be deleterious were identified in 82 men (11.8%); mutations were found in 16 genes, including BRCA2 (37 men [5.3%]), ATM (11 [1.6%]), CHEK2 (10 [1.9% of 534 men with data]), BRCA1 (6 [0.9%]), RAD51D (3 [0.4%]), and PALB2 (3 [0.4%]). Mutation frequencies did not differ according to whether a family history of prostate cancer was present or according to age at diagnosis. Overall, the frequency of germline mutations in DNA-repair genes among men with metastatic prostate cancer significantly exceeded the prevalence of 4.6% among 499 men with localized prostate cancer (P<0.001), including men with high-risk disease, and the prevalence of 2.7% in the Exome Aggregation Consortium, which includes 53,105 persons without a known cancer diagnosis (P<0.001). CONCLUSIONS: In our multicenter study, the incidence of germline mutations in genes mediating DNA-repair processes among men with metastatic prostate cancer was 11.8%, which was significantly higher than the incidence among men with localized prostate cancer. The frequencies of germline mutations in DNA-repair genes among men with metastatic disease did not differ significantly according to age at diagnosis or family history of prostate cancer. (Funded by Stand Up To Cancer and others.).

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  1. [1]Albertsen PC Hanley JA Fine J 20-Year outcomes following conservative management of clinically localized prostate cancer JAMA 2005 293 2095 2101 15870412
  2. [3]Mucci LA Hjelmborg JB Harris JR Familial risk and heritability of cancer among twins in Nordic countries JAMA 2016 315 68 76 26746459 PMC5498110
  3. [4]Amin Al Olama A Kote-Jarai Z Schumacher FR A meta-analysis of genome-wide association studies to identify prostate cancer susceptibility loci associated with aggressive and non-aggressive disease Hum Mol Genet 2013 22 408 415 23065704 PMC3526158
  4. [5]Szulkin R Karlsson R Whitington T Genome-wide association study of prostate cancer-specific survival Cancer Epidemiol Biomarkers Prev 2015 24 1796 1800 26307654 PMC5674990
  5. [6]Helfand BT Roehl KA Cooper PR Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases Hum Genet 2015 134 439 450 25715684 PMC4586077
  6. [7]Berndt SI Wang Z Yeager M Two susceptibility loci identified for prostate cancer aggressiveness Nat Commun 2015 6 6889 25939597 PMC4422072
  7. [8]Haraldsdottir S Hampel H Wei L Prostate cancer incidence in males with Lynch syndrome Genet Med 2014 16 553 557 24434690 PMC4289599
  8. [9]Kote-Jarai Z Leongamornlert D Saunders E BRCA2 is a moderate penetrance gene contributing to youngonset prostate cancer: implications for genetic testing in prostate cancer patients Br J Cancer 2011 105 1230 1234 21952622 PMC3208504
  9. [10]Leongamornlert D Mahmud N Tymrakiewicz M Germline BRCA1 mutations increase prostate cancer risk Br J Cancer 2012 106 1697 1701 22516946 PMC3349179
  10. [11]Xu J Lange EM Lu L HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG) Hum Genet 2013 132 5 14 23064873 PMC3535370
  11. [12]Gallagher DJ Gaudet MM Pal P Germline BRCA mutations denote a clinicopathologic subset of prostate cancer Clin Cancer Res 2010 16 2115 2121 20215531 PMC3713614
  12. [13]Castro E Goh C Olmos D Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer J Clin Oncol 2013 31 1748 1757 23569316 PMC3641696
  13. [14]Leongamornlert D Saunders E Dadaev T Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease Br J Cancer 2014 110 1663 1672 24556621 PMC3960610
  14. [15]Loeb S Bjurlin MA Nicholson J Overdiagnosis and overtreatment of prostate cancer Eur Urol 2014 65 1046 1055 24439788 PMC4113338
  15. [16]Mateo J Carreira S Sandhu S DNA-repair defects and olaparib in metastatic prostate cancer N Engl J Med 2015 373 1697 1708 26510020 PMC5228595
  16. [17]Cheng HH Pritchard CC Boyd T Nelson PS Montgomery B Biallelic inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant prostate cancer Eur Urol 2016 69 992 995 26724258 PMC4909531
  17. [19]Pritchard CC Morrissey C Kumar A Complex MSH2 and MSH6 mutations in hypermutated microsatellite unstable advanced prostate cancer Nat Commun 2014 5 4988 25255306 PMC4176888
  18. [20]Pritchard CC Smith C Salipante SJ ColoSeq provides comprehensive Lynch and polyposis syndrome mutational analysis using massively parallel sequencing J Mol Diagn 2012 14 357 366 22658618 PMC3391416
  19. [21]Pritchard CC Salipante SJ Koehler K Validation and implementation of targeted capture and sequencing for the detection of actionable mutation, copy number variation, and gene rearrangement in clinical cancer specimens J Mol Diagn 2014 16 56 67 24189654 PMC3873496
  20. [22]Beltran H Eng K Mosquera JM Whole-exome sequencing of metastatic cancer and biomarkers of treatment response JAMA Oncol 2015 1 466 474 26181256 PMC4505739
  21. [23]Schrader KA Cheng DT Joseph V Germline variants in targeted tumor sequencing using matched normal DNA JAMA Oncol 2016 2 104 111 26556299 PMC5477989
  22. [25]Cancer Genome Atlas Research Network The molecular taxonomy of primary prostate cancer Cell 2015 163 1011 1025 26544944 PMC4695400
  23. [26]Shirts BH Casadei S Jacobson AL Improving performance of multigene panels for genomic analysis of cancer predisposition Genet Med 2016 2 4 (Epub ahead of print) 26845104
  24. [27]Walsh T Lee MK Casadei S Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing Proc Natl Acad Sci USA 2010 107 12629 12633 20616022 PMC2906584
  25. [29]Tapia T Smalley SV Kohen P Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors Epigenetics 2008 3 157 163 18567944
  26. [30]Meeks HD Song H Michailidou K BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers J Natl Cancer Inst 2016 108 108 PMC4907358 26586665
  27. [31]Wilt TJ Brawer MK Jones KM Radical prostatectomy versus observation for localized prostate cancer N Engl J Med 2012 367 203 213 22808955 PMC3429335
  28. [32]Schröder FH Hugosson J Roobol MJ Screening and prostate-cancer mortality in a randomized European study N Engl J Med 2009 360 1320 1328 19297566
  29. [33]Schröder FH Hugosson J Carlsson S Screening for prostate cancer decreases the risk of developing metastatic disease: findings from the European Randomized Study of Screening for Prostate Cancer (ERSPC) Eur Urol 2012 62 745 752 22704366
  30. [34]Mohler JL Armstrong AJ Bahnson RR Prostate cancer, version 1.2016 J Natl Compr Canc Netw 2016 14 19 30 26733552
  31. [35]Jeggo PA Pearl LH Carr AM DNA repair, genome stability and cancer: a historical perspective Nat Rev Cancer 2016 16 35 42 26667849
  32. [36]Isakoff SJ Mayer EL He L TB-CRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer J Clin Oncol 2015 33 1902 1909 25847936 PMC4451173
  33. [37]Alsop K Fereday S Meldrum C BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group J Clin Oncol 2012 30 2654 2663 22711857 PMC3413277
  34. [38]King MC Marks JH Mandell JB Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 Science 2003 302 643 646 14576434
  35. [39]Weitzel JN Lagos VI Cullinane CA Limited family structure and BRCA gene mutation status in single cases of breast cancer JAMA 2007 297 2587 2595 17579227
  36. [40]National Comprehensive Cancer Network Genetic/familial high-risk assessment: breast and ovarian, version 2.2016 (https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf) 26850485

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Authors
Pritchard, C. C., Mateo, J., Walsh, M. F., De Sarkar, N., Abida, W., Beltran, H., Garofalo, A., Gulati, R., Carreira, S., Eeles, R., Elemento, O., Rubin, M. A., Robinson, D., Lonigro, R., Hussain, M., Chinnaiyan, A., Vinson, J., Filipenko, J., Garraway, L., Taplin, M.-E., AlDubayan, S., Han, G. C., Beightol, M., Morrissey, C., Nghiem, B., Cheng, H. H., Montgomery, B., Walsh, T., Casadei, S., Berger, M., Zhang, L., Zehir, A., Vijai, J., Scher, H. I., Sawyers, C., Schultz, N., Kantoff, P. W., Solit, D., Robson, M., Van Allen, E. M., Offit, K., de Bono, J., & Nelson, P. S.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
2016-08-04
Volume
375
Issue
5
Pages
443-453
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejmoa1603144
PMC
PMC4986616
OpenAlex
W2462985846
Cited by
1,680
References
4
Citations by year
2026: 122 · 2025: 152 · 2024: 170 · 2023: 166 · 2022: 205 · 2021: 217 · 2020: 186 · 2019: 161 · 2018: 141 · 2017: 120 · 2016: 36 · 2014: 1
FWCI
123.33
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • U.S. Department of Defense (PC131820)
  • Howard Hughes Medical Institute
  • American Association for Cancer Research (SU2C-AACR-DT0712)
  • Prostate Cancer Foundation (P30 CA008748, P50CA097186, PC131820, SU2C-AACR-DT0712)
  • Damon Runyon Cancer Research Foundation
  • Entertainment Industry Foundation
  • Wayne State University
  • Lucas Foundation (P50CA097186)
  • Memorial Sloan-Kettering Cancer Center (P30 CA008748)
  • University of Washington
  • Movember Foundation
  • Andrew Sabin Family Foundation
  • Institute for Prostate Cancer Research
  • Cancer Research UK (15007, 17528)
  • Prostate Cancer UK
  • National Institutes of Health
  • Weill Cornell Medical College
  • Stand Up To Cancer (SU2C-AACR-DT0712)
  • Marie-Josée and Henry R. Kravis Center for Molecular Oncology
  • Medical Research Council (MR/M003272/1)
  • National Cancer Institute (K08CA188615, PC131820, P50 CA92629, R01CA175716, R01CA116337, PC140799, R35CA197458, R01CA155169, P30CA008748, P50CA097186, P50CA180995, P50CA092629, R01CA193837)
  • National Institute of General Medical Sciences (T32GM007266)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
Keywords
metastatic prostate cancer, germline mutations, DNA repair genes, BRCA2, ATM, CHEK2, BRCA1, RAD51D, PALB2, hereditary cancer predisposition, localized prostate cancer, mutation prevalence, family history of prostate cancer, age at diagnosis
MeSH terms
Age Factors, Aged, Aged, 80 and over, DNA Mutational Analysis, DNA Repair, Humans, Male, Middle Aged, Neoplasm Metastasis, Prostatic Neoplasms, Incidence, Germ-Line Mutation, Genetic Predisposition to Disease

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