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

By C. Pritchard, J. Mateo, M. Walsh, N. Sarkar, W. Abida, H. Beltran, A. Garofalo, R. Gulati, S. Carreira, R. Eeles and 33 more. New England Journal of Medicine, 2016

1,457 citations recorded by the source corpus.

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.)

Subfields: Cancer Research, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/5f3b0c09056a8fa2a5ae7bbaedb6786cf2054279

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Arul M. Chinnaiyan
2. C. Lord
3. S. Roychowdhury
4. R. DePinho

In Pulmonary and Respiratory Medicine

1. Arul M. Chinnaiyan

Citations in the corpus

• A decade of clinical development of PARP inhibitors in perspective (2019, background): “Several genomic landscape studies have estimated that 8%–12% of all mPrC have BRCA2 mutations and homozygous deletions, with around half of these cases being linked to a germline mutation [43, 44].”
• Precision Cancer Medicine: Challenges and Opportunities (2019, background): “Gene expression microarrays, in contrast, can be used to derive genome-wide expression profiles across all transcripts and identify gene expression signatures associated with tumor prognosis [60–65] or tumor sub-classification [66, 67].”
• Olaparib for Metastatic Castration-Resistant Prostate Cancer. (2020, neutral): “Adverse event Any 244 (95) 130 (51) 114 (88) 49 (38) Anemia† 119 (46) 55 (21) 20 (15) 7 (5) Nausea 106 (41) 3 (1) 25 (19) 0 Fatigue or asthenia 105 (41) 7 (3) 42 (32) 7 (5) Decreased appetite 77 (30) 3 (1) 23 (18) 1 (<1) Diarrhea 54 (21) 2 (<1) 9 (7) 0 Vomiting 47 (18) 6 (2) 16 (12) 1 (<1) Constipat”
• Integrative Clinical Genomics of Metastatic Cancer (2017, positive): “Next, we compared the frequencies in genes with PPGMs discovered in the MET500 cohort to the population frequencies in 52,790 individuals compiled by the Exome Aggregation Consortium (ExAC) (http://exac.broadinstitute.org/) excluding TCGA cancer samples 17 .”
• Genetics and biology of prostate cancer (2018, background): “Germline mutations in BRCA genes are associated with increased risk for prostate cancer or a more aggressive phenotype and worse outcomes (Pritchard et al. 2016; Barbieri et al. 2017; Sumanasuriya and De Bono 2018).”
• Genomic correlates of clinical outcome in advanced prostate cancer (2019, neutral): “Some 262 216 179 217 81 47 81 223 99 185 8 8 63 98 17 173 43 12 89 9 35 173 20 7 7 36 exon6-3'UTR exon5-8 exon4-9 exon2-5 exon2-4 exon2-CE4' exon1-4 exon1-3 exon1-CE4 exon3-5 exon2-3(long exon3) ARv8es=AR-V14 (7-9) ARv78es=AR-V13 (6-9) ARv7es (6-8) ARv567es (4-8) ARv5es (4-6) AR-V9 (3-CE5) AR-V8 (3-”