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

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.)

Heterogeneity of advanced prostate cancer: clinical implications of genomics

“…As inherited mutations in DNA-repair genes are associated with increased risks of lethal prostate cancer, Pritchard et al used a 20-gene targeted sequencing panel to determine the prevalence of germline DNA-repair mutations. 4 The frequency of 11.8% (82/692) was surprisingly high, demonstrating that a sizeable proportion of DNA aberrations found in mCRPC are indeed heritable. The remainder of this article focuses on how this knowledge of inter-patient heterogeneity is being exploited to improve therapeutic options, response assessment and clinical trial design.…”

Prognostic and predictive biomarkers of prostate cancer

“…Секвени-рование метастатических опухолей 150 мужчин с крРПЖ выявило у каждого 4-го пациента изменения в генах репарации ДНК [24]. Герминативные мутации в генах репарации ДНК, таких как BRCA2 [10], BRIP1, FANCA и MUTYH [25,26], ассоциируются с повышен-ным риском метастатического распространения опу-холи. Экспрессия одного или более белков системы РОР (таких как MLH1, MSH2, MSH6, PMS1 и PMS2) снижена в клетках РПЖ вследствие мутаций в их ге-нах.…”

“…У мужчин с ранним началом данного заболевания имеется более высокое суммар-ное число аллелей риска по сравнению с пациентами старшего возраста. Герминативные мутации при РПЖ зарегистрированы в генах ELAC2 / HPC2, MSR1, HPC1 / RNASEL, PALB2 [9], BRCA1 [10] , BRCA2, HOXB13, TRRAP, FLT3, CDX2, FANCA, ATP1A1, BRIP1, CBFA2T3, CLTCL1, CREBBP, ERCC4, FANCE, FRFR3, HOXD11, MUTYH, NOTCH1, PDGFRA, RAD51B, SMAR-CA4, TCF3 [11], AR [12].…”

“…Высокие значе-ния индекса Глисона указывают на то, что герминатив-ные мутации способствуют высокой злокачественности [11]. Частота герминативных мутаций у пациентов с метастатическим РПЖ (мРПЖ) значительно превы-шает их распространенность у пациентов с локализо-ванным РПЖ, в том числе высокого риска, независимо от возраста на момент постановки диагноза [10].…”

Targeted Gene Sequencing of Gallbladder Carcinoma Identifies High-impact Somatic and Rare Germline Mutations

“…Several cancer drivers and progression markers were established in this way. More recently, the cancer research field has begun to understand the importance of rare deleterious germline variants in carcinogenesis and progression (28,29,37). GBC is not among the most heritable types of human cancer, although variability in its ethnic and geographical incidence rates has been partly associated with cancer predisposition (38)(39)(40).…”