Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death

Na, R.; Zheng, S.L.; Han, M.; Yu, H.; Jiang, D.; Shah, S.; Ewing, C.; Zhang, L.; Novakovic, K.; Petkewicz, J.; Gulukota, K.; Helseth, D.; Quinn, M.; Humphries, E.; Wiley, K.; Isaacs, S.; Wu, Y.; Liu, X.; Zhang, Naijun; Wang, Chenbin; Khandekar, J.; Hulick, P.; Shevrin, D.; Cooney, K.; Shen, Z.; Partin, A.; Carter, H.B.; Carducci, M.; Eisenberger, M.; Denmeade, S.; McGuire, M.; Walsh, P.; Helfand, B.; Brendler, C.; Ding, Q.; Xu, J.; Isaacs, W.

doi:10.1016/s1569-9056(17)30541-9

Cited by 59 publications

(84 citation statements)

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“…For example, men with BRCA2 germline mutations are known to be at increased risk for prostate cancer, and typically display an earlier age of onset of disease and aggressive clinical phenotypes. 6,7,25,26 These high-risk prostate cancer features have led to guideline recommendations for prostate cancer screening beginning at age 40 in unaffected BRCA2 mutation carriers. Our current study also suggests that use of multigene panel genetic tests may be particularly useful in this population given the varied tumor phenotypes, genes mutated, and the finding that a majority of the mutation carriers did not meet current NCCN guidelines for clinical genetic testing for hereditary cancer syndromes.…”

Section: Discussionmentioning

confidence: 99%

Germline genetic variants in men with prostate cancer and one or more additional cancers

Pilié

Johnson

Hanson

et al. 2017

Cancer

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Purpose Prostate cancer has a significant heritable component, and rare deleterious germline variants in certain genes can increase the risk of prostate cancer. Our aim was to describe the prevalence of pathogenic germline variants in cancer predisposing genes in men with prostate cancer and at least one additional primary cancer. Patients and Methods Using a multi-gene panel, we sequenced germline DNA from 102 men with prostate cancer and at least one additional primary cancer who also met one or more of the following criteria: 1) age ≤ 55 at diagnosis of first malignancy, 2) rare tumor type or atypical presentation of a common tumor, and/or 3) three or more primary malignancies. Cancer family history and clinicopathologic data were independently reviewed by a clinical genetic counselor to determine if the patient met established criteria for testing for a hereditary cancer syndrome. Results Sequencing identified ~3500 variants. Nine protein truncating deleterious mutations were found across six genes including BRCA2, ATM, MLH1, BRIP1, PALB2, and FGFR3. Likely pathogenic missense variants were identified in CHEK2 and HOXB13. In total, 11/102 (10.8%) subjects were found to have pathogenic or likely pathogenic mutations in cancer predisposing genes. The majority of these men (64%) did not meet current clinical criteria for germline testing. Conclusion Men with prostate cancer and at least one additional primary cancer are enriched for harboring a germline deleterious mutation in a cancer predisposing gene that may impact cancer prognosis and treatment, but most do not meet current criteria for clinical genetic testing.

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Section: Discussionmentioning

confidence: 99%

Germline genetic variants in men with prostate cancer and one or more additional cancers

Pilié

Johnson

Hanson

et al. 2017

Cancer

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“…A customized next‐generation sequencing panel that targeted 222 cancer‐related genes was used to sequence the germline DNA samples, including 54 DNA repair genes and 168 cancer‐related genes in other biological pathways. The pipelines used for sequencing and bioinformatics analysis were described in our previous study . Notably, more stringent criteria were used to identify the pathogenicity of variants in addition to the American College of Medical Genetics and Genomics criteria .…”

Section: Methodsmentioning

confidence: 99%

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

Jiang

et al. 2018

BJU International

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“…Furthermore, some panelists raised questions on testing all men with metastatic PCA and not limiting testing to the castrationresistance setting. Because most of the current data on germline mutations are in the castration-resistant setting, [31][32][33][34] proposed criteria were focused on mCRPC, which may change over time. Postconsensus discussion also included the potential for broader scope of genetic testing criteria in the treatment setting versus the risk-assessment setting, which can be considered in future consensus updates.…”

Section: 47mentioning

confidence: 99%

“…[25][26][27][28][29][30] Furthermore, inherited genetic mutations are being uncovered in up to 12% of men with metastatic PCA, primarily in DNA repair genes such as BRCA1, BRCA2, and ATM, 31,32 with improved clinical outcomes by specific targeted agents. 33,34 Identifying genetic mutations of inherited PCA, therefore, has implications for cancer risk assessment for men and their families, 35,36 for precision treatment of metastatic disease, 33,34 and is being incorporated into guidelines for individualized PCA screening strategies specifically for male BRCA1/2 mutation carriers.…”

Section: Introductionmentioning

confidence: 99%

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

Giri

Knudsen

Kelly

et al. 2018

JCO

164

142

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Guidelines are limited for genetic testing for prostate cancer (PCA). The goal of this conference was to develop an expert consensus-driven working framework for comprehensive genetic evaluation of inherited PCA in the multigene testing era addressing genetic counseling, testing, and genetically informed management. MethodsAn expert consensus conference was convened including key stakeholders to address genetic counseling and testing, PCA screening, and management informed by evidence review. ResultsConsensus was strong that patients should engage in shared decision making for genetic testing. There was strong consensus to test HOXB13 for suspected hereditary PCA, BRCA1/2 for suspected hereditary breast and ovarian cancer, and DNA mismatch repair genes for suspected Lynch syndrome. There was strong consensus to factor BRCA2 mutations into PCA screening discussions. BRCA2 achieved moderate consensus for factoring into early-stage management discussion, with stronger consensus in high-risk/advanced and metastatic setting. Agreement was moderate to test all men with metastatic castration-resistant PCA, regardless of family history, with stronger agreement to test BRCA1/2 and moderate agreement to test ATM to inform prognosis and targeted therapy. ConclusionTo our knowledge, this is the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited PCA in the multigene testing era. Future research should focus on developing a working definition of familial PCA for clinical genetic testing, expanding understanding of genetic contribution to aggressive PCA, exploring clinical use of genetic testing for PCA management, genetic testing of African American males, and addressing the value framework of genetic evaluation and testing men at risk for PCA-a clinically heterogeneous disease. J Clin Oncol 36:414-424. © 2017 by American Society of Clinical Oncology INTRODUCTIONProstate cancer (PCA) is the third leading cause of cancer-related death in US men, accounting for 26,730 deaths in 2017. 1 There is increasing evidence that PCA has substantial inherited predisposition, 2,3 with higher risks conferred by BRCA2 and BRCA1 (associated with hereditary breast and ovarian cancer [HBOC] syndrome), and HOXB13 (associated with hereditary prostate cancer [HPC]). Furthermore, BRCA2 mutations have been associated with poor PCA-specific outcomes. [9][10][11][12][13] There is also emerging evidence of the link between PCA Author affiliations and support information (if applicable) appear at the end of this article.Published at jco.org on December 13, 2017. and DNA mismatch repair (MMR) gene mutations (accounting for Lynch syndrome [LS]). [25][26][27][28][29][30] Furthermore, inherited genetic mutations are being uncovered in up to 12% of men with metastatic PCA, primarily in DNA repair genes such as BRCA1, BRCA2, and ATM, 31,32 with improved clinical outcomes by specific targeted agents. 33,34 Identifying genetic mutations of inherited PCA, therefore, has implications for cancer...

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Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death

Abstract: Author contributions: Jianfeng Xu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Xu, Isaacs, Ding.

Cited by 59 publications

References 23 publications

Germline genetic variants in men with prostate cancer and one or more additional cancers

Germline genetic variants in men with prostate cancer and one or more additional cancers

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

Role of Genetic Testing for Inherited Prostate Cancer Risk: Philadelphia Prostate Cancer Consensus Conference 2017

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