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

Pilié, Patrick G.; Johnson, Anna; Hanson, Kristen; Dayno, M.; Kapron, Ashley L.; Stoffel, Elena M.; Cooney, Kathleen A.

doi:10.1002/cncr.30817

Cited by 49 publications

(49 citation statements)

References 33 publications

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“…This incomplete penetrance suggests that modifier genes, epigenetic events and environmental factors may determine the cancer phenotype. 15 Interestingly, the presence of three prostate cancer cases in this family would be in agreement with other studies describing the association of BRIP1 mutations with prostate cancer cases in the context of Hereditary Breast Cancer families 16,17 One of the prostate cancers in our family (II.9) is an obligate carrier, but it could not be ascertained in the other two cases (II.6, II.8), so it would be advisable to test male relatives and follow-up of carriers.…”

Section: Discussionsupporting

confidence: 91%

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Velázquez

Esteban-Cardeñosa

Lastra³

et al. 2018

Molecular Carcinogenesis

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BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of "variants of uncertain significance" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing Finder predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.

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Section: Discussionsupporting

confidence: 91%

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Velázquez

Esteban-Cardeñosa

Lastra³

et al. 2018

Molecular Carcinogenesis

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“…Before those studies, there had been limited work investigating a potential role for ATM in prostate cancer predisposition. Various studies now confirm that germline alterations in ATM can be identified in men who have prostate cancer . Further evidence that germline alterations in ATM contribute to the risk of prostate cancer was produced by comparing their frequency in patients who had prostate cancer with a population of noncancer controls in the Exome Aggregation Consortium (EXAC).…”

Section: Genetic Basis Of Prostate Cancer Predispositionmentioning

confidence: 99%

“…Although these guidelines share similarities, there is still a clear need to establish uniform guidelines for risk assessment. It was recently reported that expanding testing to patients with a second cancer diagnosis may identify germline cancer alterations in >10% of individuals; however, restricting testing to the above guidelines may miss the majority of these patients …”

Section: The Role Of Genetic Counseling Risk Assessment and Testingmentioning

confidence: 99%

“…Various studies now confirm that germline alterations in ATM can be identified in men who have prostate cancer. 36 Further evidence that germline alterations in ATM contribute to the risk of prostate cancer was produced by comparing their frequency in patients who had prostate cancer with a population of noncancer controls in the Exome Aggregation Consortium (EXAC). The estimated RR of metastatic prostate cancer in ATM carriers was 6.3 (95% CI, 3.2-11.3; P < .001).…”

Section: Genes Associated With Prostate Cancermentioning

confidence: 99%

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Genetic testing for hereditary prostate cancer: Current status and limitations

Zhen

Syed

Nguyen

et al. 2018

Cancer

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A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

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“…Mutations are associated with lifetime risks of 80% for breast cancer and 15%-40% for cancer of the ovary or fallopian tube for BRCA2 and BRCA1 respectively 3 . BRCA2 is the most frequently mutated gene in both prostate cancer 4,5 and pancreatic cancer [6][7][8] , and patients with BRCA2 mutations can benefit from novel therapies such as cis-platinum 9 . Annually, about 8500 cases of prostate cancer and 2150 cases of pancreatic cancer are diagnosed in Ontario, but very few of those patients are being tested for BRCA2.…”

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confidence: 99%

Coming of Age in Canada: A Study of Population-Based Genetic Testing for Breast and Ovarian Cancer

2017

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The BRCA1 and BRCA2 genes are the two most commonly mutated in hereditary breast and ovarian cancer, and they are the canonical pair when it comes to cancer testing 1 . There are many other candidate genes, and large-panel testing is increasingly the norm even though not all practitioners are in agreement 2 that testing for 20 genes is better than testing for 2. Mutations are associated with lifetime risks of 80% for breast cancer and 15%-40% for cancer of the ovary or fallopian tube for BRCA2 and BRCA1 respectively 3 . BRCA2 is the most frequently mutated gene in both prostate cancer 4,5 and pancreatic cancer [6][7][8] , and patients with BRCA2 mutations can benefit from novel therapies such as cis-platinum 9 . Annually, about 8500 cases of prostate cancer and 2150 cases of pancreatic cancer are diagnosed in Ontario, but very few of those patients are being tested for BRCA2.Genetic screening is now mainstream as a consequence of diminished sequencing costs, increased public awareness, celebrity endorsement, and the now wide availability to women of preventive surgery through public and private health insurance. Intensified screening for mutation carriers with annual magnetic resonance imaging is advocated and is increasingly available 10 . Additionally, women with hereditary breast cancer can benefit from personalized treatment (both surgical and medical), which might include bilateral mastectomy, salpingo-oophorectomy, and tailored chemotherapy (cis-platinum or olaparib) 11 .The current model of delivering genetic testing for the BRCA genes in North America dates to the mid-1990s, at a time when genetic testing was expensive and the clinical benefits were largely unproven. Because of the high cost, public and private insurers were not willing to pay for testing for all comers. In the resulting model, a women is referred by her physician to a specialized cancer genetics clinic, where a formal assessment is conducted. If the risk estimate for carrying a mutation exceeds a threshold value (usually 10%), then genetic testing for the BRCA genes ensues. If not, then the woman is reassured and sent off with a number of recommendations based on her personal and family history of cancer. In many clinics, the volume of patient requests now exceeds the number of available appointments, and triage is conducted by mail or telephone. The genetics counsellor serves two purposes: informing women about cancer risk, management options, and the testing process; and ensuring that testing is rationed first to the women who are the most suitable candidates.We believe that the current model is outdated, and here we propose an alternative model based on direct-toconsumer population-based testing. The reasons are these:■ First, a significant proportion of BRCA mutation carriers do not reach the 10% threshold; they therefore represent missed opportunities for identification 12 . ■ Very few patients with prostate cancer or pancreatic cancer are being tested. In addition, many individuals who do qualify for genetic testing fail to be ide...

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

Cited by 49 publications

References 33 publications

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Genetic testing for hereditary prostate cancer: Current status and limitations

Coming of Age in Canada: A Study of Population-Based Genetic Testing for Breast and Ovarian Cancer

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