Rare germline mutations in African American men diagnosed with early‐onset prostate cancer

Beebe‐Dimmer, Jennifer L.; Zuhlke, Kimberly A.; Johnson, Anna; Liesman, Daniel; Cooney, Kathleen A.

doi:10.1002/pros.23464

Cited by 24 publications

(20 citation statements)

References 47 publications

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“…Beebe-Dimmer and colleagues performed targeted exome sequencing of 160 genes in a cohort of 96 AA men with early-onset CaP (≤55 years at diagnosis) to characterize rare germline mutations in young AA men diagnosed with clinically significant CaP. They identified protein-truncating mutations in BRCA2 and BRIP1/FANCJ in three men with early onset CaP, as well as rare, missense variants in BRCA1 , BRCA2 , PMS2 , and ATM that were likely to be pathogenic [ 101 ].…”

Section: Germline Mutations Associated With Hereditary Prostate Camentioning

confidence: 99%

“…Men from families with hereditary cancer syndromes, including Hereditary Prostate Cancer (HPC), Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS), which are associated with defects in HOXB13 , BRCA1/2 and DNA Mismatch Repair genes, respectively, may benefit from genetic testing ( A ). Frequency of pathogenic germline alterations in DDR genes [ 30 , 100 , 101 ] and in genes associated with hereditary cancer syndromes (HPC [ 29 , 102 ], HBOC [ 103 ], and LS [ 104 , 105 , 106 ]) detected in metastatic prostate cancers ( B ).…”

Section: Figurementioning

confidence: 99%

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Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Tan

Petrovics

Srivastava

2018

IJMS

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Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of male cancer deaths in the United States. Among African American (AA) men, CaP is the most prevalent malignancy, with disproportionately higher incidence and mortality rates. Even after discounting the influence of socioeconomic factors, the effect of molecular and genetic factors on racial disparity of CaP is evident. Earlier studies on the molecular basis for CaP disparity have focused on the influence of heritable mutations and single-nucleotide polymorphisms (SNPs). Most CaP susceptibility alleles identified based on genome-wide association studies (GWAS) were common, low-penetrance variants. Germline CaP-associated mutations that are highly penetrant, such as those found in HOXB13 and BRCA2, are usually rare. More recently, genomic studies enabled by Next-Gen Sequencing (NGS) technologies have focused on the identification of somatic mutations that contribute to CaP tumorigenesis. These studies confirmed the high prevalence of ERG gene fusions and PTEN deletions among Caucasian Americans and identified novel somatic alterations in SPOP and FOXA1 genes in early stages of CaP. Individuals with African ancestry and other minorities are often underrepresented in these large-scale genomic studies, which are performed primarily using tumors from men of European ancestry. The insufficient number of specimens from AA men and other minority populations, together with the heterogeneity in the molecular etiology of CaP across populations, challenge the generalizability of findings from these projects. Efforts to close this gap by sequencing larger numbers of tumor specimens from more diverse populations, although still at an early stage, have discovered distinct genomic alterations. These research findings can have a direct impact on the diagnosis of CaP, the stratification of patients for treatment, and can help to address the disparity in incidence and mortality of CaP. This review examines the progress of understanding in CaP genetics and genomics and highlight the need to increase the representation from minority populations.

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Section: Germline Mutations Associated With Hereditary Prostate Camentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Tan

Petrovics

Srivastava

2018

IJMS

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“…Table 2b). We identified 7 suggestive (FDR < 0.05 in the TFT analysis) ancestry-specific cancer-gene associations in the African ancestry, 6 of which have been previously described including SDHB in PCPG [27], ATM in PRAD [28,29], FH in KIRP [30], VHL in KIRC [31], PTEN in UCEC [32], and BRCA2 in OV [33]. We also re-discovered the potentially novel association of BRCA2 in LUSC described above.…”

Section: Ancestry-specific Cancer Predisposing Genesmentioning

confidence: 53%

Ancestry-Specific Predisposing Germline Variants in Cancer

Oak

Cherniack

Mashl

et al. 2020

Preprint

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Background: Cancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry.Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds. Methods:We performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestryspecific predisposing variants and their associated somatic two-hit events and gene expression levels.Results: Recent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184 , 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association of BRCA2 in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4];FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84];FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; and FH splice-site variant carriers showed mis-splicing of FH. Conclusions:While several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestryspecific genetic predisposition to inform personalized diagnosis and screening strategies.

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“…Recent studies demonstrated that germline mutations in BRCA1 and BRCA2 can be essential in identifying men with higher risk of developing PCa, and are associated with a more aggressive phenotype and poorer outcome when mutated [ 48 , 49 , 50 , 51 ]. A few studies have indicated that mutation frequencies in BRCA1 and BRCA2 may differ by ethnic and racial groups [ 52 , 53 , 54 ]. Specifically, the BRCA2 gene may be involved in early-onset PCa in MAA [ 53 ].…”

Section: Genetic Influential Factors For Prostate Cancer Riskmentioning

confidence: 99%

“…A few studies have indicated that mutation frequencies in BRCA1 and BRCA2 may differ by ethnic and racial groups [ 52 , 53 , 54 ]. Specifically, the BRCA2 gene may be involved in early-onset PCa in MAA [ 53 ]. This may suggest that genetic testing could possibly provide significant information regarding treatment stratification.…”

Section: Genetic Influential Factors For Prostate Cancer Riskmentioning

confidence: 99%

The Impact of African Ancestry on Prostate Cancer Disparities in the Era of Precision Medicine

Lewis

Cropp

2020

Genes

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Prostate cancer disproportionately affects men of African ancestry at nearly twice the rate of men of European ancestry despite the advancement of treatment strategies and prevention. In this review, we discuss the underlying causes of these disparities including genetics, environmental/behavioral, and social determinants of health while highlighting the implications and challenges that contribute to the stark underrepresentation of men of African ancestry in clinical trials and genetic research studies. Reducing prostate cancer disparities through the development of personalized medicine approaches based on genetics will require a holistic understanding of the complex interplay of non-genetic factors that disproportionately exacerbate the observed disparity between men of African and European ancestries.

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Rare germline mutations in African American men diagnosed with early‐onset prostate cancer

Abstract: Protein-truncating mutations in BRCA2 and BRIP1 were discovered in African American men diagnosed with early-onset prostate cancer. Further study is necessary to determine the role of rare, missense variants to prostate cancer incidence, and progression in this group of high-risk men.

Cited by 24 publications

References 47 publications

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Prostate Cancer Genomics: Recent Advances and the Prevailing Underrepresentation from Racial and Ethnic Minorities

Ancestry-Specific Predisposing Germline Variants in Cancer

The Impact of African Ancestry on Prostate Cancer Disparities in the Era of Precision Medicine

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