Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Kidd, LaCreis R.; Coulibaly, A.; Templeton, Tiva; Chen, W; Long, Layron; Mason, Terry; Bonilla, Carolina; Akereyeni, Folasade; Freeman, Vincent L.; Isaacs, William B.; Ahaghotu, Chiledum; Kittles, Rick A.

doi:10.1038/sj.pcan.4500884

Cited by 16 publications

(13 citation statements)

References 37 publications

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“…Bcl-2 expression has also been implicated in the pathogenesis of cancers [37, 38], and the expression of Bcl-2 to Bax ratio seems to be important in determining both in vitro and in vivo response to chemotherapeutic drugs [39]. Recently, variant allele of Bcl-2 −938C>A was found to be associated with reduced prostate cancer risk in Caucasians in a small case-control study, possibly due to the elimination of an Sp1 binding site, a downregulation of Bcl-2 mRNA transcript levels, and unregulated programmed cell death [40], which is consistent with what we found in the current study (the variant A allele carriers were associated with high-AC phenotype that may help eliminating possible malignant cells).…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Chen

et al. 2008

Journal of Cancer Epidemiology

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Apoptotic capacity (AC) in primary lymphocytes may be a marker for cancer susceptibility, and functional single nucleotide polymorphisms (SNPs) in genes involved in apoptotic pathways may modulate cellular AC in response to DNA damage. To further examine the correlation between apoptotic genotypes and phenotype, we genotyped 14 published SNPs in 11 apoptosis-related genes (i.e., p53, Bcl-2, BAX, CASP9, DR4, Fas, FasL, CASP8, CASP10, CASP3, and CASP7) and assessed the AC in response to benzo[a]pyrene-7,8-9,10-diol epoxide (BPDE) in cultured primary lymphocytes from 172 cancer-free subjects. We found that among these 14 SNPs, R72P, intron 3 16-bp del/ins, and intron 6 G>A in p53, −938C>A in Bcl-2, and I522L in CASP10 were significant predictors of the BPDE-induced lymphocytic AC in single-locus analysis. In the combined analysis of the three p53 variants, we found that the individuals with the diplotypes carrying 0-1 copy of the common p53 R-del-G haplotype had higher AC values compared to other genotypes. Although the study size may not have the statistical power to detect the role of other SNPs in AC, our findings suggest that some SNPs in genes involved in the intrinsic apoptotic pathway may modulate lymphocytic AC in response to BPDE exposure in the general population. Larger studies are needed to validate these findings for further studying individual susceptibility to cancer and other apoptosis-related diseases.

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Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Chen

et al. 2008

Journal of Cancer Epidemiology

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“…African Americans were recruited from Washington, DC (N = 106) and Columbia, S.C. (N = 426). African American and Caribbean subjects were recruited for various cancer genetic studies [36], [37], [38], [39]. West African samples (N = 508), included 48 Bini from Edo State, Nigeria; 64 Ibo from Enugu State, Nigeria; 18 Hausa from Jos, Nigeria, 49 Yoruba from Ibadan, Nigeria; 61 Yoruba from Lagos, Nigeria; 28 Urhobo and 21 Itsekiri from the Warri Delta region of Nigeria; 34 Kru from Freetown, Liberia; 47 Mende and 34 Temne from Freetown, Sierra Leone [38]; 19 Mandinka from Dakar, Senegal; and 85 Bamileke from Yaounde, Cameroon [38], [40], [41], [42].…”

Section: Methodsmentioning

confidence: 99%

Y Chromosome Lineages in Men of West African Descent

et al. 2012

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The early African experience in the Americas is marked by the transatlantic slave trade from ∼1619 to 1850 and the rise of the plantation system. The origins of enslaved Africans were largely dependent on European preferences as well as the availability of potential laborers within Africa. Rice production was a key industry of many colonial South Carolina low country plantations. Accordingly, rice plantations owners within South Carolina often requested enslaved Africans from the so-called “Grain Coast” of western Africa (Senegal to Sierra Leone). Studies on the African origins of the enslaved within other regions of the Americas have been limited. To address the issue of origins of people of African descent within the Americas and understand more about the genetic heterogeneity present within Africa and the African Diaspora, we typed Y chromosome specific markers in 1,319 men consisting of 508 west and central Africans (from 12 populations), 188 Caribbeans (from 2 islands), 532 African Americans (AAs from Washington, DC and Columbia, SC), and 91 European Americans. Principal component and admixture analyses provide support for significant Grain Coast ancestry among African American men in South Carolina. AA men from DC and the Caribbean showed a closer affinity to populations from the Bight of Biafra. Furthermore, 30–40% of the paternal lineages in African descent populations in the Americas are of European ancestry. Diverse west African ancestries and sex-biased gene flow from EAs has contributed greatly to the genetic heterogeneity of African populations throughout the Americas and has significant implications for gene mapping efforts in these populations.

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“…The A allele is associated with higher expression levels of Bcl‐2 in different malignant tissues, and −938C>A genotypes were associated with survival of patients suffering from the corresponding cancers,26–28 including a most recent report on the correlation of the −938C>A promoter SNP with biochemical recurrence after radical prostectomy in a small cohort of Japanese men 29. Furthermore, Kidd et al showed an association of this polymorphism with risk for prostate cancer in a small cohort 30. However, a study in CLL patients has reported no association of genotypes with BCL2 mRNA levels and overall survival 31…”

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confidence: 99%

Regulatory BCL2 promoter polymorphism (−938C>A) is associated with adverse outcome in patients with prostate carcinoma

Bachmann¹,

Heukamp

Schmitz

et al. 2011

Intl Journal of Cancer

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Molecular markers predictive of prostate cancer prognosis are urgently needed. Overexpression of the antiapoptotic protein, Bcl‐2, has repeatedly been shown to be associated with adverse outcome in this malignancy. We hypothesized that a regulatory BCL2 −938C>A promoter polymorphism, which significantly affects promoter activity and Bcl‐2 expression in different malignancies, may influence survival. Reporter assays and electrophoretic mobility shift assays reveled that the −938C>A BCL2 promoter polymorphism significantly affects promoter activity and transcription factor binding in prostate cancer cells. Significantly higher BCL2 mRNA expression was observed in primary prostate carcinomas derived from patients with the AA, compared to CC, genotype. Survival analysis showed that the −938AA genotype was an independent, unfavorable prognostic factor for relapse‐free survival in a primary cohort of 142 patients and in an independent replication cohort of 148 patients, with hazard ratios (HR) of 4.4 (95% CI, 1.3–15.1; p = 0.018) and 4.6 (95% CI, 1.5–14.2; p = 0.009). Furthermore, the −938AA genotype was independently associated with worse overall survival in the replication series, with a HR of 10.9 (95% CI, 1.2–99.3; p = 0.034). We conclude that the BCL2 −938C>A polymorphism is an independent predictor of relapse‐free and overall survival in patients with prostate cancer. The BCL2 −938C>A polymorphism should be evaluated prospectively and may also have promise in assisting optimal patient choice for treatment with BCL2‐targeted drugs already in evaluation for prostate cancer treatment.

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Germline BCL-2 sequence variants and inherited predisposition to prostate cancer

Cited by 16 publications

References 37 publications

Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Single Nucleotide Polymorphisms in Selected Apoptotic Genes and BPDE-Induced Apoptotic Capacity in Apparently Normal Primary Lymphocytes: A Genotype-Phenotype Correlation Analysis

Y Chromosome Lineages in Men of West African Descent

Regulatory BCL2 promoter polymorphism (−938C>A) is associated with adverse outcome in patients with prostate carcinoma

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