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Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.

Yin J, Liu H, Liu Z, Wang LE, Chen WV, Zhu D, Amos CI, Fang S, Lee JE, Wei Q - J. Invest. Dermatol. (2014)

Bottom Line: CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001).Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS).The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA [2] Department of Epidemiology and Biostatistics, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

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SNP-gene associationsAnalyses of BRCA2 expression levels, by genotypes of (a) rs10492396, (b) rs206118, (c) rs3752447 and (d) combined risk genotypes (i.e., rs206118 CC, rs10492396 AG, rs3752447 CC) in 270 HapMap lymphoblastoid cell lines from all population. The number of individuals with missing data for rs10492396, rs206118 and combined risk genotypes were 2, 2 and 4, respectively. The Y axis is the normalized gene expression levels.
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Figure 4: SNP-gene associationsAnalyses of BRCA2 expression levels, by genotypes of (a) rs10492396, (b) rs206118, (c) rs3752447 and (d) combined risk genotypes (i.e., rs206118 CC, rs10492396 AG, rs3752447 CC) in 270 HapMap lymphoblastoid cell lines from all population. The number of individuals with missing data for rs10492396, rs206118 and combined risk genotypes were 2, 2 and 4, respectively. The Y axis is the normalized gene expression levels.

Mentions: We further evaluated the correlations between SNPs and their corresponding mRNA expression levels in normal cells, using the published expression data of the HapMap normal lymphoblastoid cell lines. Such expression data were available for BRCA2 rs206118, rs10492396, and rs3752447. Consistent with the observed associations, the rs3752447 CC genotype was associated with significant higher levels of mRNA expression of BRCA2, compared with the TT+TC genotypes (P=0.040); whereas for rs10492396, the AG genotype carriers had a marginally higher BRCA2 expression than those with the GG genotype (no AA carrier; P=0.073). No significant correlation was found between rs206118 genotypes and BRCA2 mRNA expression levels (P=0.414) in a recessive model. However, the BRCA2 mRNA expression levels increased in a linear manner with the increasing number of risk genotypes, when combining rs206118, rs10492396, and rs3752447 (P trend = 0.019, Figure 4). We did not find any significant result in an additive model (Figure S2), which supports our findings in the risk associations that follow a recessive genetic model.


Genetic variants in fanconi anemia pathway genes BRCA2 and FANCA predict melanoma survival.

Yin J, Liu H, Liu Z, Wang LE, Chen WV, Zhu D, Amos CI, Fang S, Lee JE, Wei Q - J. Invest. Dermatol. (2014)

SNP-gene associationsAnalyses of BRCA2 expression levels, by genotypes of (a) rs10492396, (b) rs206118, (c) rs3752447 and (d) combined risk genotypes (i.e., rs206118 CC, rs10492396 AG, rs3752447 CC) in 270 HapMap lymphoblastoid cell lines from all population. The number of individuals with missing data for rs10492396, rs206118 and combined risk genotypes were 2, 2 and 4, respectively. The Y axis is the normalized gene expression levels.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4289462&req=5

Figure 4: SNP-gene associationsAnalyses of BRCA2 expression levels, by genotypes of (a) rs10492396, (b) rs206118, (c) rs3752447 and (d) combined risk genotypes (i.e., rs206118 CC, rs10492396 AG, rs3752447 CC) in 270 HapMap lymphoblastoid cell lines from all population. The number of individuals with missing data for rs10492396, rs206118 and combined risk genotypes were 2, 2 and 4, respectively. The Y axis is the normalized gene expression levels.
Mentions: We further evaluated the correlations between SNPs and their corresponding mRNA expression levels in normal cells, using the published expression data of the HapMap normal lymphoblastoid cell lines. Such expression data were available for BRCA2 rs206118, rs10492396, and rs3752447. Consistent with the observed associations, the rs3752447 CC genotype was associated with significant higher levels of mRNA expression of BRCA2, compared with the TT+TC genotypes (P=0.040); whereas for rs10492396, the AG genotype carriers had a marginally higher BRCA2 expression than those with the GG genotype (no AA carrier; P=0.073). No significant correlation was found between rs206118 genotypes and BRCA2 mRNA expression levels (P=0.414) in a recessive model. However, the BRCA2 mRNA expression levels increased in a linear manner with the increasing number of risk genotypes, when combining rs206118, rs10492396, and rs3752447 (P trend = 0.019, Figure 4). We did not find any significant result in an additive model (Figure S2), which supports our findings in the risk associations that follow a recessive genetic model.

Bottom Line: CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001).Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS).The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Medicine, Duke University School of Medicine and Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina, USA [2] Department of Epidemiology and Biostatistics, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

ABSTRACT
Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Show MeSH
Related in: MedlinePlus