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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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Related in: MedlinePlus

Kaplan-Meier survival analysisFor CM OS (a) by 0, 1, 2, 3/4 NUG (i.e., rs10492396 AG, rs206118 CC, rs3752447 CC, rs62068372 TT) and (b) by 0-1 and 2-4 NUG; for CM MSS (c) by 0, 1, 2, 3/4 NUG and (d) by 0-1 and 2-4 NUG.
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Figure 1: Kaplan-Meier survival analysisFor CM OS (a) by 0, 1, 2, 3/4 NUG (i.e., rs10492396 AG, rs206118 CC, rs3752447 CC, rs62068372 TT) and (b) by 0-1 and 2-4 NUG; for CM MSS (c) by 0, 1, 2, 3/4 NUG and (d) by 0-1 and 2-4 NUG.

Mentions: We next dichotomized all patients into a low-risk group (with 0-1 NUG) and a high-risk group (with 2-4 NUG). We found that compared with the low-risk group, the high-risk group died at twice due to all causes (adjHR=2.41, 95% CI=1.67-3.48, P<0.0001) or CM (adjHR=2.53, 95% CI=1.65-3.89, P<0.0001). For illustrative purpose, Kaplan Meier curves of the associations with OS, MSS and NUG are shown in Figure 1.


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)

Kaplan-Meier survival analysisFor CM OS (a) by 0, 1, 2, 3/4 NUG (i.e., rs10492396 AG, rs206118 CC, rs3752447 CC, rs62068372 TT) and (b) by 0-1 and 2-4 NUG; for CM MSS (c) by 0, 1, 2, 3/4 NUG and (d) by 0-1 and 2-4 NUG.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Kaplan-Meier survival analysisFor CM OS (a) by 0, 1, 2, 3/4 NUG (i.e., rs10492396 AG, rs206118 CC, rs3752447 CC, rs62068372 TT) and (b) by 0-1 and 2-4 NUG; for CM MSS (c) by 0, 1, 2, 3/4 NUG and (d) by 0-1 and 2-4 NUG.
Mentions: We next dichotomized all patients into a low-risk group (with 0-1 NUG) and a high-risk group (with 2-4 NUG). We found that compared with the low-risk group, the high-risk group died at twice due to all causes (adjHR=2.41, 95% CI=1.67-3.48, P<0.0001) or CM (adjHR=2.53, 95% CI=1.65-3.89, P<0.0001). For illustrative purpose, Kaplan Meier curves of the associations with OS, MSS and NUG are shown in Figure 1.

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