Gupta Sameer, Artomov Mykyta, Goggins William, Daly Mark, Tsao Hensin
Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (SG, HT); Analytic and Translational Genetic Unit, Massachusetts General Hospital, Boston, MA (MA, MD); Broad Institute, Cambridge, MA (MA, MD); Chemistry and Chemical Biology Department, Harvard University, Cambridge, MA (MA); School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong (WG).
J Natl Cancer Inst. 2015 Aug 20;107(11). doi: 10.1093/jnci/djv221. Print 2015 Nov.
Gender differences in melanoma incidence and outcome have been consistently observed but remain biologically unexplained. We hypothesized that tumors are genetically distinct between men and women and analyzed the mutation spectra in 266 metastatic melanomas (102 women and 164 men) from The Cancer Genome Atlas (TCGA). We found a statistically significantly greater burden of missense mutations among men (male median 298 vs female median = 211.5; male-to-female ratio [M:F] = 1.85, 95% confidence interval [CI] = 1.44 to 2.39). We validated these initial findings using available data from a separate melanoma exome cohort (n = 95) and found a similar increase in missense mutations among men (male median 393 vs female median 259; M:F = 1.59, 95% CI = 1.12 to 2.27). In addition, we found improved survival with increasing log-transformed missense mutation count (univariate hazard ratio = 0.82, 95% CI = 0.69 to 0.98) for TCGA samples. Our analyses demonstrate for the first time a gender difference in mutation burden in cutaneous melanoma.
黑色素瘤发病率和预后的性别差异一直存在，但在生物学上仍无法解释。我们推测男性和女性的肿瘤在基因上存在差异，并分析了来自癌症基因组图谱（TCGA）的266例转移性黑色素瘤（102例女性和164例男性）的突变谱。我们发现男性错义突变负担在统计学上显著更高（男性中位数为298，女性中位数为211.5；男女性别比[M:F]=1.85，95%置信区间[CI]=1.44至2.39）。我们使用来自另一个黑色素瘤外显子组队列（n=95）的可用数据验证了这些初步发现，发现男性错义突变也有类似增加（男性中位数为393，女性中位数为259；M:F=1.59，95%CI=1.12至2.27）。此外，我们发现对于TCGA样本，随着错义突变计数的对数转换增加，生存率提高（单变量风险比=0.82，95%CI=0.69至0.98）。我们的分析首次证明了皮肤黑色素瘤在突变负担上存在性别差异。
