Département de Génétique, Hôpital Bichat-Claude Bernard, APHP, Paris, France.
Pigment Cell Melanoma Res. 2013 Jan;26(1):88-96. doi: 10.1111/pcmr.12032. Epub 2012 Nov 23.
As loss of KIT frequently occurs in melanoma progression, we hypothesized that KIT is implicated in predisposition to melanoma (MM). Thus, we sequenced the KIT coding region in 112 familial MM cases and 143 matched controls and genotyped tag single-nucleotide polymorphisms (SNPs) in two cohorts of melanoma patients and matched controls. Five rare KIT substitutions, all predicted possibly or probably deleterious, were identified in five patients, but none in controls [RR = 2.26 (1.26-2.26)]. Expressed in melanocyte lines, three substitutions inhibited KIT signaling. Comparison with exomes database (7020 alleles) confirmed a significant excess of rare deleterious KIT substitutions in patients. Additionally, a common SNP, rs2237028, was associated with MM risk, and 6 KIT variants were associated with nevus count. Our data strongly suggest that rare KIT substitutions predispose to melanoma and that common variants at KIT locus may also impact nevus count and melanoma risk.
由于 KIT 在黑色素瘤进展中经常丢失，我们假设 KIT 参与了黑色素瘤（MM）的易感性。因此，我们对 112 例家族性 MM 病例和 143 例匹配对照进行了 KIT 编码区测序，并对两个黑色素瘤患者和匹配对照的标签单核苷酸多态性（SNP）进行了基因分型。在五名患者中发现了五个罕见的 KIT 取代，所有这些取代均预测为可能或可能有害，而在对照组中均未发现[RR=2.26（1.26-2.26）]。在黑素细胞系中表达时，三个取代抑制了 KIT 信号传导。与外显子组数据库（7020 个等位基因）的比较证实，患者中罕见的有害 KIT 取代明显过多。此外，常见的 SNP rs2237028 与 MM 风险相关，6 种 KIT 变体与痣计数相关。我们的数据强烈表明，罕见的 KIT 取代易患黑色素瘤，而 KIT 基因座的常见变体也可能影响痣计数和黑色素瘤风险。
