A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Bui-Raborn Linh T, Pastorino Lorenza, Calista Donato, Hoang Phuc H, Scales Jessica L, Xu Mai, Papiernik Sophie, Wang Xiaoyu, Dalmasso Bruna, Thakur Rohit, Pellegrini Stefania, Yon Joshuah, Myers Timothy, Lee Chia-Han, Williams Jacob, Zhang Haoyu, Zhang Tongwu, Bruno William, García-Casado Zaida, Tanda Enrica Teresa, Spagnolo Francesco, Di Prete Monia, Bottillo Irene, Manukian Siranoush, Scaini Maria Chiara, Kypreou Katerina P, Di Nardo Lucia, Potrony Miriam, Aguilera-Peiró Paula, Shahrour Nesreen, Tran Tam-Anh, Yu Yao, Huff Chad D, Scheet Paul, Wheless Lee E, Hartman Rebecca I, Liu Jia, Zhou Weiyin, Luo Wen, Vogt Aurélie, Jones Kristine M, Hicks Belynda D, Rodolfo Monica, Stefanaki Irene, Pellegrini Cristina, Cota Carlo, Menin Chiara, Fargnoli Maria Concetta, Peris Ketty, Puig Susana, Nagore Eduardo, Grammatico Paola, Italian Melanoma Intergroup, The MelaNostrum Consortium, Shi Jianxin, Ghiorzo Paola, Brown Kevin M, Landi Maria Teresa
Аннотация
Approximately 10% of cutaneous malignant melanoma cases are familial. Variants in CDKN2A account for up to 40% of melanoma-prone families, with an additional ~10% explained by other genes. Many CDKN2A mutation-negative families show linkage to chromosome-band 9p21, which harbors CDKN2A, suggesting non-coding variants may contribute to familial risk. Here, whole-genome sequencing revealed a novel 100 kb deletion mapping to 9p21 in a gene-desert region, 205 kb from CDKN2A, cosegregating in a four-case family from Genoa, Italy. The deletion overlaps melanocyte enhancers that interact with the promoters of CDKN2A p16 and p14 transcripts and is predicted to reduce p16 expression. Using a nearby rare exonic variant in MTAP (rs755147810) on the deletion haplotype, we searched for deletion carriers in WES data from high-risk melanoma patients and controls and identified 22 cases and a single control carrying rs755147810 and the deletion. The association with melanoma in case-control analysis was highly significant (3,319 cases and 5,680 controls; P=1.27x10-6; OR=27.50). We observe loss-of-heterozygosity of the wild-type allele in a carrier's tumor sample. The founder haplotype with the most recent common ancestor dates approximately 26 generations, broadly overlapping the period when Italy was struck by devastating outbreaks of plague that decimated the population creating a genetic bottleneck. Our results provide evidence of a high-penetrance intergenic variant conferring melanoma susceptibility, with potential for genetic screening of high-risk individuals.