Tonomura Noriko, Elvers Ingegerd, Thomas Rachael, Megquier Kate, Turner-Maier Jason, Howald Cedric, Sarver Aaron L, Swofford Ross, Frantz Aric M, Ito Daisuke, Mauceli Evan, Arendt Maja, Noh Hyun Ji, Koltookian Michele, Biagi Tara, Fryc Sarah, Williams Christina, Avery Anne C, Kim Jong-Hyuk, Barber Lisa, Burgess Kristine, Lander Eric S, Karlsson Elinor K, Azuma Chieko, Modiano Jaime F, Breen Matthew, Lindblad-Toh Kerstin
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, Massachusetts, United States of America.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America; Science for Life Laboratory, Dept. of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
PLoS Genet. 2015 Feb 2;11(2):e1004922. doi: 10.1371/journal.pgen.1004922. eCollection 2015 Feb.
Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6%) and hemangiosarcoma (20%). We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.
狗因其品种决定的有限遗传背景，是包括癌症在内的人类疾病的理想模型。犬B细胞淋巴瘤和血管肉瘤都是血液系统的恶性肿瘤，在临床和组织学上分别与人类B细胞非霍奇金淋巴瘤和血管肉瘤相似。美国的金毛猎犬患B细胞淋巴瘤（6%）和血管肉瘤（20%）的终生风险显著升高。我们对血管肉瘤和B细胞淋巴瘤进行了全基因组关联研究，确定了两个共同的易感位点。这两个相关位点位于5号染色体上，共同导致了约20%的患癌风险。每个位点的顶级单核苷酸多态性（SNP）的全基因组p值分别为4.6×10-7和2.7×10-6。对9例病例和对照进行全基因组重测序，随后进行基因分型和详细分析，在这两个位点内确定了三个共同的和一个B细胞淋巴瘤特异性风险单倍型，但没有编码变化与风险单倍型相关。B细胞淋巴瘤肿瘤的基因表达分析表明，在第一个位点携带风险单倍型与几个附近基因的下调有关，包括近端基因TRPC6，TRPC6是一种参与T细胞激活等功能的瞬时受体Ca2+通道。第二个位点的共同风险单倍型与囊泡运输和释放基因STX8重叠。携带共同风险单倍型与100个基因的表达变化有关，这些基因富集于参与免疫细胞激活的通路。因此，B细胞淋巴瘤和血管肉瘤的易感种系突变似乎是调控性的，并影响肿瘤中T细胞介导的免疫反应所涉及的通路。这表明免疫系统与恶性细胞之间的相互作用在这些相对不同的癌症的肿瘤发生中起共同作用。
