Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus.
Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus.
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DOI：
10.3390/genes12121964
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发表时间：
2021-12-09
期刊：
影响因子：
3.5
通讯作者：
Drögemüller C
中科院分区：
文献类型：
--
作者：
Letko A;Minor KM;Norton EM;Marinescu VD;Drögemüller M;Ivansson E;Megquier K;Noh HJ;Starkey M;Friedenberg SG;Lindblad-Toh K;Mickelson JR;Drögemüller C
狗代表了一种独特的自发性癌症模型。骨肉瘤 (OSA) 是狗最常见的原发性骨肿瘤 (OMIA 001441-9615)，与人类的 OSA 非常相似。包括 Leonberger 在内的几种大型犬品种患 OSA 的风险大大增加。我们对 273 个中位年龄为 8.1 [3.1-13.5] 岁的 Leonberger 病例和 365 个年龄超过 8 岁的对照病例的高密度推算 SNP 基因型数据进行了全基因组关联分析。这项分析揭示了犬 11 号染色体上的 CDKN2A/B 基因位点的显着关联，这与之前在其他犬种（例如灰狗）中的发现相一致，这些犬种也显示 OSA 风险升高。根据 20% 的品种流行率，确定遗传力 (h2SNP) 为 20.6%（SE = 0.08；p 值 = 5.7 × 10−4）。整个基因组的2563个SNP几乎占了OSA的所有h2SNP，其中2183个小效应SNP，316个中度效应SNP，64个大效应SNP。与许多其他癌症一样，调节性非编码变异可能是癌症发展风险增加的基础。我们的研究结果证实了 OSA 的复杂遗传基础、中等遗传性以及 CDKN2A/B 基因座在狗中导致强烈癌症易感性的关键作用。研究和比较人类 OSA 中与犬 OSA 相关的已知基因位点最终会很有趣。
Dogs represent a unique spontaneous cancer model. Osteosarcoma (OSA) is the most common primary bone tumor in dogs (OMIA 001441-9615), and strongly resembles human forms of OSA. Several large- to giant-sized dog breeds, including the Leonberger, have a greatly increased risk of developing OSA. We performed genome-wide association analysis with high-density imputed SNP genotype data from 273 Leonberger cases with a median age of 8.1 [3.1–13.5] years and 365 controls older than eight years. This analysis revealed significant associations at the CDKN2A/B gene locus on canine chromosome 11, mirroring previous findings in other dog breeds, such as the greyhound, that also show an elevated risk for OSA. Heritability (h2SNP) was determined to be 20.6% (SE = 0.08; p-value = 5.7 × 10−4) based on a breed prevalence of 20%. The 2563 SNPs across the genome accounted for nearly all the h2SNP of OSA, with 2183 SNPs of small effect, 316 SNPs of moderate effect, and 64 SNPs of large effect. As with many other cancers it is likely that regulatory, non-coding variants underlie the increased risk for cancer development. Our findings confirm a complex genetic basis of OSA, moderate heritability, and the crucial role of the CDKN2A/B locus leading to strong cancer predisposition in dogs. It will ultimately be interesting to study and compare the known genetic loci associated with canine OSA in human OSA.
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影响因子：
12.3
作者：
Karlsson EK;Sigurdsson S;Ivansson E;Thomas R;Elvers I;Wright J;Howald C;Tonomura N;Perloski M;Swofford R;Biagi T;Fryc S;Anderson N;Courtay-Cahen C;Youell L;Ricketts SL;Mandlebaum S;Rivera P;von Euler H;Kisseberth WC;London CA;Lander ES;Couto G;Comstock K;Starkey MP;Modiano JF;Breen M;Lindblad-Toh K
通讯作者：
Lindblad-Toh K
DOI：
10.1093/g3journal/jkab225
发表时间：
2021-10-19
期刊：
G3 (Bethesda, Md.)
影响因子：
--
作者：
Mollandin F;Rau A;Croiseau P
通讯作者：
Croiseau P
影响因子：
4.5
作者：
Moser G;Lee SH;Hayes BJ;Goddard ME;Wray NR;Visscher PM
通讯作者：
Visscher PM
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
5.2
作者：
Megquier, Kate;Turner-Maier, Jason;Lindblad-Toh, Kerstin
通讯作者：
Lindblad-Toh, Kerstin