Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.
Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B.
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DOI：
10.1186/gb-2013-14-12-r132
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发表时间：
2013-12-12
期刊：
影响因子：
12.3
通讯作者：
Lindblad-Toh K
中科院分区：
文献类型：
--
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
犬类骨肉瘤在临床上与人类疾病几乎相同，但很常见，遗传性很高，这使得基因解剖是可行的。通过对三个品种(灰狗、罗威犬和爱尔兰猎狼犬)的全基因组关联分析，我们确定了33个遗传风险基因座，可以解释每个品种55%到85%的表型差异。灰狗基因的关联性最强，位于CDKN2A/B基因上游150kb，也是犬骨肉瘤中重排最多的基因。在罗特韦尔犬和爱尔兰猎狼犬中发现了90%频率最高的种系候选变异，并改变了我们显示的在人类骨肉瘤细胞中具有强烈增强活性的进化限制因子。在所有三个品种中，骨肉瘤相关基因和杂合度降低的区域都富含与骨骼分化和生长相关的基因。几条途径，包括一条由miR124调控的基因，也丰富了肿瘤中的体细胞拷贝数变化。绘制多个犬种的复杂癌症图谱，揭示了生殖系风险因素的多基因谱，指出特定的致病途径。
Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
4.1
作者：
Horowitz, Mark C.;Fretz, Jackie A.;Lorenzo, Joseph A.
通讯作者：
Lorenzo, Joseph A.
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
DOI：
10.1073/pnas.0710052104
发表时间：
2007-12-11
影响因子：
11.1
作者：
Beroukhim, Rameen;Getz, Gad;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
11.2
作者：
Jones KB;Salah Z;Del Mare S;Galasso M;Gaudio E;Nuovo GJ;Lovat F;LeBlanc K;Palatini J;Randall RL;Volinia S;Stein GS;Croce CM;Lian JB;Aqeilan RI
通讯作者：
Aqeilan RI