Monogenic and polygenic determinants of sarcoma risk: an international genetic study
Monogenic and polygenic determinants of sarcoma risk: an international genetic study
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DOI：
10.1016/s1470-2045(16)30147-4
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发表时间：
2016-09-01
期刊：
影响因子：
51.1
通讯作者：
Thomas, David M.
中科院分区：
文献类型：
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作者：
Ballinger, Mandy L.;Goode, David L.;Thomas, David M.
背景 肉瘤是一种罕见的、表型异质性的癌症，对年轻人的影响尤为严重。除了罕见综合征外，其遗传起源的性质、范围和临床意义尚不清楚。我们的目的是调查常规临床实践中出现的骨和软组织肉瘤的遗传基础。 方法 在这项遗传研究中，我们纳入了来自四个队列（国际肉瘤亲属研究 [ISKS]，966 位先证者；Project GENESIS，48 位先证者；Asan Bio-Resource Center，138 位先证者；和 kConFab，10 位先证者）的 1162 名肉瘤患者，这些患者年龄超过 15 岁年在 同意时并经组织学确诊为肉瘤，从肉瘤专科诊所招募，不考虑家族史。收集详细的临床、病理和谱系信息，并独立验证先证者和亲属的癌症诊断。使用血液 (n=1114) 或唾液 (n=48) 样本对 72 个基因（由于与癌症风险增加相关而选择）进行了靶向外显子测序，罕见变异被分层为接近国际癌症研究机构 (IARC) 遗传变异临床分类的类别。我们使用来自三个队列的 6545 名白人对照（ISKS，235 名对照；LifePool，2010 名对照；以及国家心肺和血液研究所外显子组测序项目 [ESP]，4300 名对照）进行了病例对照罕见变异负荷分析。结果 1162 名肉瘤先证者中癌症诊断的中位年龄为 46 岁（IQR 29-58），170 (15%) 1162 名先证者中的 155 名（17%）患有多种原发性癌症，而 911 个具有丰富谱系的家庭中有 155 个（17%）患有可识别的癌症综合征。使用病例对照罕见变异负荷分析，1162 名肉瘤先证者中的 638 名 (55%) 携带过量的致病性种系变异（综合比值比 [OR] 1.43，95% CI 1.24-1.64，p
Background Sarcomas are rare, phenotypically heterogeneous cancers that disproportionately affect the young. Outside rare syndromes, the nature, extent, and clinical significance of their genetic origins are not known. We aimed to investigate the genetic basis for bone and soft-tissue sarcoma seen in routine clinical practice.Methods In this genetic study, we included 1162 patients with sarcoma from four cohorts (the International Sarcoma Kindred Study [ISKS], 966 probands; Project GENESIS, 48 probands; Asan Bio-Resource Center, 138 probands; and kConFab, ten probands), who were older than 15 years at the time of consent and had a histologically confirmed diagnosis of sarcoma, recruited from specialist sarcoma clinics without regard to family history. Detailed clinical, pathological, and pedigree information was collected, and cancer diagnoses in probands and relatives were independently verified. Targeted exon sequencing using blood (n=1114) or saliva (n=48) samples was done on 72 genes (selected due to associations with increased cancer risk) and rare variants were stratified into classes approximating the International Agency for Research on Cancer (IARC) clinical classification for genetic variation. We did a case-control rare variant burden analysis using 6545 Caucasian controls included from three cohorts (ISKS, 235 controls; LifePool, 2010 controls; and National Heart, Lung, and Blood Institute Exome Sequencing Project [ESP], 4300 controls).Findings The median age at cancer diagnosis in 1162 sarcoma probands was 46 years (IQR 29-58), 170 (15%) of 1162 probands had multiple primary cancers, and 155 (17%) of 911 families with informative pedigrees fitted recognisable cancer syndromes. Using a case-control rare variant burden analysis, 638 (55%) of 1162 sarcoma probands bore an excess of pathogenic germline variants (combined odds ratio [OR] 1.43, 95% CI 1.24-1.64, p