摘要：(1) 总体来说，55%的肉瘤患者携带过量的致病基因突变；(2) 常见的基因突变是TP53、ATM、ATR、BRCA2和ERCC2。

最近一项国际多中心研究发现，超过50%的肉瘤患者具有过多的单基因和多基因突变，其中不少的突变基因是新的与癌症有关的基因。这项研究发表在8月的The Lancet Oncology上。

该研究选择了1162名15岁以上的肉瘤患者，收集唾液（48名患者）和血液（1114名患者）通过目标外显子测序分析72个基因，与6545名正常白人的基因作为对照。638名患者（55%）具有过多的病理遗传变异（combined odds ratio [OR] = 1.43, P < .0001），217个患者中检测出227个已知或者预测的病理基因变异。通过这些基因数据 ，能为肉瘤患者提供更好的风险管理和制定精准治疗方案。

参考文献 
Mandy L Ballinger, David L Goode, Isabelle Ray-Coquard et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. The lancet Oncology. 04 August 2016. DOI:http://dx.doi.org/10.1016/S1470-2045(16)30147-4.

Study Finds Genetic Risk Variants in Half of Patients With Sarcoma

Key Points

? Overall, 55% of sarcoma probands carried an excess of pathogenic variants.

? Enrichment for pathogenic variants was observed in TP53, ATM, ATR,BRCA2, and ERCC2.

In an international genetic study (International Sarcoma Kindred Study) reported in The Lancet Oncology, Ballinger et al found that approximately half of all patients with sarcoma harbored potentially pathogenic monogenic and polygenic variation in known and novel cancer genes.

Study Details

The study included 1,162 patients with sarcoma aged ≥ 15 years from 4 cohorts. Targeted exon sequencing using blood (n = 1,114) or saliva (n = 48) was performed for 72 genes selected on the basis of association with increased cancer risk. A case-control rare variant burden analysis included 6,545 white controls from 3 cohorts. Rare variants were classified as known, expected, or predicted.

Excess of Pathogenic Variants

Median age at cancer diagnosis was 46 years in the sarcoma probands. Multiple primary cancers were found in 170 patients (15%), and 155 (17%) of 911 families with informative pedigrees fitted recognizable cancer syndromes. On case-control rare variant burden analysis,638 (55%) of the probands exhibited an excess of pathogenic germline variants (combined odds ratio [OR] = 1.43, P < .0001); 227 known or expected pathogenic variants were identified in 217 probands. The presence of known, expected, or predicted pathogenic variants was associated with an earlier age of cancer onset.

Genes Affected

Significant enrichment for pathogenic variants was observed in TP53, ATM, and ATR (implicated in DNA-damage sensing and BRCA2 (implicated in homologous recombination) in probands vs controls. An unexpected excess of pathogenic variants was also observed in ERCC2 (implicated in DNA binding, DNA-damage sensing, helices activity, and basal transcription). Probands were significantly more likely than controls to have multiple pathogenic variants (OR = 2.21, P < .0001). The cumulative burden of multiple variants was significantly associated with earlier age at cancer diagnosis (P = .0032). Notifiable variants were identified in 66 (5.7%) of the probands, and variants with potentially actionable therapeutic significance were found in 293 (25%) of the probands.

The investigators concluded: “About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment.”

Mandy L Ballinger, David L Goode, Isabelle Ray-Coquard et al. Monogenic and polygenic determinants of sarcoma risk: an international genetic study. The lancet Oncology. 04 August 2016. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30147-4.