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Targeted genomic analysis of 364 adrenocortical carcinomas.
Endocrine-Related Cancer ( IF 3.9 ) Pub Date : 2021-08-16 , DOI: 10.1530/erc-21-0040
Nikita Pozdeyev 1, 2 , Lauren Fishbein 1, 2 , Laurie M Gay 3 , Ethan S Sokol 3 , Ryan Hartmaier 3 , Jeffrey S Ross 3, 4 , Sourat Darabi 5 , Michael J Demeure 5, 6 , Adwitiya Kar 1 , Lindsey J Foust 1 , Katrina Koc 1 , Daniel W Bowles 7 , Stephen Leong 7 , Margaret E Wierman 1, 8 , Katja Kiseljak-Vassiliades 1, 8
Affiliation  

Despite recent advances in elucidating molecular pathways underlying adrenocortical carcinoma (ACC), this orphan malignancy is associated with poor survival. Identification of targetable genomic alterations is critical to improve outcomes. The objective of this study was to characterize the genomic profile of a large cohort of patient ACC samples to identify actionable genomic alterations. Three hundred sixty-four individual patient ACC tumors were analyzed. The median age of the cohort was 52 years and 60.9% (n = 222) were female. ACC samples had common alterations in epigenetic pathways with 38% of tumors carrying alterations in genes involved in histone modification, 21% in telomere lengthening, and 21% in SWI/SNF complex. Tumor suppressor genes and WNT signaling pathway were each mutated in 51% of tumors. Fifty (13.7%) ACC tumors had a genomic alteration in genes involved in the DNA mismatch repair (MMR) pathway with many tumors also displaying an unusually high number of mutations and a corresponding MMR mutation signature. In addition, genomic alterations in several genes not previously associated with ACC were observed, including IL7R, LRP1B, FRS2 mutated in 6, 8 and 4% of tumors, respectively. In total, 58.5% of ACC (n = 213) had at least one potentially actionable genomic alteration in 46 different genes. As more than half of ACC have one or more potentially actionable genomic alterations, this highlights the value of targeted sequencing for this orphan cancer with a poor prognosis. In addition, significant incidence of MMR gene alterations suggests that immunotherapy is a promising therapeutic for a considerable subset of ACC patients.

中文翻译:

364 例肾上腺皮质癌的靶向基因组分析。

尽管最近在阐明肾上腺皮质癌 (ACC) 的分子途径方面取得了进展,但这种孤儿恶性肿瘤与较差的生存率有关。识别可靶向的基因组改变对于改善结果至关重要。本研究的目的是表征大量患者 ACC 样本的基因组谱,以确定可操作的基因组改变。分析了 364 名个体患者 ACC 肿瘤。该队列的中位年龄为 52 岁,60.9% (n = 222) 为女性。ACC 样本在表观遗传途径中有共同的改变,38% 的肿瘤携带与组蛋白修饰有关的基因改变,21% 的端粒延长,21% 的 SWI/SNF 复合物。肿瘤抑制基因和 WNT 信号通路分别在 51% 的肿瘤中发生突变。五十(13。7%) ACC 肿瘤在参与 DNA 错配修复 (MMR) 通路的基因中发生了基因组改变,许多肿瘤也显示出异常多的突变和相应的 MMR 突变特征。此外,观察到几个以前与 ACC 无关的基因的基因组改变,包括 IL7R、LRP1B、FRS2 分别在 6%、8% 和 4% 的肿瘤中发生突变。总共有 58.5% 的 ACC(n = 213)在 46 个不同基因中至少有一个潜在的可操作基因组改变。由于超过一半的 ACC 有一个或多个潜在可操作的基因组改变,这突出了靶向测序对这种预后不良的孤儿癌的价值。此外,MMR 基因改变的显着发生率表明,免疫疗法对于相当一部分 ACC 患者来说是一种有希望的治疗方法。
更新日期:2021-08-16
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