Columbia University Irving Medical Center, New York, NY, 10032, USA.
James J. Peters Bronx VA Medical Center, Bronx, NY, USA.
BMC Med Genomics. 2020 Nov 4;13(1):165. doi: 10.1186/s12920-020-00809-7.
Adrenocortical carcinoma (ACC) is a rare, often-aggressive neoplasm of the adrenal cortex, with a 14-17 month median overall survival. We asked whether tumors from patients with advanced or metastatic ACC would offer clues as to putative genes that might have critical roles in disease progression or in more aggressive disease biology.
We conducted comprehensive genomic and expression analyses of ACCs from 43 patients, 30 female, and 42 from metastatic sites, including deep sequencing, copy number analysis, mRNA expression and microRNA arrays.
Copy number gains and losses were similar to that previously reported for ACC. We identified a median mutation rate of 3.38 per megabase (Mb). The mutational signature was characterized by a predominance of C > T, C > A and T > C transitions. Only cancer genes TP53 (26%) and beta-catenin (CTNNB1, 14%) were mutated in more than 10% of samples. The TCGA-identified putative cancer genes MEN1 and PRKAR1A were found in low frequency-4.7 and 2.3%, respectively. The majority of the mutations were in genes not implicated in the etiology or maintenance of cancer. Specifically, amongst the 38 genes that were mutated in more than 9% of samples, only four were represented in Tier 1 of the 576 COSMIC Cancer Gene Census (CCGC). Thus, 82% of genes found to have mutations likely have no role in the etiology or biology of ACC; while the role of the other 18%, if any, remains to be proven. Finally, the transcript length for the 38 most frequently mutated genes in ACC is statistically longer than the average of all coding genes, raising the question of whether transcript length in part determined mutation probability.
We conclude that the mutational and expression profiles of advanced and metastatic tumors are very similar to those from newly diagnosed patients-with very little in the way of genomic aberration to explain differences in biology. With relatively low mutation rates, few major oncogenic drivers, and loss of function mutations in several epigenetic regulators, an epigenetic basis for ACC may be postulated and serve as the basis for future studies.
肾上腺皮质癌（ACC）是一种罕见的、常具侵袭性的肾上腺皮质肿瘤，总生存期中位数为 14-17 个月。我们想知道，来自晚期或转移性 ACC 患者的肿瘤是否能提供线索，说明哪些基因可能在疾病进展或更具侵袭性的疾病生物学中具有关键作用。
我们对 43 名患者的 ACC 进行了全面的基因组和表达分析，其中 30 名女性，42 名来自转移部位，包括深度测序、拷贝数分析、mRNA 表达和 microRNA 阵列。
拷贝数的增益和丢失与之前报道的 ACC 相似。我们确定的突变率中位数为每百万碱基 3.38 个。突变特征以 C>T、C>A 和 T>C 转换为主。只有癌症基因 TP53（26%）和 beta-catenin（CTNNB1，14%）在超过 10%的样本中发生突变。TCGA 确定的潜在致癌基因 MEN1 和 PRKAR1A 的检出率分别为 4.7%和 2.3%。大多数突变发生在与癌症的病因或维持无关的基因中。具体来说，在 38 个突变频率超过 9%的样本中，只有 4 个基因在 576 个 COSMIC 癌症基因普查（CCGC）的第 1 层中。因此，82%的发现有突变的基因可能在 ACC 的病因或生物学中没有作用；而其他 18%的基因，如果有作用的话，其作用仍有待证明。最后，在 ACC 中最常突变的 38 个基因的转录长度统计上长于所有编码基因的平均值，这就提出了转录长度是否在一定程度上决定了突变概率的问题。
我们的结论是，晚期和转移性肿瘤的突变和表达谱与新诊断患者非常相似——在生物学差异方面几乎没有基因组异常。由于突变率相对较低，很少有主要的致癌驱动基因，并且几个表观遗传调节剂的功能丧失突变，ACC 的表观遗传基础可能被假设，并作为未来研究的基础。
