Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations.
Whole-Genome Sequencing of Common Salivary Gland Carcinomas: Subtype-Restricted and Shared Genetic Alterations.
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DOI：
10.1158/1078-0432.ccr-20-4071
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发表时间：
2021-07-15
期刊：
影响因子：
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通讯作者：
El-Naggar AK
中科院分区：
文献类型：
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作者：
Karpinets TV;Mitani Y;Liu B;Zhang J;Pytynia KB;Sellen LD;Karagiannis DT;Ferrarotto R;Futreal AP;El-Naggar AK
涎腺癌（SGCs）在病理学上可分为几种不同的亚型，其中腺样囊性癌（ACC）、粘液表皮样癌（MEC）和涎腺导管癌（SDC）是最常见的。这些亚型的比较遗传分析提供了与其肿瘤发生相关的遗传改变的详细信息，并可能导致生物标志物的鉴定，以指导肿瘤特异性临床试验。对58种常见的SGC（20种ACC，20种SDC和18种MEC）进行全基因组测序，以分类结构变异，拷贝数，重排和驱动突变。数据进行生物信息学分析，并与临床病理参数，并选定的目标进行验证。新的和复发的类型特异性和共享的遗传变异内和3个亚型之间进行了鉴定。在ACC和MEC中鉴定了相互排斥的典型融合和非融合基因组改变。在ACC中，染色体12 q丢失在MYB或MYBL 1融合阳性肿瘤中占主导地位，NOTCH通路突变在这些融合阴性肿瘤中更常见。在MEC中，CRTC 1-MAML 2融合阳性肿瘤表现出频繁的BAP 1突变，而缺乏这种融合的肿瘤则富含LRFN 1突变。SDC表现出相当大的遗传不稳定性，缺乏复发性染色体重排，并在一个肿瘤亚组中表现出非重叠的TP 53突变和ERBB 2扩增。有限的遗传改变，包括8 q21-q23的局灶性扩增，被所有亚型所共有，并与生存率低相关。这项研究描绘了与早期表型定型和常见SGCs生物学进展相关的类型特异性和共享遗传改变。这些改变经过验证后，可以作为肿瘤特异性临床试验中的生物标志物。
Salivary gland carcinomas (SGCs) are pathologically classified into several widely diverse subtypes, of which adenoid cystic (ACC), mucoepidermoid (MEC), and salivary duct (SDC) carcinomas are the most commonly encountered. A comparative genetic analysis of these subtypes provides detailed information on the genetic alterations that are associated with their tumorigenesis and may lead to the identification of biomarkers to guide tumor-specific clinical trials. Whole-genome sequencing of 58 common SGCs (20 ACCs, 20 SDCs, and 18 MECs) was performed to catalogue structural variations, copy number, rearrangements, and driver mutations. Data were bioinformatically analyzed and correlated with clinicopathologic parameters, and selected targets were validated. Novel and recurrent type-specific and shared genetic alterations were identified within and among 3 subtypes. Mutually exclusive canonical fusion and non-fusion genomic alterations were identified in both ACC and MEC. In ACCs, loss of chromosome 12q was dominant in MYB or MYBL1 fusion-positive tumors and mutations of NOTCH pathway were more common in these fusion-negatives. In MECs, CRTC1-MAML2 fusion-positive tumors showed frequent BAP1 mutation, and tumors lacking this fusion were enriched with LRFN1 mutation. SDCs displayed considerable genetic instability, lacked recurrent chromosomal rearrangements, and demonstrated non-overlapping TP53 mutation and ERBB2 amplification in a subset of tumors. Limited genetic alterations, including focal amplifications of 8q21-q23, were shared by all subtypes and were associated with poor survival. This study delineates type-specific and shared genetic alterations that are associated with early phenotypic commitment and the biologic progression of common SGCs. These alterations, upon validation, could serve as biomarkers in tumor-specific clinical trials.