MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma.
MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma.
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DOI：
10.1158/1078-0432.ccr-21-4183
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发表时间：
2022-10-14
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描述低级别浆液性卵巢癌（LGSC）的体细胞突变特征，研究遗传改变与临床结局之间的相关性，并确定致病性生殖系突变的患病率。对LGSC肿瘤患者进行了多达505个基因的基于组的测序。收集了有关体细胞和种系突变、拷贝数改变和临床病理特征（包括诊断时年龄、铂类药物敏感性和总生存期（OS））的数据。在中心病理学重新审查后，确定了119例LGSC患者进行分析。110例（92%）患者患有晚期疾病（III/IV期）。体细胞KRAS（33%）、NRAS（11%）、EIF 1AX（10%）和BRAF（11%）改变是最常见的;在60%（n=71）的LGSC中发现了丝裂原活化蛋白激酶（MAPK）通路改变。KRAS突变与诊断时年龄>50岁（p=0.02）和铂敏感性疾病（p=0.03）显著相关。在多变量分析中，MAPK通路改变（p=0.02）和铂敏感性（p=0.005）与OS改善显著相关。79例患者（66%）接受了生殖系基因检测;确定了7种致病性生殖系突变，包括1种双等位基因MUTYH突变（c.1187G>A（p.Gly396Asp））和6种单等位基因突变。仅在双等位基因MUTYH突变携带者中观察到肿瘤中生殖系突变基因座处野生型等位基因的体细胞丢失（杂合性丢失）。没有生殖细胞BRCA 1/2突变。这项研究表明，LGSC中的MAPK通路改变，包括KRAS突变，与铂敏感性和生存期延长独立相关。生殖系数据有限，在LGSC患者中发现了很少的致病性生殖系突变。
To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSCs). Patients with LGSC tumors that underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations, copy number alterations, and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Following central pathology re-review, 119 patients with LGSC were identified for analysis. One hundred ten (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; mitogen-activated protein kinase (MAPK) pathway alterations were found in 60% (n=71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis >50 years (p=0.02) and platinum-sensitive disease (p=0.03). On multivariate analysis, MAPK pathway alterations (p=0.02) and platinum sensitivity (p=0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; 7 pathogenic germline mutations, including 1 bi-allelic MUTYH mutation (c.1187G>A (p.Gly396Asp)) and 6 mono-allelic alterations, were identified. Somatic loss of the wildtype allele (loss of heterozygosity) in the tumor at the locus of the germline mutation was only observed in the bi-allelic MUTYH mutation carrier. There were no germline BRCA1/2 mutations. This study showed MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.