Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2022 Oct 14;28(20):4456-4465. doi: 10.1158/1078-0432.CCR-21-4183.
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 (LGSC).
Patients with LGSC tumors who 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 rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 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; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation.
This study showed that 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. See related commentary by Veneziani and Oza, p. 4357.
描述体突变谱，研究遗传改变与临床结局之间的关系，并确定低级别浆液性卵巢癌 (LGSC) 中致病性种系突变的发生率。
鉴定了接受多达 505 个基因进行基于面板的测序的 LGSC 肿瘤患者。收集了体细胞和种系突变、拷贝数改变以及临床病理特征（包括诊断时的年龄、铂类药物敏感性和总生存期 (OS)）的数据。
经过中心病理重新审查，确定了 119 例 LGSC 患者进行分析。其中，110 例（92%）为晚期疾病（III/IV 期）。最常见的体细胞 KRAS（33%）、NRAS（11%）、EIF1AX（10%）和 BRAF（11%）改变；MAPK 通路改变见于 60%（n=71）的 LGSCs。KRAS 突变与诊断时年龄超过 50 岁（P=0.02）和铂类药物敏感性疾病（P=0.03）显著相关。多变量分析显示，MAPK 通路改变（P=0.02）和铂类药物敏感性（P=0.005）与 OS 改善显著相关。79 例（66%）患者接受了种系基因检测；鉴定出 7 种致病性种系突变：MUTYH（n=2）、BAP1（n=1）、RB1（n=1）、CHEK2（n=1）、APC（n=1）和 FANCA（n=1）。未发现种系 BRCA1/2 突变。1 例种系 MUTYH 相关 LGSC 在 MUTYH 基因座存在杂合性丢失，携带种系 BAP1 突变的患者还存在体细胞 BAP1 移码突变。
本研究表明，LGSC 中的 MAPK 通路改变，包括 KRAS 突变，与铂类药物敏感性和延长的生存独立相关。种系数据有限，在 LGSC 患者中仅鉴定出少数致病性种系突变。另见 Veneziani 和 Oza 的相关评论，第 4357 页。
