Loss of copy numbers of retrotransposons (HERVK) on chromosome 7p11.2 impacts EGFR (Epidermal Growth Factor Receptor)‐induced phenotypes for platinum sensitivity and long‐term survival in ovarian cancer—A study from the OVCAD consortium

表皮生长因子受体 生物 杂合子丢失 外显子 卵巢癌 癌症研究 等位基因 内科学 肿瘤科 癌症 遗传学 基因 医学
作者
Gesa Fromhage,Eva Obermayr,Natalia Bednarz‐Knoll,Toon Van Gorp,Eva Welsch,Stephan Polterauer,Elena Ioana Braicu,Sven� Mahner,Jalid Sehouli,Ignace Vergote,Nicole Concin,Stefan Kurtz,Sascha Steinbiss,Antje Torge,Robert Zeillinger,Linn Wölber,Burkhard Brandt
出处
期刊:International Journal of Cancer [Wiley]
标识
DOI:10.1002/ijc.34976
摘要

Abstract We analyzed variations in the epidermal growth factor receptor ( EGFR ) gene and 5′‐upstream region to identify potential molecular predictors of treatment response in primary epithelial ovarian cancer. Tumor tissues collected during debulking surgery from the prospective multicenter OVCAD study were investigated. Copy number variations in the human endogenous retrovirus sequence human endogenous retrovirus K9 (HERVK9) and EGFR Exons 7 and 9, as well as repeat length and loss of heterozygosity of polymorphic CA‐SSR I and relative EGFR mRNA expression were determined quantitatively. At least one EGFR variation was observed in 94% of the patients. Among the 30 combinations of variations discovered, enhanced platinum sensitivity ( n = 151) was found dominantly with HERVK9 haploidy and Exon 7 tetraploidy, overrepresented among patients with survival ≥120 months (24/29, p = .0212). EGFR overexpression (≥80 percentile) was significantly less likely in the responders (17% vs. 32%, p = .044). Multivariate Cox regression analysis, including age, FIGO stage, and grade, indicated that the patients' subgroup was prognostically significant for CA‐SSR I repeat length <18 CA for both alleles (HR 0.276, 95% confidence interval 0.109–0.655, p = .001). Although EGFR variations occur in ovarian cancer, the mRNA levels remain low compared to other EGFR ‐mutated cancers. Notably, the inherited length of the CA‐SSR I repeat, HERVK9 haploidy, and Exon 7 tetraploidy conferred three times higher odds ratio to survive for more than 10 years under therapy. This may add value in guiding therapies if determined during follow‐up in circulating tumor cells or circulating tumor DNA and offers HERVK9 as a potential therapeutic target.
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