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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.

Titel:	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.
Autor/in / Beteiligte Person:	Fromhage, G ; Obermayr, E ; Bednarz-Knoll, N ; Van Gorp, T ; Welsch, E ; Polterauer, S ; Braicu, EI ; Mahner, S ; Sehouli, J ; Vergote, I ; Concin, N ; Kurtz, S ; Steinbiss, S ; Torge, A ; Zeillinger, R ; Wölber, L ; Brandt, B
Link:	Full Text Finder (Volltext)
Zeitschrift:	International journal of cancer, 2024-05-06
Veröffentlichung:	Ahead of Print, 2024
Medientyp:	academicJournal
ISSN:	1097-0215 (electronic)
DOI:	10.1002/ijc.34976
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Int J Cancer] 2024 May 06. <i>Date of Electronic Publication: </i>2024 May 06. References: Levantini E, Maroni G, Del Re M, Tenen DG. EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol. 2022;85:253‐275. doi:10.1016/J.SEMCANCER.2022.04.002. ; Despierre E, Vergote I, Anderson R, et al. Epidermal growth factor receptor (EGFR) pathway biomarkers in the randomized phase III trial of erlotinib versus observation in ovarian cancer patients with no evidence of disease progression after first‐line platinum‐based chemotherapy. Target Oncol. 2015;10(4):583‐596. doi:10.1007/S11523‐015‐0369‐6. ; Rendell A, Thomas‐Bland I, McCuish L, Taylor C, Binju M, Yu Y. Targeting tyrosine kinases in ovarian cancer: small molecule inhibitor and monoclonal antibody, where are we now? 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Olaparib plus bevacizumab as first‐line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416‐2428. doi:10.1056/NEJMOA1911361. Grant Information: 109064 United Kingdom WT_ Wellcome Trust Contributed Indexing: Keywords: EGFR; chemotherapy; long‐term‐survival; ovarian cancer; retrotransposon HERVK9 Entry Date(s): Date Created: 20240506 Latest Revision: 20240506 Update Code: 20240507

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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.