論文 - 詳細
| RRC ID | 67339 |
|---|---|
| 著者 | Kloth M, Ruesseler V, Engel C, Koenig K, Peifer M, Mariotti E, Kuenstlinger H, Florin A, Rommerscheidt-Fuss U, Koitzsch U, Wodtke C, Ueckeroth F, Holzapfel S, Aretz S, Propping P, Loeffler M, Merkelbach-Bruse S, Odenthal M, Friedrichs N, Heukamp LC, Zander T, Buettner R. |
| タイトル | Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer. |
| ジャーナル | Gut |
| Abstract |
OBJECTIVE:Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC. DESIGN:Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown. RESULTS:Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors. CONCLUSIONS:We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC. |
| 巻・号 | 65(8) |
| ページ | 1296-305 |
| 公開日 | 2016-8-1 |
| DOI | 10.1136/gutjnl-2014-309026 |
| PII | gutjnl-2014-309026 |
| PMID | 26001389 |
| MeSH | Antineoplastic Agents / pharmacology Cell Culture Techniques Cetuximab / pharmacology* Colorectal Neoplasms* / drug therapy Colorectal Neoplasms* / genetics Colorectal Neoplasms* / pathology Colorectal Neoplasms, Hereditary Nonpolyposis* / drug therapy Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics Colorectal Neoplasms, Hereditary Nonpolyposis* / pathology DNA Mismatch Repair ErbB Receptors* / antagonists & inhibitors ErbB Receptors* / genetics Female Humans Male Microsatellite Instability Middle Aged Pharmacogenomic Testing / methods Receptor, ErbB-2* / antagonists & inhibitors Receptor, ErbB-2* / genetics Trastuzumab / pharmacology* |
| IF | 19.819 |
| リソース情報 | |
| ヒト・動物細胞 | CW-2(RCB0778) COLO205(RCB2127) COLO-320(RCB1193) |