ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype Journal Article
| Authors: | Brodeur, M. N.; Selenica, P.; Ma, W.; Moufarrij, S.; Dagher, C.; Basili, T.; Abu-Rustum, N. R.; Aghajanian, C.; Zhou, Q.; Iasonos, A.; Ellenson, L. H.; Weigelt, B.; Chui, M. H. |
| Article Title: | ERBB2 mutations define a subgroup of endometrial carcinomas associated with high tumor mutational burden and the microsatellite instability-high (MSI-H) molecular subtype |
| Abstract: | Anti-HER2 therapy is indicated for erb-b2 receptor tyrosine kinase 2 (ERBB2)-amplified/overexpressing endometrial carcinoma (EC). Mutations constitute another mode of ERBB2 activation, but only rare ERBB2-mutated ECs have been reported. We sought to characterize the clinicopathologic and genetic features of ERBB2-mutated EC. From an institutional cohort of 2638 ECs subjected to clinical tumor-normal panel sequencing, 69 (2.6%) with pathogenic ERBB2 mutation(s) were identified, of which 11 were also ERBB2-amplified. The most frequent ERBB2 hotspot mutations were V842I (38%) and R678Q (25%). ERBB2 mutations were clonal in 87% of evaluable cases. Immunohistochemistry revealed low HER2 protein expression in most ERBB2-mutated ECs (0/1+ in 66%, 2+ in 27%); all 3+ tumors (7.3%) were also ERBB2-amplified. Compared to ERBB2-wildtype ECs (with or without ERBB2 amplification), ERBB2-mutated/non-amplified ECs were enriched for the microsatellite instability-high (MSI-H) and, to a lesser extent, DNA polymerase epsilon, catalytic subunit (POLE) molecular subtypes, and associated with high tumor mutational burden and low chromosomal instability. Survival outcomes were similar between patients with ERBB2-mutated/non-amplified versus wildtype EC, whereas ERBB2 amplification was associated with worse prognosis on univariate, but not multivariate, analyses. In conclusion, ERBB2 mutation defines a rare subgroup of ECs that is pathogenically distinct from ERBB2-wildtype and ERBB2-amplified ECs. © 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. |
| Keywords: | immunohistochemistry; adult; controlled study; human tissue; treatment response; primary tumor; gene mutation; major clinical study; mutation; histopathology; endometrial cancer; endometrium carcinoma; epidermal growth factor receptor 2; cohort analysis; in vitro study; retrospective study; microsatellite instability; clear cell carcinoma; trastuzumab; tumor gene; erbb2; rank sum test; her2; enzyme active site; dna directed dna polymerase epsilon; clinical outcome; human; female; article; tumor mutational burden |
| Journal Title: | Molecular Oncology |
| Volume: | 18 |
| Issue: | 10 |
| ISSN: | 1878-0261 |
| Publisher: | FEBS Press |
| Date Published: | 2024-10-01 |
| Start Page: | 2356 |
| End Page: | 2368 |
| Language: | English |
| DOI: | 10.1002/1878-0261.13698 |
| PROVIDER: | scopus |
| PMCID: | PMC11459037 |
| PUBMED: | 39031567 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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