Molecular classification of appendiceal adenocarcinoma Journal Article
| Authors: | Foote, M. B.; Walch, H.; Chatila, W.; Vakiani, E.; Chandler, C.; Steinruecke, F.; Nash, G. M.; Stadler, Z.; Chung, S.; Yaeger, R.; Braghrioli, M. I.; Shia, J.; Kemel, Y.; Maio, A.; Sheehan, M.; Rousseau, B.; Argilés, G.; Berger, M.; Solit, D.; Schultz, N.; Diaz, L. A. Jr; Cercek, A. |
| Article Title: | Molecular classification of appendiceal adenocarcinoma |
| Abstract: | PURPOSEAppendiceal adenocarcinomas (ACs) are rare, histologically diverse malignancies treated as colorectal cancers despite having distinct biology and clinical behavior. To guide clinical decision making, we defined molecular subtypes of AC associated with patient survival, metastatic burden, and chemotherapy response.PATIENTS AND METHODSA comprehensive molecular analysis was performed in patients with AC to define molecular subtypes. Associations between molecular subtype and overall survival, intraoperative peritoneal cancer index, and first-line chemotherapy response were assessed adjusting for histopathologic and clinical variables using multivariable Cox proportional hazards, linear regression, and logistic regression models.RESULTSWe defined distinct molecular lineages of mucinous appendiceal adenocarcinoma (MAAP) from co-occurring mutations in GNAS, RAS, and TP53. Of 164 MAAP tumors, 24 were RAS-mutant (mut) predominant (RAS-mut/GNAS-wild-type [wt]/TP53-wt) with significantly decreased mutations and chromosomal alterations compared with tumors with GNAS mutations (GNAS-mut predominant) or TP53 mutations (TP53-mut predominant). No patient with RAS-mut predominant subtype metastatic MAAP died of cancer, and overall survival in this subgroup was significantly improved compared with patients with GNAS-mut (P =.05) and TP53-mut (P =.004) predominant subtypes. TP53-mut predominant subtypes were highly aneuploid; increased tumor aneuploidy was independently (P =.001) associated with poor prognosis. The findings retained significance in patients with any metastatic AC. RAS-mut predominant metastases exhibited reduced peritoneal tumor bulk (P =.04) and stromal invasion (P <.001) compared with GNAS-mut or TP53-mut predominant tumors, respectively. Patients with RAS-mut predominant MAAP responded more to first-line chemotherapy (50%) compared with patients with GNAS-mut predominant tumors (6%, P =.03).CONCLUSIONAC molecular patterns identify distinct molecular subtypes: a clinically indolent RAS-mut/GNAS-wt/TP53-wt subtype; a chemotherapy-resistant GNAS-mut predominant subtype; and an aggressive, highly aneuploid TP53-mut predominant subtype. Each subtype exhibits conserved clinical behavior irrespective of histopathology. © American Society of Clinical Oncology. |
| Keywords: | genetics; mutation; adenocarcinoma; peritoneal neoplasms; adenocarcinoma, mucinous; pathology; colloid carcinoma; peritoneum tumor; appendix tumor; appendiceal neoplasms; humans; human |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 41 |
| Issue: | 8 |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2023-03-10 |
| Start Page: | 1553 |
| End Page: | 1564 |
| Language: | English |
| DOI: | 10.1200/jco.22.01392 |
| PUBMED: | 36493333 |
| PROVIDER: | scopus |
| PMCID: | PMC10043565 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Andrea Cercek -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work