Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients

Abstract

Tumor profiling of DNA alterations, i.e. gene point mutations, somatic copy number aberrations (CNAs) and structural variants (SVs), improves insight into the molecular pathology of cancer and clinical outcome. Here, associations between genomic aberrations and disease recurrence in stage II and III colon cancers were investigated. A series of 114 stage II and III microsatellite stable colon cancer samples were analyzed by high-resolution array-comparative genomic hybridization (array-CGH) to detect CNAs and CNA-associated chromosomal breakpoints (SVs). For 60 of these samples mutation status of APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, BRAF and NRAS was determined using targeted massive parallel sequencing. Loss of chromosome 18q12.1-18q12.2 occurred more frequently in tumors that relapsed than in relapse-free tumors (p < 0.001; FDR = 0.13). In total, 267 genes were recurrently affected by SVs (FDR < 0.1). CNAs and SVs were not associated with disease-free survival (DFS). Mutations in APC and TP53 were associated with increased CNAs. APC mutations were associated with poor prognosis in (5-fluorouracil treated) stage III colon cancers (p = 0.005; HR = 4.1), an effect that was further enhanced by mutations in MAPK pathway (KRAS, NRAS, BRAF) genes. We conclude that among multiple genomic alterations in CRC, strongest associations with clinical outcome were observed for common mutations in APC.

Genomic Profiling of Stage II Colorectal Cancer Identifies Candidate Genes Associated with Recurrence-Free Survival, Tumor Location, and Differentiation Grade

“…Mutations in KRAS, BRAF and APC are important genetic events in the aberrant activation of the MAPK and the Wnt signaling pathways, respectively [15,32]. The frequency of gene mutations of BRAF (20%), KRAS (29%), and of APC (52%) observed here were of similar magnitude as those published by others [32][33][34][35][36][37][38]. These genes have been studied extensively.…”

“…Central gene mutations (KRAS, NRAS, BRAF, APC, and CTNNB1) in these pathways are almost mutually exclusive [33,43]. Separate and combined analysis of these genes has been associated with RFS in MSI stable stage III patients, but not in MSI stable stage II patients [38,42]. Similar observations were done here in stage II, although MSI status was unknown in our study population.…”

Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting

“…In studies of colorectal cancer as a whole, APC mutational status does not strongly correlate with outcome [16, 17]. Nevertheless, APC mutations exhibit an interesting pattern of differential distribution in the recognized subtypes of colorectal cancer (Fig.…”

“…Interestingly, CTNNB1 mutations are significantly more prevalent in small adenomas than in large adenomas or adenocarcinomas, [18], whereas APC mutations are well-represented across all stages of tumorigenesis. It has recently emerged that APC mutational status has value as a predictive marker of poor prognosis in Stage III colorectal cancers [17], raising the possibility that APC mutations not only initiate colorectal cancer development, but drive clinical phenotypes relevant to progression and metastasis as well.…”

Genomic Alterations and Their Implications on Survival in Nonmetastatic Colorectal Cancer: Status Quo and Future Perspectives

“…Associated with a better outcome [8,[10][11][12][13]30], especially in stage II CRC [14][15][16][17] Conflicting results: Shorter survival in patients treated with adjuvant 5-FU [10,23,24,67] Stage II CRC had improved RFS treated with 5-FU + irinotecan [14] APC Conflicting results: Poor prognostic marker in 5-FU treated stage III CRC [68] Associated with better outcomes in MSS tumors [69] No prognostic value [70][71][72] No predictive value Glossary: DFS; disease-free survival, OS; overall survival, RFS; recurrence-free survival, pMMR; proficient mismatch repair, 5-FU; 5-fluorouracil, CRC; colorectal cancer dMMR (n = 35) vs. pMMR (n = 261) 5-FU treated and no ACT 80% vs. 75% DFS respectively, p = 0.5 89% vs. 85% OS respectively, p = 0.6 no survival benefit, according to MMR status dMMR (n = 18) vs. pMMR (n = 191) 5-FU treated and no ACT 73% vs. 61% DFS respectively, p = 0.4 78% vs. 75% OS respectively, p = 0.8 no survival benefit according to MMR status The underlined terms refer to a subgroup, the italicized terms indicate which independent factors are being assessed in that subgroup for prognostic/predictive value, the regular text details the survival data, and the bolded text is the data interpretation and summary.…”