The TGF-beta pathway alterations in young-onset colorectal cancer.

Abstract

218 Background: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related deaths worldwide. The epidemiological evidence suggests an increased incidence of young-onset CRC, defined as the CRC in individuals 50 years old or younger. The TGF-beta alterations are among the pivotal events in the CRC carcinogenesis. However, the rate of mutations leading to TGF-beta alterations are yet to be defined in young-onset CRC. Therefore, we conducted a bioinformatics analysis of the mutations associated with TGF-pathway alterations according to age (≤50 years of age vs. >50 years) and primary tumor location (colon vs. rectum). Methods: We used published genomic data of 6286 patients with CRC from the 16 CRC datasets included in the cBioPortal database. The presence of mutations in the following genes was used to define TGF-beta alterations: TGFBR2, TGFB2, TGFBRAP1, TGFBR1, TGFBR3, TGFB1I1, TGFBI, TGFB1, TGFBR3L, TGFB3, TGFA, SMAD1-9, BMPR2, BMPER, BMP3, BMP2K, BMP1, BMP5, BMP10, BMPR1A, BMP15, BMP7, BMP23, BMP4, BMP6, BMPR1B, BMP8B, BMP8A. The presence of TGF-beta alterations according to the age (≤50 years of age vs. >50 years) were evaluated with Chi-square tests. The association between primary tumor distribution (colon vs. rectal) and age were evaluated across patients with and without TGF-beta pathway alterations. The effect of WNT pathway alterations on the overall survival and survival after the metastatic stage was evaluated with Kaplan-Meier survival curves. A type-I error level of 5% (p<0.05) was considered the threshold limit for statistical significance. Results: A total of 2280 patients with available age data was included in the analyses.The mutations associated with TGF-beta pathway alterations was more common >50 years of age compared to ≤50 years of age. (28% vs. 17.4%, p<0.001). Additionally, mutations associated with TGF-beta pathway alterations were more frequent in colon cancer compared to rectum (25.4% vs. 18.7, p<0.001). While progression-free survival was higher in patients with mutations associated with TGF-beta pathway alterations (12.5 vs. 10.7 months, p=0.012), the overall survival (59.6 vs. 58.9 months, p=0.896) and survival after metastatic stage (49.7 vs. 56.5 months, p=0.109) were similar across two groups. Conclusions: In this study, we observed a higher rate of mutations associated with TGF-beta pathway alterations in older CRC patients compared to patients with young-onset CRC. Furthermore, the mutations associated with TGF-beta pathway alterations were more frequent in colon primaries. The overall survival was independent of these mutations. Further research is required to delineate the association between TGF-beta pathway alterations and onset of CRC, as well as the CRC prognosis.