Comparative proteogenomic analysis of right-sided colon cancer, left-sided colon cancer and rectal cancer reveals distinct mutational profiles

Abstract

Right-sided colon cancer (RCC) has worse prognosis compared to left-sided colon cancer (LCC) and rectal cancer. The reason for this difference in outcomes is not well understood. We performed comparative somatic and proteomic analyses of RCC, LCC and rectal cancers to understand the unique molecular features of each tumor sub-types. Utilizing a novel in silico clonal evolution algorithm, we identified common tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor development and selection of downstream somatic alterations were distinct in all three anatomical locations. Some similarities were noted between LCC and rectal cancer. Hotspot mutation analysis identified a nonsense mutation, APC R1450* specific to RCC. In addition, we discovered new significantly mutated genes at each tumor location, Further in silico proteomic analysis, developed by our group, found distinct central or hub proteins with unique interactomes among each location. Our study revealed significant differences between RCC, LCC and rectal cancers not only at somatic but also at proteomic level that may have therapeutic relevance in these highly complex and heterogeneous tumors.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0923-9) contains supplementary material, which is available to authorized users.

Comprehensive tumor profiling reveals unique molecular differences between peritoneal metastases and primary colorectal adenocarcinoma

“…The reason for this clinical difference in outcomes is poorly understood, however, and likely differences in molecular biology are to explain. Common initial tumor‐initiating events involving APC, KRAS , and TP53 genes are observed irrespective of sidedness for RS, LS, and rectal cancers but different mutational behavior characterized by significant somatic and proteomic differences at each location have been identified 49 . RS cancers have higher rates of microsatellite instability, mutational burden, and BRAF and PIK3CA mutation rates than LS colon and rectal cancers, whereas rectal cancers have higher rates of TOPO1 expression and Her2/neu amplification 39 .…”

c‐Fos separation from Lamin A/C by GDF15 promotes colon cancer invasion and metastasis in inflammatory microenvironment

“…Colon cancer is a leading cause of cancer deaths worldwide, and roughly 600,000 people die from colorectal cancer every year (Brenner, Kloor, & Pox, ; Siegel, Miller, & Jemal, ). Colon cancer is a malignancy of multiple stages, and other than gene mutations such as KRAS, BRAF, TP53, and DNA mismatch pair genes, chronic inflammation is recognized as a major cause for the development of colon cancer (Chen et al, ; Hale et al, ; Imperial et al, ). Although surgical resection combined with adjuvant therapy is efficient at early stages of the disease, subsequent relapse and metastasis such as liver and lung metastasis often occur, which is an important reason for deaths of patients (Bu et al, ; J. Li et al, ).…”

Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study

“…Differential biological features have been described for right-sided colon cancer (RCC, originating from cecum, ascending colon, and proximal two-third of the transversum) and left-sided one (LCC, originating from the distal one-third of the transversum, descending colon, sigma, and rectum) [17]. Rectal cancer displays some molecular peculiarities as compared to LCC [18,19], although usually included in this group. Evidences have been provided suggesting that primary tumor location is not only prognostic, but also predictive of the efficacy of anti-EGFR agents.…”