Cancer driver–passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer

Abstract

Herein we report a proof of principle study illustrating a novel dog-human comparison strategy that addresses a central aim of cancer research, namely cancer driver–passenger distinction. We previously demonstrated that sporadic canine colorectal cancers (CRCs) share similar molecular pathogenesis mechanisms as their human counterparts. In this study, we compared the genome-wide copy number abnormalities between 29 human- and 10 canine sporadic CRCs. This led to the identification of 73 driver candidate genes (DCGs), altered in both species and with 27 from the whole genome and 46 from dog-human genomic rearrangement breakpoint (GRB) regions, as well as 38 passenger candidate genes (PCGs), altered in humans only and located in GRB regions. We noted that DCGs significantly differ from PCGs in every analysis conducted to assess their cancer relevance and biological functions. Importantly, while PCGs are not enriched in any specific functions, DCGs possess significantly enhanced functionality closely associated with cell proliferation and death regulation, as well as with epithelial cell apicobasal polarity establishment/maintenance. These observations support the notion that, in sporadic CRCs of both species, cell polarity genes not only contribute in preventing cancer cell invasion and spreading, but also likely serve as tumor suppressors by modulating cell growth. This pilot study validates our novel strategy and has uncovered four new potential cell polarity and colorectal tumor suppressor genes (RASA3, NUPL1, DENND5A, and AVL9). Expansion of this study would make more driver-passenger distinctions for cancers with large genomic amplifications or deletions, and address key questions regarding the relationship between cancer pathogenesis and epithelial cell polarity control in mammals.

Cancer driver candidate genes AVL9, DENND5A and NUPL1 contribute to MDCK cystogenesis

“…Bioinformatic analysis indicates that whereas passenger candidate genes' functions appear to be random, driver candidate genes are significantly enriched in functions that are associated with epithelial apicobasal polarity establishment and maintenance [1]. This is consistent with the observation that loss of cell polarity is a hallmark of epithelial cancers [4, 5], and supports the notion that epithelial polarity is a tumor suppressor [4-11].…”

“…Via dog-human comparative genomics and oncology studies, we have identified 73 driver candidate genes (likely cancer-causative when altered) and 38 passenger candidate genes (of which alterations are unlikely cancer-causative) for colorectal cancer [1-3]. Bioinformatic analysis indicates that whereas passenger candidate genes' functions appear to be random, driver candidate genes are significantly enriched in functions that are associated with epithelial apicobasal polarity establishment and maintenance [1].…”

“…They are deleted in colorectal cancer and restrict cell proliferation of HCT116 and other cancer lines [1]. They are hence classified as putative tumor suppressors.…”

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma

“…Although a functional role for RASA3 in cancer remains to be definitively established, studies from other biological fields have shown that RASA3 can inhibit RAP1 (122), which in turn has been implicated in invasion and metastasis in various cancers (123,124). RASA3 depletion can enhance signaling by integrins (125) and MAPK (64), and the possibility that RASA3 can act as a tumor suppressor has also been recently suggested through independent cross-species cancer studies (126). Our results suggest that RASA3 may play a more complex role in cancer, as the expression of WT RASA3 inhibited cell migration and invasion in gastric cancer cell lines, whereas N-terminal Var RASA3 enhanced migration and invasion.…”

Molecular Homology and Difference between Spontaneous Canine Mammary Cancer and Human Breast Cancer

“…For example, for cancers with large genomic CNAs, we can apply the dog-human comparison strategy for effective driver-passenger discrimination as described (7). Critically, as elegantly discussed in several publications (2-4), these canine cancers, which bridge a gap between traditional rodent models and human clinical trials, can significantly speed up new anticancer drug development.…”