Differential colorectal cancer genomics between east and west (2019)

Colorectal cancer (CRC) is a heterogeneous and complex disease driven by genetic alterations. Over the past decades, great efforts have been dedicated to elucidate the genomic landscape of CRC and to unravel the reasons for the significant inter-patient differences in prognosis and therapy response. Studies on genetic and molecular landscapes of CRC support classification of CRC into distinct molecular subtypes in Asian and/or Western populations.1-4 These studies have compared differential expression of genes between cancer patients and normal controls or between cancer tissues and paired normal tissues.5-8 However, most of the published works are based on CRC cases from single populations, which may produce cohort-specific results. Moreover, analysis of the sequencing data could be further confounded by the profound variations in ethnicity-dependent gene expression in normal tissues.9, 10 Hence, identification of robust, universal biomarkers that can be consistently replicated in CRC patients of different ethnicities is important to unravel better biomarkers for the prognosis and diagnosis of CRC. To this end, in this issue of the Journal, Song et al. examined 2233 CRC samples collected from multiple databases led to the discovery of 26 genes that are universally upregulated or downregulated in CRC samples11 in diverse populations, including the USA, France, Germany, Japan, and Singapore. Analyzing these samples enabled Song et al. to pinpoint commonly dysregulated genes across Asian and Western populations. In particular, AJUBA and EGFL6 were shown to be upregulated in all CRC tissues studied but lowly expressed in normal colorectal tissues. LPAR1, on the other hand, was downregulated in all CRC tissues studied but highly expressed in normal colorectal tissues. Further functional studies delineated how altered expression of these genes disrupted pathways for ribosome biogenesis, cell proliferation, and cell cycle and provides insights into the development of diagnostic biomarkers and therapeutic targets. The study by Song et al. primarily focused on gene expression at mRNA level. Previous studies have also attempted to highlight the similarity and differences between Asian and Western populations in terms of somatic mutations using multi-cohort analyses.5 Huang et al. performed a comprehensive analysis of published work to elucidate the association between key driver genes and CRC metastasis. The results showed that p53 mutations were associated with CRC metastasis in Asian, European, and American populations whereas mutations in BRAF were associated with CRC metastasis in Asian population only. Distinct mutational patterns were observed between Asian and European/American populations, but more studies are required to validate their findings. In another study, analysis of genetic mutations of Chinese CRC patients identified three novel significantly mutated genes, namely, CDH10, FAT4, and DOCK2.12 This study illustrated that mutation status of a five-gene signature predicts survival of patients independent of TNM staging in Chinese as well as Western populations (from Cancer Genome Atlas database).12 With multi-cohort validation, these mutated genes may expand the current list of druggable targets and accelerate the development of novel therapeutics. Apart from genetic and transcriptome alterations, epigenetic dysregulation has been well documented in colorectal carcinogenesis. RAS protein family has a notorious reputation in cancer with KRAS, NRAS, and BRAF mutations as major driver genes in many cancer types. However, lesser-known members of RAS family could actually function as tumor suppressors. In this issue of the Journal, Oh et al. demonstrated that the Ras association domain family 1 isoform A (RASSF1A) functions as a tumor suppressor in CRC and it inhibits CRC cell growth via the p53-p21WAF1 pathway.13 Mechanistically, RASSF1A induces not only cell cycle arrest but also the expression of p21WAF1 in a p53-dependent manner. Oh et al. further demonstrated that RASSF1A promotes the ubiquitin-mediated degradation of MDM2 and stabilizes p53.13 RASSF1A has also been reported be frequently silenced in various cancer types14-17 and reported to exert tumor suppressive effects.18-20 Interestingly, several studies on Asian populations suggest that loss of RASSF1 is consistent in non-Caucasians and in other cancer types such as hepatocellular carcinoma21 and thyroid cancer.22 It would be of interest to further validate whether RASSF1A is a universal tumor suppressor that is commonly silenced in CRC from diverse ethnicities. The heterogeneity of CRC is likely to be much bigger than what we have known. It is important to escalate on our understanding the genomics of CRC in order to find better ways to improve diagnosis and treatment of the disease. Further studies performed on various ethnic populations are required to determine genetic and epigenetic factors that contribute to the development and progression of CRC as well as their response to therapy. A better fundamental understanding of the difference in genetic alterations between Asian and Western CRC patients will facilitate biomarker development and help physicians select patients who are likely to respond to therapy. Overall, large-scale population studies composing of diverse ethnicities will generate useful information that can be used to rationalize treatments and improve clinical outcomes.