Molecular subtyping of colorectal cancer: Recent progress, new challenges and emerging opportunities

Wei Wang, Raju Kandimalla, Hao Huang, Lina Zhu, Ying Li, Feng Gao, Ajay Goel, Xin Wang
2018 Seminars in Cancer Biology  
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Similar to many other malignancies, CRC is a heterogeneous disease, making it a clinical challenge for optimization of treatment modalities in reducing the morbidity and mortality associated with this disease. A more precise understanding of the biological properties that distinguish patients with colorectal tumors, especially in terms of their clinical features, is a key requirement towards a more robust,
more » ... argeted-drug design, and implementation of individualized therapies. In the recent decades, extensive studies have reported distinct CRC subtypes, with a mutation-centered view of tumor heterogeneity. However, more recently, the paradigm has shifted towards transcriptomebased classifications, represented by six independent CRC taxonomies. In 2015, the colorectal cancer subtyping consortium reported the identification of four consensus molecular subtypes (CMSs), providing thus far the most robust classification system for CRC. In this review, we summarize the historical timeline of CRC classification approaches; discuss their salient features and potential limitations that may require further refinement in near future. In other words, in spite of the recent encouraging progress, several major challenges prevent translation of molecular knowledge gleaned from CMSs into the clinic. Herein, we summarize some of these potential challenges and discuss exciting new opportunities currently emerging in related fields. We believe, close collaborations between basic researchers, bioinformaticians and clinicians are imperative for display a near diploid karyotype and carry a set of unique gene mutations that are distinct from those seen in CIN CRCs [22] . The clinical relevance of MSI has been well characterized before. For instance, MSI was shown to be associated with better prognosis and reduced metastasis [23] . High-frequency microsatellite instability (MSI-H) or defective MMR (dMMR) was also predictive of response to Fluorouracil-based adjuvant therapy [24] as well as immunotherapy [25] . Recently, pembrolizumab, an anti-PD1 immunotherapy, has been approved by FDA for treatment of MSI-H or dMMR colorectal cancer. Epigenetic instability caused by promoter CpG island hypermethylation is another well recognized pathway in CRCs. Aberrant DNA methylation is present in essentially all CRCs, however, ~10-20% of patients exhibit extremely high frequency of aberrantly methylated CpG loci, often characterized as having a CpG Island Methylator Phenotype (CIMP) [26] . According to the level of CIMP [26], CRC tumors can be divided into CIMP-high and CIMP-low CRC groups, associated with different precursor lesions [27] [28] [29] . Compared to CIMP-low patients with a CIMP-high phenotype often demonstrate worse prognosis. When MSI is taken into consideration, CIMP-high patients with MSI have a more favorable survival [30, 31] . These patients also tend to associate with MSI and BRAF mutations, but lack KRAS and TP53 mutations [32] [33] [34] . However, the exact relationships between CIMP, MSI and BRAF remain elusive. Mutation-centered CRC classifications The pathogenesis of CRC involves both genetic and epigenetic changes that result in histologic differences, and is most clearly described in the model of "adenoma-carcinoma" sequence proposed by Fearon and Vogelstein [35, 36] . In this model, CRC pathogenesis is illustrated as a stepwise process, involving accumulation of genetic and epigenetic alterations that contribute to the transformation of normal mucosa to an adenoma and the subsequent progression to a more malignant stage. Acquisition of APC inactivated mutations evolve first, subsequently mutations occur in KRAS, followed by further mutations in elements of TP53, PI3K, TGF-β and other pathways [37, 38] . Along the "adenoma-carcinoma" sequence, mutations in several key genes such as KRAS and TP53 have demonstrated prognostic and predictive values. KRAS mutations are found in ~30-50% of CRC patients [39, 40] . Of these, 90% of KRAS mutations occur in codons 12 and 13 within the second exon (G12/13 changed to valine) [41] [42] [43] , causing constitutive activation of the mitogen-activated protein kinase (MAPK) cascade. There are conflicting reports on the association of KRAS mutations and CRC prognosis. However, in metastatic CRC, KRAS mutant patients are currently not considered for anti-EGFR based therapy [44] . Also prominent in CRC are mutations in the TP53 tumor suppressor gene, which play a crucial role in cell proliferation and apoptosis [45, 46] . The loss of function of TP53 is a late event in CRC progression and has been identified in up to 60% of CRCs [47] . The presence of TP53 mutations are predictive of decreased cancer cell sensitivity to most chemotherapeutic agents, particularly 5-fluorouracil [48, 49] .
doi:10.1016/j.semcancer.2018.05.002 pmid:29775690 pmcid:PMC6240404 fatcat:jtfffdfoznenfmigdydgekqxby