Colorectal cancer (CRC) affects approximately 1.9 million individuals worldwide based on the latest global estimates. It ranks third among all cancers in terms of incidence and is the second most common cause of death. In recent years, increased incidence in young patients has been observed globally for both sporadic cases and those with identified hereditary predispositions. This is in stark contrast to the declining incidence of late-onset CRC (LO-CRC) as a result of effective screening programs. Young-onset colorectal cancer (YO-CRC) carries clinical-pathological features that portend a poor prognosis: poorly differentiated histology, mucinous or signet ring histopathologic subtypes, and more advanced stages upon diagnosis. The implications are that young patients may need to undergo cancer screening earlier. Disease progression and mortality also seem to be worse in young patients even with the availability of standard chemotherapy regimens — although this observation needs to be further validated. Nonetheless, this suggests that treatment may have to be modified to improve survival and that unique biomarkers for early detection may need to be identified for this subgroup.
Multiple studies suggest that the mutational signature of YO-CRC is different from that of late-onset cases and there appear to be differences as well between ethnic groups — in particular, mutations in EGFR cellular proliferation and survival pathway genes such as KRAS, NRAS, BRAF, PIK3CA, and PTEN. It is not entirely known whether the mutational profiles of LO-CRC and YO-CRC are distinct or partly overlapping, at least as far as EGFR pathway genes are concerned. Comparison of mutations in other pathways implicated in CRC progression such as Notch, transforming growth factor-β (TGF-β), and Wnt signaling remains largely unexplored.

Next-generation sequencing technologies facilitated the explosion of cancer genome sequencing projects worldwide. This expanded our view of the mutational landscape of CRC in general throughout the progression of the disease. Uncharacterized mutations in oncogenes and tumor suppressors continue to be reported. Their significance in terms of cancer aggressiveness, prognostic value, and resistance to therapy remains to be fully unraveled.

This Research Topic aims to discuss the mutational signature of LO-CRC and YO-CRC by the identification and characterization of recurrent as well as novel and non-hotspot mutations in genes reported to be involved in CRC progression. In the long term, the data gathered for these mutations may be useful for prognostication, matched combinatorial therapies, and drug effectiveness screening.
We invite submissions of Original Articles, Brief Research Reports, Case Reports, Clinical Trials, Hypothesis & Theories, Methods, Mini Reviews, Opinions, Perspectives, Reviews, and Systematic Reviews addressing any of the following specific themes:

1. Recurrent, novel, and non-hotspot mutations identified and/or functionally characterized from LO-CRC and YO-CRC patients/cohorts. For the latter, those from sporadic cases with no identified familial predisposition to CRC and with a microsatellite stable (MSS) profile are of particular interest.

2. Clinical data of patients correlated with novel and canonical mutations identified

3. Mutational landscape of EGFR signaling and associated pathways implicated in LO-CRC and YO-CRC across races/ethnicities as outputs of NGS, targeted NGS, or exome sequencing projects accompanied by validation

4. Studies demonstrating the prognostic value of the identified novel mutations, or their role as a de novo mode of resistance

Please note: manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) will not be accepted in any of the sections of Frontiers in Oncology.

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