MAP3K21 – Colorectal Cancer

MAP3K21 (also referred to as MLK4) has emerged as an important gene in the context of colorectal cancer. Multiple studies have analyzed a panel of tyrosine kinases in colorectal cancer samples, and while early mutation screening in cell lines and resected tumors indicated a generally low mutation frequency, a notable variant (c.1408C>T (p.Arg470Cys)) was identified in a subset of samples (PMID:17016444). This observation, albeit in a limited number of cases, raises the possibility that infrequent, yet functionally critical, alterations in MAP3K21 may contribute to tumorigenesis.

Genetic evidence supporting the role of MAP3K21 in colorectal cancer is reinforced by additional tumor sequencing studies. Although large-scale screening in Japanese colorectal cancer patients and dietary association studies did not highlight MAP3K21 as a frequently mutated gene, nominal statistical significance was noted in multi-patient analyses (PMID:39025327). The identification of the c.1408C>T (p.Arg470Cys) variant provides a molecular foothold that assigns genetic relevance to this gene despite the overall low prevalence of mutations.

The inheritance pattern in colorectal cancer is best conceptualized as somatic, with mutations arising in the tumor rather than being inherited. Segregation data in familial settings remain limited; however, the accumulation of molecular evidence points toward a somatic mechanism where loss-of-function mutations in MAP3K21 contribute to the malignant phenotype. In this context, the mutation spectrum, though limited in the number of cases, is critical for understanding the oncogenic process in colorectal tissues.

Functional and experimental studies strongly support the contribution of MAP3K21 to colorectal cancer pathogenesis. In-depth functional assessments, including those published in Cancer Research, have demonstrated that recurrent loss-of-function mutations in MLK4 (MAP3K21) result in suppressed JNK signaling. Restoration of MAP3K21 activity in colon cancer cell models led to reduced cell viability, proliferation, and colony formation, thereby underscoring its role as a tumor suppressor (PMID:26637668). Additional work has confirmed these findings by showing that experimental overexpression leads to marked inhibition of tumorigenic properties (PMID:26217104).

Some large-scale mutational analyses have reported an overall low mutation frequency for tyrosine kinases in colorectal cancer, which might seem conflicting at first glance. However, the impact of rare but recurrent loss-of-function events in MAP3K21 is compounded by the robust functional validation that demonstrates diminished JNK pathway activity and enhanced tumor cell proliferation. These contrasting findings suggest that, while not prevalent, when MAP3K21 alterations do occur they have substantial biological significance.

The integration of genetic and functional data provides a coherent narrative supporting MAP3K21 as a critical tumor suppressor in colorectal cancer. Although additional evidence may be available that exceeds the maximum ClinGen scoring criteria, the current findings are sufficiently robust to inform diagnostic decision-making and underpin future therapeutic strategies. Key take‑home message: The strong functional impact of recurrent MAP3K21 loss‑of‑function mutations on JNK signaling establishes its clinical utility as a molecular marker and a potential target in colorectal cancer management.

References

• Oncogene • 2007 • Absence of tyrosine kinase mutations in Japanese colorectal cancer patients PMID:17016444
• The American journal of clinical nutrition • 2024 • Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing PMID:39025327
• Genomics insights • 2011 • Cloning and Initial Functional Characterization of Mlk4α and Mlk4Î PMID:26217104
• Cancer research • 2016 • Recurrent MLK4 Loss-of-Function Mutations Suppress JNK Signaling to Promote Colon Tumorigenesis PMID:26637668

Evidence Based Scoring (AI generated)