SRC – Colorectal Cancer

Somatic alterations in SRC have been investigated as drivers of colorectal carcinogenesis. A truncating hotspot mutation at codon 531 (c.1591C>T (p.Gln531Ter)) was absent in 155 Italian CRC cases (PMID:11161376), while targeted NGS of 14 case-matched primary and metastatic specimens identified a de novo SRC mutation in one metachronous lung metastasis (PMID:27756406) and SRC amplifications were reported in an individual metastatic CRC case with anti-EGFR treatment resistance (PMID:38023256). Together, somatic SRC events in CRC are rare and lack recurrent pathogenic alleles.

Functionally, SRC encodes a non-receptor tyrosine kinase whose activation via altered phosphorylation sites and SH2/SH3 domain modifications enhances kinase activity, promotes transformation in cell models, and modulates adhesion and survival pathways. Although these in vitro and in vivo biochemical studies establish biological plausibility for SRC as an oncogene, direct functional validation in colorectal tumour models remains limited. Additional large-scale sequencing and CRC-specific mechanistic studies are needed to determine SRC’s role in tumorigenesis and its utility as a therapeutic target.

Key Take-home: SRC somatic mutations in colorectal cancer are infrequent and nonrecurrent; functional evidence supports oncogenic potential but current clinical data do not justify routine SRC testing outside research settings.

References

• British journal of cancer • 2001 • Lack of mutation at codon 531 of SRC in advanced colorectal cancers from Italian patients. PMID:11161376
• Molecular cancer • 2016 • Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. PMID:27756406
• Frontiers in oncology • 2023 • Case Report: Progressive disease of BRCA2-mutant colon adenocarcinoma following talazoparib therapy. PMID:38023256

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