Changing the story of colorectal cancer: Insights from COSMIC v103

COSMIC v103 focuses on colorectal cancer (CRC), the third most common cancer in the world bringing insights to support the research community. 

For this release, we reviewed CRC-related papers from PubMed and identified early onset colorectal cancer (EOCRC) as a key area of interest. EOCRC, diagnosed in individuals under 50, is an increasing global concern. 

To ensure COSMIC continues to reflect the full genetic diversity of cancer, we also paid attention to rarer CRC subtypes and studies involving underrepresented ethnic groups. Combining computational analysis with expert review, this release captures high quality, comprehensive mutation data that supports continued progress in understanding colorectal cancer.

In this blog, we highlight a selection of papers from this release that showcase recent advances in colorectal cancer research and illustrate the breadth of data now available in COSMIC v103.

Exceptionally rare paediatric case with no familial history 

Though Colorectal cancers are typically associated with diagnosis post 50 years of age, we are increasingly facing younger and younger patients.

For example, one paper curated as part of v103, PMID: 40291278, illustrates an 11-year-old Iranian boy with no family history of colorectal cancer diagnosed with colorectal adenocarcinoma showing a KRAS mutation. The cancer was highly aggressive, with widespread metastases, including to the brain, a rare site for colorectal cancer spread.

This case reminds us that pediatric colorectal cancer, though extremely rare, can arise sporadically and display genetic features typically seen in adult cases and unusual metastasis. It reinforces the importance of early molecular testing to better understand tumour biology and to guide timely, personalised care in these uncommon and challenging situations.

Need for genetic evaluation in young CRC patients

A striking example highlighting the importance of early molecular testing comes from the rare case of early-onset colorectal cancer in a child reported in PMID 32904697 associated with a novel germline MYH mutation. This mutation impairs DNA base-excision repair and, combined with somatic mutations in SMAD4 (R361C) and TP53 (Y234H), likely sped up tumour development.

The young patient presented with an aggressive form of colorectal cancer typical with paediatric cases, which tend to be poorly differentiated, diagnosed late, and carry a poor prognosis.

This study serves as a powerful reminder that, although paediatric colorectal cancer is rare, it can result from a combination of inherited and acquired genetic changes. Early genetic screening can make a real difference by helping to identify at-risk children and enabling timely monitoring and intervention.

Monitoring treatment response using circulating tumour DNA

Even after a successful diagnosis, ongoing disease monitoring plays a crucial role in guiding treatment decisions and improving outcomes.

Curated paper PMID 35734602 sheds light on this through the case of a young patient with early-onset rectal adenocarcinoma patient who was monitored through circulating tumour DNA (ctDNA) at multiple time points during treatment. The tumour carried a nonsense APC mutation, while BRAF, KRAS, NRAS, and HRAS were wild type.

Interestingly, although KRAS appeared wild type at first, ctDNA analysis revealed an increase in KRAS gene copy number during cetuximab therapy, around when treatment resistance arises. This suggests that KRAS amplification, not just mutation, can act as an important warning sign for treatment resistance.

The study highlights how regular liquid biopsies can provide a real-time glimpse into tumour evolution and identify resistance mechanisms. The authors propose this could be a potential tool for guiding treatment in metastatic or early-onset rectal cancer.

Changing the outlook

Though still uncommon, early-onset CRC is increasingly diagnosed at advanced stages, when treatment options are limited.

This update brings together genomic data revealing mutations that drive aggressive disease forms, and potential biomarkers for disease progression. Such insights highlight the potential of genetic testing to identify at-risk individuals long before symptoms appear, paving the way for earlier intervention and precision care.

Together, these advances underscore how genomic knowledge can help change the outlook for patients of all ages, no matter when diagnosis occurs.