Cancer Dictionary · Gastrointestinal

Colorectal Cancer

Colorectal cancer has one of the longest-established molecular testing pathways in solid tumour oncology. RAS and BRAF status, mismatch repair status and primary tumour location all shape the advanced-disease discussion. Mismatch repair testing doubles as universal screening for Lynch syndrome.

Also called Bowel cancer, Colon cancer, Rectal cancer, CRC.

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The governing idea

In colorectal cancer, several molecular results are used to rule treatment classes out as much as to rule them in, which makes profiling before first-line treatment in advanced disease unusually consequential.

01Before any molecular question

How it usually presents

Usually established first: the location of the primary tumour (right-sided, left-sided or rectal), stage, and mismatch repair status, which in most pathways is tested on all colorectal cancers regardless of age or family history. Sidedness is not a minor detail: it correlates with distinct biology and features in treatment discussions.

Usually already established

Primary tumour location: right colon, left colon or rectum
Stage, and whether metastatic disease is potentially resectable
Mismatch repair or microsatellite instability status
Whether the presentation is early-onset, which raises the germline question

Major disease categories

The divisions below are not labels. Each one changes what the treatment discussion is actually about.

Early stage, resectable colon cancer

Surgery organises the decision. Mismatch repair status informs both the adjuvant discussion and Lynch screening.

Rectal cancer

Managed on a partly different pathway from colon cancer, with a larger role for radiation and for organ preservation strategies.

Metastatic, mismatch repair proficient

The large majority. RAS and BRAF status and sidedness shape the first-line discussion.

Metastatic, mismatch repair deficient

A small minority with a distinctly different treatment discussion centred on immune approaches.

Oligometastatic disease

Where limited metastatic disease may be approached with curative intent, which changes the whole framing of treatment.

03What is discussed

Molecular considerations

KRAS, NRAS and BRAF status is central in metastatic disease, and BRAF V600E specifically carries a distinct meaning from other BRAF variants. Mismatch repair deficiency or high microsatellite instability defines a small but important group. HER2 amplification is uncommon but actionable and is often under-tested. NTRK fusions are rare and enriched in mismatch repair deficient, RAS and BRAF wild-type tumours. PIK3CA, SMAD4 and APC appear frequently but are less often directly actionable. Consensus molecular subtypes are a research classification rather than routine reporting.

Biomarkers commonly discussed

KRAS and NRAS

Status determines whether an entire treatment class is appropriate. Tested before first-line treatment in metastatic disease.

BRAF

V600E specifically. It carries different meaning from non-V600E variants.

MMR / MSI

Both a treatment-relevant marker and universal Lynch syndrome screening.

HER2 (ERBB2)

Amplification is uncommon but actionable, and is a recognised gap in testing practice.

NTRK

Rare. Enriched in MMR-deficient, RAS and BRAF wild-type tumours.

TMB

Usually tracks with mismatch repair status in this disease.

This is not an exhaustive list, and which markers are relevant depends on the individual case. Not every marker listed is assessed in every patient.

04What is tested, and from what

Testing, inherited risk and blood-based monitoring

Genomic testing considerations

Extended RAS and BRAF testing before first-line treatment in metastatic disease is long-established, and comprehensive profiling is increasingly discussed instead of sequential single-gene testing, because it captures HER2 and NTRK in the same run. Mismatch repair testing is performed on essentially all colorectal cancers. Tissue is usually available. Plasma testing is established for RAS status where tissue is insufficient, and at progression.

Germline considerations

Universal mismatch repair testing means colorectal cancer is one of the main routes by which Lynch syndrome is discovered. Beyond Lynch, familial adenomatous polyposis and MUTYH-associated polyposis are recognised syndromes, usually suggested by polyp burden. Early-onset colorectal cancer, now increasingly common, is a recognised prompt for germline evaluation regardless of family history. A confirmed inherited finding changes surveillance for the patient and opens a cascade pathway for relatives.

Cancer genetics and hereditary risk

ctDNA and liquid biopsy considerations

Colorectal cancer is one of the diseases where ctDNA for molecular residual disease after surgery is most developed, and where the central question is being actively studied: does acting on an early ctDNA signal change outcomes, or does it only detect recurrence sooner? In metastatic disease, plasma is established for RAS status and for detecting acquired resistance.

When molecular information matters

Testing that arrives after the decision it was meant to inform has already been made is a common and avoidable problem. This is the sequence in which molecular information tends to become relevant.

At diagnosis, any stageMismatch repair testing is performed on essentially all colorectal cancers, both for treatment relevance and for Lynch screening.
Before first-line treatment in metastatic diseaseExtended RAS and BRAF status, and increasingly HER2 and NTRK, need to be known before the first regimen is chosen.
After surgery with curative intentctDNA for residual disease is an active and rapidly developing area rather than settled practice.
At progressionPlasma testing is used to look for acquired resistance alterations, which can emerge as multiple subclones at once.
For relativesWhere an inherited condition is confirmed, relatives may act on it before any cancer develops.

06Take these to your team

Questions worth raising

When a decision is being made

Questions worth raising with a treating team.

Has extended RAS and BRAF testing been completed before the first-line regimen was chosen, rather than after?
Has HER2 amplification been assessed, since it is actionable and commonly missed?
Has mismatch repair status been established, both for treatment and for Lynch syndrome screening?
Has the sidedness of the primary tumour been factored into the discussion?
In early-onset disease, has germline testing been offered regardless of family history?

At progression, recurrence or resistance

The molecular picture at diagnosis is not always the molecular picture later.

Has plasma testing been used at progression to look for acquired resistance alterations?
Where resistance has emerged, is it a single alteration or a set of subclones, since that distinction affects what is worth trying next?
Has the possibility of rechallenge been discussed, given the evidence on clonal dynamics over time?

07What shapes eligibility

Clinical trial considerations

Eligibility is commonly written around RAS and BRAF status, mismatch repair status, HER2 amplification and prior treatment lines. Molecular residual disease trials after surgery are a large and active category with their own eligibility logic.

Ask about trial matching

Plain-language glossary for this entry (5 terms)

Term	What it means
Sidedness	Whether the primary tumour arose in the right or left colon. Correlates with different biology.
Extended RAS testing	Testing multiple regions of KRAS and NRAS rather than only the most common hotspot.
Wild-type	Not mutated. In colorectal cancer, RAS wild-type status is what makes a particular treatment class appropriate.
Molecular residual disease	Cancer left behind after treatment at a level too small to see on scans.
Oligometastatic	A limited number of metastatic sites, sometimes approachable with curative intent.

Where OnKommon fits

These are the services most often relevant to this cancer. Which of them applies is a clinical question, not an automatic one.

Signature STb O+The 523-gene comprehensive panel, with TMB and MSI.See how it works ClearMolecular residual disease surveillance after curative-intent treatment.See how it works HeritageInherited-risk testing, and a tested pathway for relatives.See how it works SentinelSerial monitoring during active treatment.See how it works

This entry is educational. It describes what is commonly discussed in this cancer, not what should happen for any individual. Which of it applies depends on the specific diagnosis, stage, prior treatment and the person themselves. Nothing here is a recommendation, and no list of biomarkers here is exhaustive. Decisions belong with a treating team who know the whole case.

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