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Classification of colorectal cancer

The majority of colorectal cancers are adenocarcinomas (made up of glandular epithelium), though rarely they may be squamous cell carcinomas or neuroendocrine tumours (sometimes called carcinoid tumours).

Around 15% of colorectal adenocarcinomas will demonstrate mismatch repair deficiency (so called mismatch repair deficient or MMRd tumours), which is usually associated with microsatellite instability (MSI).

Epidemiology of colorectal cancer

Incidence of colorectal cancer increases with age, peaking in the ninth decade of life. In recent years, however, incidence of colorectal cancer has increased in younger age groups and the reasons for this are still being explored.

Colorectal cancer caused by hereditary disorders is more likely to occur at a younger age than sporadic cancer.

Sporadic colorectal cancer has been linked to risk factors such as obesity, processed meat, smoking and alcohol consumption.

Genetics of colorectal cancer

Somatic genetics and colorectal cancer

Most cases of colorectal cancer are caused by somatic (tumour) mutations acquired during an individual’s lifetime, affecting genes that control cell growth and division or DNA repair mechanisms. Somatic mutations are those that have arisen by chance in the tumour, and are not present in constitutional (germline) DNA, so cannot be passed on to offspring.


  • Around 15% of colorectal adenocarcinomas will demonstrate MMR deficiency and/or MSI.
  • Two-thirds of MMR deficiency is attributable to hypermethylation of MLH-1 promoter. This leads to inactivation of the MLH1 gene, with associated loss of expression of the MLH1 protein along with its binding partner PMS2.
  • Pathogenic somatic BRAF variants (usually BRAF V600E) are common in sporadic MLH1/PMS2-deficient colorectal cancers. BRAF variants are found in around two-thirds of MMR-deficient cancers caused by hypermethylation of the MLH1 promoter, which accounts for the majority of cancers demonstrating this pattern of IHC. In contrast, somatic BRAF variants are rare in MLH1/PMS2-deficient cancers caused by Lynch syndrome.
  • MMR deficiency is usually associated with a characteristic pattern of mutations, known as a mutational signature in the tumour genome sequence.
  • MMRd tumours tend to have higher numbers of single nucleotide variants and small insertions and deletions (defined as the tumour mutation burden, or TMB), and fewer of the structural variants seen in MMR-proficient colorectal cancers.

Wnt signalling

  • Mutations in the Wnt signalling pathway, predominantly the APC gene, are almost ubiquitous in MMR-proficient colorectal cancer.

RAS mutations

  • Around 40% of colorectal cancers harbour a mutation in KRAS codons 12 and 13 of exon 2.
  • A further 2%–7% of colorectal cancers have KRAS mutations in exons 3 and 4 or NRAS mutations in exons 2-4.
  • RAS mutations suggest that the patient is unlikely to benefit from anti-EGFR therapy. (See Results: Patient with colorectal cancer – somatic (tumour) KRAS variant identified).
  • Certain KRAS variants may be more suggestive of an underlying hereditary cause of bowel cancer. For example, c.34G>T, (p.Gly12Cys), G12C accounts for only 2% of KRAS variants in sporadic colorectal cancers, but is present in 65% of MUTYH-associated cancers.

BRAF mutations

  • Around 10%–15% of patients with colorectal cancer harbour a mutation in BRAF. The most common variant is BRAF V600E.
  • As well as being associated with MSI-H tumours, mutations in BRAF itself confers a poor prognosis.
  • The presence of a pathogenic somatic (tumour) BRAF variant in an MLH1/PMS2-deficient colorectal cancer tumour indicates that the tumour is most likely to have arisen as a sporadic cancer rather than due to Lynch syndrome.
  • BRAF and KRAS mutations are usually mutually exclusive.

Constitutional (germline) genetics and colorectal cancer

Around 5% of colorectal cancer cases have an underlying inherited genetic cause.

Lynch syndrome

  • One-third of MMRd colorectal cancers arise from Lynch syndrome, most commonly caused by a single constitutional (germline) pathogenic variant in one of the four genes encoding the ‘major’ MMR proteins (MLH1, PMS2, MSH2 and MSH6) or rarely in EPCAM, a gene immediately upstream of MSH2. A further ‘hit’ (variant or deletion) is then required in the second allele (see Knudson two-hit hypothesis) of the same gene to confer malignant potential to a cell. This may be evident by ‘loss of heterozygosity’ at the locus of interest.
  • A rare cause of Lynch syndrome is constitutional hypermethylation of the MLH1 promoter. In this situation, hypermethylation of the MLH1 promoter will be evident in constitutional (germline) DNA as well as in the tumour.
  • Patients with Lynch syndrome have a genetic predisposition to colorectal cancer (50%–80%) at a younger than expected age, as well as other cancer types. Variants causing Lynch syndrome very rarely occur de novo; the majority are inherited, such that patients will frequently have a family history of colorectal cancer or of other associated cancers such as endometrial, stomach, ovarian and urinary tract cancer.
  • Lynch syndrome shows autosomal dominant inheritance and high penetrance. Overall, it accounts for between 1% and 4% of colorectal cancers.

Familial adenomatous polyposis

  • Although somatic (tumour) APC mutations are common, 1% of colorectal cancers are linked to constitutional (germline) pathogenic variants in APC, which leads to the autosomal dominant condition familial adenomatous polyposis (FAP).
  • A second somatic mutational ‘hit’ to APC then results in hundreds of colorectal adenomas, with almost 100% risk of cancer developing by the fifth decade of life, necessitating prophylactic colectomy.
  • Some patients with FAP have a lower polyp burden, with later age of onset, so called attenuated FAP (aFAP).
  • FAP also has extracolonic manifestations including desmoid tumours, thyroid cancers (specifically the cribriform-morular variant of papillary thyroid cancer), medulloblastoma, and polyps of the stomach and duodenum, and congenital hypertrophy of the retinal pigment epithelium (CHRPE).

MUTYH-associated polyposis

  • Approximately 0.3% of patients with colorectal cancers have MUTYH-associated polyposis.
  • This has a similar colonic phenotype to FAP, although polyp burden tends to be less significant and extracolonic manifestations are less common.
  • It is inherited in an autosomal recessive fashion, with two mutated MUTYH alleles (biallelic variants) required to increase colorectal cancer risk.
  • The carrier frequency of MUTYH variants is very high, with an estimated 1-in-50 individuals of European ancestry carrying a single variant in one copy of MUTYH (heterozygotes). Heterozygous carriers of MUTYH gene variants do not have a significantly increased risk of cancer compared to non-carriers, and are not usually recommended to have enhanced cancer screening compared to the general population.

Rare syndromes associated with CRC predisposition

  • Other rare hereditary causes of bowel cancer may include NTHL1 tumour predisposition syndrome, Peutz Jegher syndrome, PTEN Hamartoma tumour syndrome and juvenile polyposis syndrome, among others.

Management implications of genomic testing

MMRd /MSI-H tumours

  • MSI-H tumours have a different response to standard chemotherapy. In the adjuvant setting following curative surgery, chemotherapy with 5-fluorouracil is typically given to high-risk stage 2 patients with colorectal cancer (as determined by histological features and node positivity). Trials showed that patients who were MSI-H and stage 2 did not gain the same benefit from chemotherapy with 5-fluorouracil as other patients, and so this treatment is not usually offered to such patients.
  • In the metastatic setting, there is evidence that MSI-H tumours respond better to immunotherapy, as these tumours provoke more of an inflammatory response, which must then be dampened by the tumour by upregulating immune checkpoint molecule, such as PDL1. Immunotherapy drugs targeting those molecules have been shown to be effective in clinical trials and are currently available through the Cancer Drugs Fund while being considered by NICE.
  • If Lynch syndrome is confirmed, there is a high risk of a second primary colorectal cancer developing. This risk can be discussed with patients prior to any surgery and they can be offered subtotal colectomy as opposed to simple resection, as it has minimal increase in morbidity. Patients with remaining bowel in situ may also be offered aspirin long term, as this has been shown to reduce development of colorectal cancer types in patients with Lynch syndrome (see CAPP2 trial). This strategy is known as chemoprevention. Surveillance of any residual colon or rectum should be continued.
  • Diagnosing unaffected relatives with Lynch syndrome enables them to be offered:
    • surveillance for colorectal cancer development with biennial colonoscopy from the age of 25–35 (depending on underlying genotype);
    • chemoprevention with aspirin between ages 25–65; and/or
    • prophylactic hysterectomy (+/- oophorectomy depending on genotype) at age 40 to reduce risk of endometrial and ovarian cancer.

See gene-specific guidelines here.

RAS mutations

  • Patients with mutations in KRAS codons 12 and 13 of exon 2, exons 3 or 4, or with NRAS mutations in exons 2-4 have inferior outcomes to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab and panitumumab) in the metastatic setting.
  • The biological mechanism for this is that EGFR signals through the RAS-RAF-BRAF-MAPK where KRAS and NRAS are the most active proteins in the RAS superfamily.
  • A hotspot variant in KRAS (c.34G>T, (p.Gly12Cys), G12C), rare in sporadic colorectal cancer, has been reported to occur with increased frequency in cancers occurring within the context of MUTYH-associated polyposis – being found in 65% of MAP related cancers. This, in itself, is not an indication for constitutional (germline) MUTYH testing, but should prompt an assessment of polyp phenotype and family history.  

BRAF mutations

  • The BRAF inhibitor Encorafenib has shown promise in combination with cetuximab in BRAF V600E mutated metastatic colorectal cancer. This is currently available through the Cancer Drugs Fund while being considered by NICE.


  • Polyposis syndromes are usually suspected from family history or appearances of the bowel at colonoscopy or surgery.
  • Because the phenotype of FAP and MAP have considerable overlap, and given the high carrier frequency of MUTYH variants in the European population, testing of APC and MUTYH is recommended simultaneously in people presenting with colorectal cancer and polyposis. Testing of further genes associated with rarer forms of polyposis is offered simultaneously to eligible patients as part of the R211 panel (Inherited polyposis and early onset colorectal cancer).
  • In cases of FAP, total colectomy is usually recommended whereas MAP may be managed by surveillance and polypectomy depending on polyp burden.


For clinicians


For patients

Tagged: Somatic mutations, Colorectal cancer, Constitutional mutations

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  • Last reviewed: 04/05/2022
  • Next review due: 04/05/2024
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh