Biomarkers

Bowel cancer isn’t just one thing.

There are lots of bowel cancers.

The way that we characterise these cancers is largely through biomarkers.

  • Biomarkers can indicate that normal cell processes are not working correctly.
  • Biomarkers are molecules that can be found in your body tissues, blood, or tumours.
  • Biomarkers can be used to choose targeted treatment to make it more effective.

If you are aware of a pattern of bowel cancer within your family – ask for a referral to the family or clinical genetics department.

Important biomarkers for bowel cancer:

  • MLH1 (Lynch Syndrome)
  • MSH2 (Lynch Syndrome)
  • MSH6 (Lynch Syndrome)
  • PMS2 (Lynch Syndrome)
  • EPCAM (Lynch Syndrome)
  • HER2 (somatic)
  • KRAS (somatic)
  • BRAF (somatic)
  • NRAS (somatic)
  • MSS, MSI & MMR Microsatellite stability/instability and MisMatch Repair Gene

How do I find out if I have a Biomarker?

The analysis of your tissue or tumour should be given on your patient record.

It may well be written on a letter to you giving the full diagnosis.

Online access to patient records (Electronic Health Record or EHR) is being rolled out across the country. You may need an app to access them. Your GP surgery may have a particular app they work with.

Current list of APPS able to access NHS records

Testing

In the UK patient biopsies and tumours are typically tested for the Lynch, KRAS, NRAS, BRAF and MMR biomarkers. If tested from a biopsy you may get this information soon after the colonoscopy.

National Genomic Test Directory has full details of which biomarker tests should be carried out.

Somatic testing

Testing of tumours identifies somatic changes. These are gene mutations that are being expressed in the tumour cells, but are not inherited. They arise in the cancer cell. These may be the mutations that caused the cancer, or may be mutations that have come about as a result of the cancer.

Amplification In a tumour cell, the cancer mechanisms usually result in a particular gene going into overdrive and producing too much of a particular protein. When this happens the tests will find an abnormally high level of the gene, its DNA, RNA or resultant protein. This is called amplification.

Genomic Testing

A whole body genome sequence would show what genetic variations you have inherited, but not the genetic make up of the tumour. These genomic or germline variations may be important in how the cancer develops. However, Whole Genome Sequencing (WGS) is an expensive test.

There are cheaper and quicker tests for important genomic mutations , eg Lynch Syndrome genes: MLH1, MSH2, MSH6, PMS2, EPCAM.

Although cancers that occur in people with Lynch Syndrome are termed Inherited Tumours, that does not mean the person has inherited the cancer. Lynch did not cause the cancer. Lynch Syndrome indicates that there are mutations in the genes that help to protect us from cancer. So, if you get a cancer mutation, these important genes may not be as effective at stopping the mutation from spreading out of control.

Tests for genetic factors is often done after treatment. We argue that it should be done at the time of diagnosis, because it can affect the kind of treatment that is most appropriate.

About 30% of bowel cancers are considered to have an inherited component. However, Lynch only makes up about 5% of all bowel cancers and these are the only ones that are tested for. There are 25% of inherited cancers that we do not have specific tests for.

Other Inherited Factors.

There are other inherited factors that can predispose one to bowel cancer. This topic is addressed in more detail here – Inherited Tumours

Implications of Biomarkers

The presence of particular versions of biomarkers may indicate which forms of chemotherapy and immunotherapy are most effective. For example, certain biomarkers might indicate that the normal (SoC or standard of care) chemotherapy would be inappropriate. For advanced cancers it may be appropriate to use a targeted combination therapy including immunotherapy. Visit the Cancer Research UK page on Targeted Therapy

Example: In 2021 researchers found that a proportion (5-10%) of rectal cancer patients, those with the MMRd & MSI-H biomarkers could be successfully treated with immunotherapy (dostarlimab) and acheive a complete response, ie the tumours disappear. Avoiding the need for chemotherapy and surgery. Article

The Global Colon Cancer Association has a guide to biomarkers: Know your biomarker

Lynch Syndrome

  • Lynch Syndrome involves several inherited genes which normally protect the body from cancer, but mutations in any of these genes may inhibit this function.
  • If someone has a Lynch Syndrome mutation it does NOT mean they will definitely get cancer, there are other factors involved.
  • If you have one of the Lynch Syndrome mutations, this has implications for your family. Your elders, siblings and offspring. If they too have the same mutations, they will be more susceptible to bowel and other cancers.
  • You should contact members of your family and advise them to get tested.
  • Anyone with Lynch Syndrome can reduce their cancer risk.
  • People with Lynch Syndrome are entitled to advanced cancer screening, to catch cancer early and cure it.
  • There is evidence that some people with Lynch Syndrome diagnosed with a bowel cancer are more likely to develop secondary cancers.
  • Lynch Syndrome UK is a support group for people with these mutations.

KRAS

  • An important ‘family’ of biomarkers are known as KRAS. Mutations in the KRAS gene can reduce the body’s own defence mechanisms against cancer.
  • There are many possible sites for mutations on the KRAS. Analysis will often detail which mutation is present. G12, G13 and Q61 are the key locations for mutations that affect the function of the gene.
  • Within G12 there are 15 different possible mutations that would have consequence:
    G12A, G12D, G12F, G12K, G12N, G12S, G12V, G12Y, G12C, G12E, G12I, G12L, G12R, G12T, G12W
  • G13 had two: G13C and G13D
  • Q61 has four: Q61H, Q61K, Q61L, Q61R
  • KRAS Kickers is a US based group that provides support and detailed information about the KRAS biomarkers. They have set up a FaceBook Group for people in the UK. KRAS Kickers UK

BRAF

  • The BRAF gene makes a protein called BRAF.
  • The BRAF protein is part of the growth control mechanism in the cell.
  • Certain BRAF mutations cause the cell to produce to much protein and grow out of control.
  • The most common BRAF mutation is at location V600E.
  • Breaking BRAF is a UK group for people with the BRAF mutation.
  • Breaking BRAF website
  • Breaking BRAF Facebook group

HER2

  • Human Epidermal Growth Factor Receptor 2. This refers to a gene and the protein it creates.
  • This protein is part of signalling pathways that promote cell growth.
  • Some tumours show an abnormal abundance (called amplification) of this protein in each cell.
  • HER2 amplification is more common in breast cancer than Colorectal Cancers (CRC).
  • Work is ongoing to repurpose drugs used in the treatment of breast cancer for use in patients with bowel cancers.
  • HER2 protein is not commonly tested for in bowel cancer patients in the UK.
  • HER2 amplification is estimated to be present in 7% of bowel cancers.

MMR

  • MMR refers to the MisMatch Repair gene and the protein it produces.
  • All colorectal cancers should be tested for the MMR protein.
  • Getting mutations in our DNA and RNA is not uncommon, however the MisMatch Repair gene is there to identify mutations and fix the problem. It is a kind of immune system for our genes.
  • MMR deficient (MMRd) cancers describes the situation where the MMR gene is not doing its job in stopping or correcting errors. This typically leads to multiple mutations in genes concerned with the way that cells replicate.
  • MMR deficiency can cause inactivation of two key genes (MLH1 and PMS2) important in reparing DNA.
  • MMR deficient (MMRd) cancer cells often exhibit high microsatellite instability (MSI-H) [see below].
  • MMRd cancers may be associated with Lynch Syndrome where genetic mutations in MLH1 and PMS2 can inherited.
  • MMR proficient (MMRp) cancers indicate that the main cancer pathways to not implicate MMR gene mutations.
  • MMR status is important in determining the most appropriate forms of treatment.

MSS/MSI

  • Microsatellite Stability (MSS) and Microsatellite Instability (MSI)
  • Microsatellites are short repeated sections of DNA sequences found when a gene is copied.
  • Microsatellite Stability (MSS) indicates that the copied sequences match the original.
  • Microsatellite Instability (MSI) indicates that the copied sequences differ from the original
  • If the Microsatellite Instability is High (MSI-H), these means there are many differences between the copied sequences and the original.
  • Conversely Low Microsatellite Instability (MSI-L) means there are few differences.
  • MSI-H indicates there is an problem with the way mutations are detected and repaired – It is found where the MisMatch Repair mechanisms are ineffective (MMRd).
  • The nature of microsatellite stability or instability is used to determine which kinds of therapy are most appropriate in treating the cancer.
  • MSI-H cancers do not respond as well to 5FU chemotherapy.
  • Some MSI-H cancers respond well to types of immunotherapy.

Page Contributors: Stephen Rowley & Steve Clark

Page updated 10th May, 2023