Biomarkers of colorectal cancer

• What are tumour biomarkers?
• How are tumour biomarkers used?
• How and when are they measured?

• What are some examples of tumour biomarkers and their uses?
• What is K-ras
• K-ras as a tumour biomarker

What are tumour biomarkers?

Tumour biomarkers are chemicals that are made by tumour cells or other cells of our body, in response to cancer or other benign conditions. Different types of cancers or tumours may be associated with different tumour biomarkers. Colorectal cancer (CRC), which includes colon cancer and rectal cancer is responsible for half a million deaths worldwide every year. There are also about one million new cases diagnosed annually, making it the third most common cancer in the world. Early detection, accurate diagnosis and intensive surveillance are important for best improving a patient’s prognosis and response to therapy.

There are a number of methods that doctors use to detect CRC including sigmoidoscopy, colonoscopy and barium enema. Some newer techniques being investigated for effective detection and monitoring of CRC are CT colonography and molecular biomarkers. The use of tumour biomarkers gives doctors a non-invasive way of detecting and monitoring CRC.

How are tumour biomarkers used?

Doctors can use tumour biomarkers in the detection, prognosis and management of some types of cancer, including CRC. An abnormal level of tumour biomarker is usually not enough for a complete diagnosis of cancer and is usually combined with other tests such as a biopsy. The type of biomarker detected and its levels can give an indication to what type of cancer may be present, whether or not it is malignant and what the best treatment may be.

Tumour markers are used during the treatment of cancer in order to monitor the effectiveness of a therapy and how the patient may be responding to the treatment. If levels of a tumour biomarker decrease it may mean that the cancer is responding to treatment. If levels remain the same or increase after treatment it may be an indication that the therapy is not working. Continued monitoring of tumour biomarker levels following treatment can be used to check for recurrence of the cancer.

How and when are they measured?

Different tumour biomarkers are measured in different ways and from different sources. Some markers are found in blood or urine, so these would require you provide a small amount of blood or a urine sample. Other tumour biomarkers such as those involved in faecal occult blood testing (FOBT) can be isolated from faecal matter and require a stool sample. Tissue samples can also contain tumour biomarkers and may involve a tissue biopsy. This is a more invasive procedure than urine or stool sampling. After a doctor takes the sample they are sent to a laboratory for testing using various methods to determine biomarker levels. Particular foods such as red meats or fruits and vegetables can influence the assay and cause false positive results.

Two key factors for an effective tumour biomarker assay are:

1. The assay must be sensitive in its ability to accurately detect disease; and
2. The assay must be specific for the particular malignancy.

What are some examples of CRC biomarkers and their uses?

In the early detection or screening of patients for CRC, stool based markers are widely used. Tissue-based markers have been studied as possible prognostic or predictive markers of disease, while CRC biomarkers obtained from serum (blood) are primarily used for the postoperative surveillance of patients.

Tissue based markers

Tissue based markers have been investigated as possible prognostic markers and predictors of response to treatment. Thymidilate synthase (TS) is an enzyme involved in the processing of the cells genetic material and has been studied as a marker that can predict how well a patient may respond to treatment with drugs such as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine. The transcription factor p53 has also been widely investigated as a biomarker that may predict the severity of cancer how it may respond to particular anticancer drug.

The K-ras oncogene is often associated with cancer as abnormalities in this gene have been found in many tumours. K-ras is involved in sending signals that can regulate how much cells grow or multiply. K-ras mutations are linked to approximately half of all CRCs and have been found to be important in the early stages of the disease. Studies have identified an association between K-ras mutations and poor disease outcome in patients with CRC.

Stool based markers

Faecal occult blood testing (FOBT) is the most commonly used screening test for CRC. There are two main types of FOBT, the guaiac test and the immunochemical test. Both tests detect proteins that may be indicators of colorectal cancer.

The advantages of FOBT for CRC are that the tests are simple and affordable, non-invasive, require very little patient preparation and have the capability of examining the entire colorectal tract. They do however have relatively low specificity and sensitivity for both benign (or precancerous adenomas) and malignant CRC.

Faecal DNA tests are used in screening for CRC on the basis that abnormal DNA is excreted in cells shed from cancerous colorectal lesions. Tests usually use a panel of DNA markers in order to identify mutant genes. DNA markers can provide a more accurate test than FOBT and there are no restrictions on diet or medication. The test is however quite laborious, expensive, also lacks specificity. Examples of stool based DNA markers include K-ras, APC (adenomatous polyposis coli) and p53.

Serum based markers

Serum-based markers of colorectal cancer are mainly used for monitoring patients following the surgical removal of malignant tumours. Patients are monitored regularly following surgery in order to detect any cancer recurrences or metastases. As up to 50% of patients develop recurrent disease or metastases following surgery, this is an important part of CRC management. CEA (carcinoembyonic antigen) was the first serum marker used in patients with CRC, and although it’s the oldest, it still remains the most widely used. CEA is mainly used to monitor patients following surgery for primary CRC. A number of studies have shown that intensive monitoring after cancer surgery is associated with an improved outcome if regular CEA measurements were taken. Other serum-based tumour biomarkers used for CRC include markers called CA-19-9, TPA, TPS and TIMP-1

What is K-ras?

There are three main types of the mammalian ras genes: K-, H- and N-ras. Each of the ras genes makes proteins that are involved in relaying signals between different regions of the cell. These signals play important roles in a number of important biological functions including cell division and cell growth. As mentioned above, the K-ras oncogene is one of the most frequently altered in human cancers, with approximately 50% of CRCs containing mutant K-ras.

K-ras as a biomarker of CRC.

While many early investigations suggested that K-ras abnormalities were strong signs of serious disease and poor outcome for patients, more recent studies have found that this may not be correct in all cases. This meant that K-ras might not be very suitable as a prognostic marker.

While there is little evidence that K-ras mutations can be used as an effective screening tool or indicator of prognosis for CRC patients, recent research shows that the gene as a potential marker for prediction of response to specific therapies. Studies have shown that cases of CRC that are associated with mutations in K-ras will not respond well to particular treatments. For example, it has been shown that anticancer drugs such as panitumumab and cetuxamib are not effective in patients with K-ras abnormalities. While these studies do not specifically identify which therapies should be used in the treatment of K-ras associated CRC, they are able to help in the selection of an appropriate therapy.

References

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