Colorectal cancer

Colon or colorectal cancer is cancer that originates in the colon or rectum.

The colon and rectum are part of the digestive tract, the final section of our intestine. The colon is about 1.5 metres long and runs in an inverted U-shape through the abdominal cavity. Its function is to absorb water and minerals from the faeces. Right at the end of the colon is the rectum. The rectum is a little less than an inch long and is the end of the passage of our faeces, where they are stored until the time of defecation.

The incidence of colon cancer in Spain is approximately 15%. This means that 15% of all cancers diagnosed in a year in Spain are colon cancer. Overall, the lifetime risk of developing colon cancer is approximately 4%. In terms of mortality, colon cancer is the second leading cause of cancer-related death in men, after lung cancer. Similarly, colorectal cancer in women is also second only to breast cancer.

As with the other cancers, changes in a cell’s genetic material or mutations are the cause.

In up to 10% of cases, these mutations may be inherited (hereditary colorectal cancer), in about 25% there is a familial association with no known causal mutation (familial colorectal cancer) and in the remaining 65% of cases the mutations occur throughout life (sporadic colorectal cancer). They can be caused by harmful substances, but can also occur accidentally during cell division. Normally, cells have repair systems to eliminate defects that originate in genes, but these mechanisms are more likely to fail as we age.

In most patients, intestinal tumours originate in the glandular cells of the mucosa lining the inside of the intestine (adenocarcinomas). These cells begin to proliferate and generate polyps or clusters of non-cancerous (benign) cells, which slowly develop into malignant cancer cells.

Although in most cases of colorectal cancer it is not possible to find a specific cause, we do know some of the risk factors that are associated with the development of colon cancer.

• Age over 50 years
• Inflammatory bowel diseases such as ulcerative colitis or Crohn’s disease
• A diet high in fat and low in fibre
• Obesity
• Smoking
• Alcohol
• A family history of colon cancer is also a risk factor. The more members of the same family who have had colon cancer (especially first-degree relatives such as parents, siblings or children), the greater the likelihood of developing it.

It is advisable to follow a healthy lifestyle:

• Eat vegetables, fruit and whole grains and try to avoid red meat (beef, pork or lamb) and processed meats (sausages and some cold meats), which have been linked to an increased risk of colorectal cancer.
• Take regular physical exercise.
• Control your weight.
• Do not smoke.
• Do not drink alcohol.

In addition, it is important to participate in screening tests, especially for those at increased risk. These tests allow cancer to be detected before signs and symptoms appear and treatments can be started when they are most likely to be successful.

In the case of a family history, it is also advisable to have a genetic test to determine if there is an increased risk. In case of a positive result, this will help determine further preventive strategies to be taken.

Lynch syndrome is an inherited form of predisposition to some types of cancer, mainly colon cancer and endometrial or uterine cancer in women.

One of the characteristics of Lynch syndrome is the early onset (between 40 and 45 years of age) of colon cancer.

When a person is diagnosed with Lynch syndrome, their offspring have a 50% chance of inheriting the genetic mutation that causes the syndrome.

First of all, personal and family history should be established, especially colon and endometrial cancer at an early age. If this history raises the suspicion of Lynch syndrome, genetic studies and other corresponding diagnostic tests can be performed.

Almost all tissues in the body are renewed by cell division. During this process, a copy of the genetic material is created and passed on to daughter cells. Copies of the genetic material are always flawed (just as a photocopy will never be like the original document), but cells have repair systems to correct them. In Lynch syndrome patients, these repair systems are defective, leading to the accumulation of genetic errors and the development of cancer. In the specific case of Lynch syndrome these errors manifest themselves as microsatellite instability.

DNA repair systems are defective because some of the ‘repair genes’ (those encoding the proteins that carry out the actual repair) are mutated. So far, mutations in the following genes have been associated with Lynch syndrome: MLH1, MSH2, MSH6, PMS2 and EPCAM. Genetic testing for Lynch syndrome will detect whether or not a patient suspected of having Lynch syndrome (based on family history) has any of the mutations associated with this disease.

Patients with mutations in the MLH1, MSH2, MSH6, PMS2 and EPCAM genes (on average for all mutations) have a lifetime chance of developing cancer of 10% to 80% (depending on the genetic mutation causing the syndrome) compared to 4% in the general population. The lifetime prevalence of colorectal cancer is 30-75%. Women with one of these mutations develop endometrial cancer at a rate of 40-50%. The risk of stomach, ovarian, pancreatic, urothelial, biliary tract or small bowel cancer and glioblastomas is also slightly increased. Sebaceous gland adenomas and keratoacanthomas may also occur.

Familial adenomatous polyposis is a hereditary type of colorectal cancer caused by mutations in the APC gene.

It is characterised by the appearance at a very young age (from 10 years old) of a large number of initially benign polyps, mainly in the colon area. If left untreated, one or more of these polyps will develop into colon cancer (colorectal carcinoma) in an unpredictable time. Therefore, early detection and treatment of these polyps is crucial.

• Classic FAP: typically characterised by more than 100 colorectal polyps.
• Attenuated FAP (AFAP): characterised by a later age of onset and usually a much smaller number of polyps (< 100) in the colon. Despite the milder course, the lifetime risk of colon cancer is similar to that of classic FAP.
• Gardner syndrome is a variant of FAP. People with this syndrome have multiple adenomatous colon polyps, but also other tumours outside the gastrointestinal organs (epidermoid cysts, fibromas, desmoid tumours, osteomas).
• Turcot syndrome is considered a variant of FAP or Lynch syndrome. People with this syndrome have many adenomatous colon polyps, an increased risk of colorectal cancer and an increased risk of brain tumours (glioblastoma and medulloblastoma).

When a person is diagnosed with FAP, their offspring have an approximately 50% chance of inheriting the genetic mutation that causes the syndrome.

As mentioned above, genetic alterations or mutations in the APC gene are associated with the different types of FAP. In most cases it is an inherited mutation, although in 1 in 3 patients it is a de novo germline mutation in the APC gene.

Genetic testing for familial adenomatous polyposis will detect whether or not a patient suspected of having the syndrome (based on family history) has any of the mutations associated with this disease.

People with FAP are also more likely to have cancers in other organs: stomach, small intestine, pancreas and bile ducts. There is also an increased risk of hepatoblastoma, desmoid tumour/desmoid fibromatosis, papillary thyroid cancer, and a rare type of brain tumour called medulloblastoma.

Genetic diagnosis is an essential preventive tool for people with a family history suggestive of a familial mutation.
If a mutation is detected in one of the genes through genetic diagnosis, the risk of developing cancer increases considerably. It is therefore important that people carrying a mutation undergo different diagnostic methods to reduce the incidence of cancer and reduce the mortality associated with the syndrome.

Positive result matching the mutation found in the family

If you have tested positive and have been found to have the known familial mutation that is or was responsible for the development of colorectal cancer in your family, then you have a significantly higher risk of developing the disease in your lifetime than the rest of the population. It does not imply that you have or will develop the disease, but it does imply that you should intensify surveillance and follow preventive guidelines. In addition, there may be an increased risk of cancer for their offspring.

Positive result in a family in which the causal mutation is not known to exist

In the case of a positive result in a patient for whom no family member with the disease has been or can be tested, it can be assumed that the same mutation also caused the disease in family members who developed colorectal cancer. In other words, this person also has a higher risk of developing cancer.

Negative result in a family with known causal mutation

If you have a negative result, this means that the known familial mutation responsible for the development of colorectal cancer in the family is not detected in the patient or that there may be a mutation in a gene that has not yet been associated with colorectal cancer. This means that you do not have an increased risk of developing colorectal cancer. Therefore, you have the same risk as the general population (approximately 4%) of developing colorectal cancer in your lifetime.

Negative result in a family with no known causal mutation

If no known mutation has been found in any family member despite there being some people affected by colorectal cancer, it may be that another gene is responsible for the development of the cancer and/or that the cancers in your family are not due to an inherited predisposition.

Finally, the result of the genetic test may indicate the presence of a genetic variant that doctors do not have enough information about to be able to assess correctly (variant of uncertain (unknown) significance, VUS). In these situations, the benefit to the patient cannot always be defined.

For Lynch syndrome, one of the following criteria is usually used:

Amsterdam criteria 

At least 3 relatives have a cancer related to Lynch syndrome and:

• One is a first-degree relative (parent, sibling or child) of the other 2 relatives.
• At least 2 successive generations are affected.
• At least 1 relative had the cancer when they were younger than 50 years old.

Bethesda criteria:

• The person is younger than 50 years of age when diagnosed with colorectal cancer.
• The person has or has had a second colorectal cancer or another cancer (endometrial, stomach, pancreatic, small bowel, ovarian, kidney, brain, ureter, or bile duct) related to Lynch syndrome.
• The person is under 60 years of age and the cancer has certain features seen in Lynch syndrome when viewed under a microscope.
• The person has a first-degree relative (parent, sibling or child) under the age of 50 who has been diagnosed with colorectal cancer or another cancer related to Lynch syndrome.
• The person has 2 or more first- or second-degree relatives (aunts, uncles, nieces, nephews, or grandparents) who had colorectal cancer or other Lynch syndrome-related cancer at any age.

The decision about whether or not to have a genetic test to establish the risk of colorectal cancer is a personal one and should always be made after genetic counselling. This counselling should try to answer any questions about:

• What it means to do the test
• How the patient may feel while waiting for the results to come back
• What kind of actions can be considered after the results have been obtained

There are private insurance policies that cover preventive genetic analysis in first-degree relatives of affected persons with a detected familial mutation.
However, there are private insurances that do not cover the costs and are therefore paid by the patient.