Genetic predisposition to cancer

Genes and the risk of having cancer

There are different genes associated with an increased risk of falling ill with cancer. Among the most frequent and well known are the genes:

• BRCA1, BRCA2, and PALB2, associated with breast cancer.
• BRCA1, BRCA2, BRIP1, RAD51C/D and mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM), linked with ovarian cancer.
• Mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM), associated with colon and endometrial cancer.

The genes APC and MUTYH, linked with familial adenomatous polyposis –the formation of a large number of adenomatous polyps (non-malignant tumours) in the colon– and colon cancer.   

Main clinical criteria for suspected hereditary cancer 

There are different clinical criteria that may arouse the suspicion that an individual has a hereditary genetic abnormality that predisposes them to certain kinds of cancer, such as:

• The presence of the same kind of cancer in different members of the family and across different generations.
• The appearance of cancer at younger ages than usual. 
• The appearance of more than one tumour, for example breast and ovarian cancer, in the same person.
• The presence of bilateral cancer, for example, with both breasts or both kidneys being affected.
• The appearance of a cancer that is generally not common for the patient's gender, such as a breast tumour in men.

When these criteria are detected, they are referred to the genetic assessment unit specialising in cancer, where the need to perform a genetic study to rule out the possibility of a hereditary predisposition to cancer will be determined. This multi-disciplinary unit is staffed by physicians who are specialists in hereditary cancer and genetic counsellors. Here, an individual risk assessment, genetic tests, and follow-up for the carriers of the gene are carried out. 

Types of genetic predispositions to cancer, and associated genes

There are different syndromes that involve a genetic predisposition to developing cancer. For example, there are different genes that can make someone have a genetic predisposition to breast cancer.The most common are:

• Alterations in the genes BRCA1 and BRCA2, which entail a high risk of developing both breast cancer and ovarian cancer. 
• Mutations in the PALB2 gene, which are associated with a high risk of breast cancer. 
• Mutations in the TP53 gene, which are associated with Li-Fraumeni syndrome, and mutations in the STK11 gene, linked to Peutz-Jeghers syndrome. These last two, in addition to entailing a predisposition to breast cancer, are also linked to other kinds of tumours or specific manifestations, such as colon polyps or hyperpigmentation of the lips and oral mucosa.

The genetic predisposition to developing colon cancer can be divided into two types: polyposic and non-polyposic. 

There are different types of polyposic colon cancer. Familial adenomatous polyposis (FAP) presents the highest risk for developing colon cancer. It is characterised by hundreds or thousands of polyps in the colon, and sometimes also throughout the entire digestive tract. These polyps are not malignant lesions, but they can degenerate and develop into cancer.Thus, individuals with FAP end up developing colon cancer if these polyps are not removed. Pathogenic alterations in the APC gene are responsible for this condition. In addition, carriers of APC gene mutations are also at risk for other tumours or conditions (hepatoblastoma, thyroid tumours, and desmoid tumours). 

The main syndrome entailing a predisposition to non-polyposic colon cancer is Lynch syndrome. This syndrome entails a high risk of developing colon and endometrial cancer, along with a risk of developing ovarian, bile duct, urinary tract, and gastric cancer. It is caused by mutations in the genes that are in charge of DNA repair, specifically, those tasked with mismatch repair, namely MLH1, MSH2, MSH6, PMS2, and EPCAM. 

We can also find a genetic predisposition to endocrine tumours. Pheochromocytomas and paragangliomas are rare tumours that are caused by a hereditary genetic abnormality in 40% of cases. These can be caused by abnormalities in the succinate-dehydrogenase-encoding genes (SDHx), RET gene (MEN2 syndrome), MEN1 gene, NF1 gene (neurofibromatosis type 1) or FH gene, among others. 

How a genetic diagnosis is performed 

A genetic diagnosis is usually done with a blood sample, but a saliva sample or skin biopsy can also be used. DNA (present in the nucleus of our cells) is extracted from this sample for analysis.

There are different techniques for carrying out genetic studies. Currently, at our centre, we perform gene panel studies. This entails analysing different genes linked with the genetic predisposition to cancer to rule out any abnormality in them; this is also called gene sequencing. 

When a genetic abnormality is found in a family, a predictive study is carried out. This kind of study determines if an individual also presents the genetic abnormality detected in the family.

Early detection and preventative measures

Depending on the genetic change found, different measures for early detection and prevention can be recommended. For example, individuals with a mutated BRCA1/2 gene should begin to undergo an annual breast check-up, with a breast MRI and a mammogram, from the time they are 25-30 years old. Individuals with Lynch syndrome should get annual colonoscopies from the age of 25 onward.

Depending on the type of genetic disorder, risk reduction surgeries can also be an option. For example, in individuals diagnosed with FAP, depending on the number of polyps they have, a prophylactic colectomy (removal of the colon) can be performed to reduce their risk of developing colon cancer. 

Follow-up and prevention measures are determined on an individual basis in the corresponding specialist's medical consultation. Additionally, at the medical office in charge of hereditary cancer, a reproductive genetic assessment is offered, depending on the genetic abnormality.