What is Lynch Syndrome
Lynch syndrome is an autosomal dominant disease (meaning that genes are passed from parent to child) associated with a hereditary predisposition to develop various types of cancer, mainly colorectal, endometrial, and other digestive and urinary tract cancers. It is one of the most common hereditary cancer predisposition syndromes in humans and the leading hereditary cause of colorectal cancer worldwide.
The disease accounts for 2% to 3% of colorectal cancer cases worldwide and 5% of such occurrences in Brazil, where about 34,000 new cases are diagnosed each year.
The causes of Lynch syndrome are mutations in genes that control a specific type of repair when DNA is damaged. People with the disease have a 55% to 85% risk of developing colorectal cancer by age 70, while in the general population (individuals without the syndrome), this risk is 4.5%.
Generally, patients with Lynch syndrome who develop hereditary colorectal cancer syndrome receive the diagnosis around age 40, and it is more likely that the precursor lesion will be a single adenoma (polyp) of the colon – unlike the multiple adenomas presented in patients with familial adenomatous polyposis, the other main hereditary form of this type of cancer.
Women with Lynch syndrome have a 40% to 60% risk of developing endometrial cancer.
Other types of cancer associated with Lynch syndrome include skin, ovarian, stomach, urinary tract, pancreatic, small intestine, and brain cancers.
Symptoms and signs of Lynch syndrome
The symptoms of Lynch syndrome are related to the tumors associated with the syndrome, such as colorectal cancer, which presents symptoms such as:
- Sangue nas fezes;
- Alteração do funcionamento do trato intestinal (diarreia e prisão de ventre alternados);
- Dor ou desconforto abdominal;
- Fraqueza e anemia;
- Perda de peso sem causa aparente;
- Alteração na forma das fezes (fezes muito finas e compridas);
- Massa abdominal (tumoração).
Screening and diagnosis of Lynch syndrome
The specific diagnosis of Lynch syndrome is confirmed through genetic testing, but it is still complex to determine who should receive genetic testing. This is because, unlike familial adenomatous polyposis, the syndrome does not have any phenotypic appearance. Therefore, it is currently recommended that every individual with colorectal cancer undergo screening for Lynch syndrome.
The most commonly used screening tests, because they are simpler, cheaper, and provide valuable information in treatment planning, are:
- Tumor immunohistochemistry (for the Lynch syndrome proteins MLH1, MSH2, MSH6, PMS2); and/or
- Molecular analysis of microsatellite instability (an examination that allows observation of whether the typical defect of Lynch syndrome affects regions containing multiple repetitions of DNA bases – called microsatellites).
The suspicion of Lynch syndrome and the indications for germline genetic testing for diagnosis (including at least the MLH1, MSH2, MSH6, PMMS2, and EPCAM genes) are:
- Colorectal cancer below the age of 50 (independent of other factors)
- Colorectal cancer with deficiency in DNA repair proteins (MLH1, MSH2, MSH6, and PMS2).
- Colorectal cancer and familial oncologic history, such as Amsterdam II criteria (>3 relatives with colorectal cancer or cancer associated with Lynch syndrome, with colorectal cancer affecting at least two generations of the family and occurring in at least one case of colorectal cancer <50 years).
It is important to emphasize that a portion of patients with Lynch syndrome will not meet these criteria, and therefore, some specialists already advocate that every patient with colorectal cancer receive germline genetic testing for Lynch syndrome genes (universal testing).
For patients with Lynch syndrome, genetic counseling and cascade genetic testing of first-, second-, and third-degree relatives are recommended.
Risk-reducing strategies and prevention for Lynch syndrome
For individuals with the syndrome, we should discuss risk-reducing measures for colorectal cancer, endometrial cancer, and other associated tumors, such as:
- Surveillance colonoscopy every 1 or 2 years starting at a young age.
- Targeted uterine screening exams.
- Upper endoscopy.
- Discussion of chemoprevention strategies with aspirin (acetylsalicylic acid).
- Discussion about risk-reducing surgeries.
Treatment for Lynch syndrome
In general, the surgical treatment of tumors associated with the syndrome follows the same oncological principles. In some specific scenarios, in the presence of a colorectal cancer diagnosis, discussion may include not only therapeutic surgery but also prophylactic extended surgery (removal of the entire large intestine).
For patients with stage II colon cancer, the presence of Lynch syndrome (with loss of expression of DNA repair proteins by immunohistochemistry and/or microsatellite instability by molecular analysis) may favor the non-indication of adjuvant chemotherapy.
