Colorectal cancer (CRC)

Hereditary forms

About 5% of CRC cases are hereditary.

Factors that make it possible to suspect a genetic contribution to the development of CRC.

• With;
• Multiple primary cancer in a patient with CRC;
• The presence of other cancers in relatives corresponding to known syndromes that cause a hereditary risk of CRC, such as endometrial cancer;
• Hereditary CRC is most often inherited in an autosomal dominant pattern, although two syndromes are inherited in an autosomal recessive pattern (MUTYH-associated polyposis and
  • a positive family history of CRC and/or polyps);
  • multiple primary cancer in a patient with CRC;
  • the presence of CRC-associated types of cancer in relatives (cancer of the endometrium, stomach, ovaries, pancreas, ureters and renal pelvis, biliary tract and brain tumors, adenomas of the sebaceous glands and keratoacanthoma in Muir-Torre syndrome and small intestine cancer);
  • early age at diagnosis of CRC.

Lynch syndrome (hereditary non-polyposis colon cancer or HNPCC)

• 2% — 4% of all cases of CRC.
• In most cases, this disease is caused by a hereditary defect in the genes that repair damaged DNA MLH1, MSH2, MSH6, etc.
• People with Lynch syndrome may have polyps, but they are usually few.
• The lifetime risk of colorectal cancer in people with this disease can be as high as 50%, depending on the gene.
• Women with Lynch syndrome are also at a very high risk of developing endometrial cancer.
• Computer programs can predict the risk of Lynch Syndrome https://premm.dfci.harvard.edu/.

For individuals with a quantitative risk of 2.5% or higher on PREMM, genetic testing for Lynch syndrome is recommended.

Familial adenomatous polyposis (FAP)

• Caused by alterations in the APC gene.
• 1% of all CRC cases are caused by FAP.
• In the most common type of FAP, hundreds or thousands of polyps develop in the large intestine, often beginning at the age of 10-12. By the age of 20, one or more of these polyps usually develops into cancer. By the age of 40, almost all people with FAP will have CRC unless their colon is removed to prevent it.
• People with FAP also have an increased risk of cancers of the stomach, small intestine, pancreas, liver, and several other organs.

There are 3 subtypes of FAP:

• Attenuated FAP or AFAP — patients have fewer polyps (less than 100) and colorectal cancer tends to occur later (in 40-50 years).
• Gardner’s syndrome is a type of FAP that also causes benign tumors of the skin, soft tissues, and bones.
• Turcot syndrome is a rare hereditary disorder when people have an increased risk of developing many adenomatous polyps and colorectal cancer. People with Turcot syndrome, with an APC mutation, are also at risk for a type of brain cancer called medulloblastoma.

Hereditary syndromes associated with colorectal cancer

Peutz-Jeghers Syndrome

• Manifests as pigmentation on the lips or oral mucosa (and sometimes on the arms and legs) and a special type of polyps called hamartomas, in the digestive tract.
• People are at high risk of developing CRC as well as other types of cancer such as breast, ovarian and pancreatic cancer. The diagnosis is usually made at a young age.
• The syndrome is caused by mutations in the STK11 (LKB1) gene.

MUTYH-associated polyposis (MAP):

• At this syndrome numerous polyps of a large intestine develop. They almost always develop into CRC in the absence of regular colonoscopy screening.
• Increased risk of other gastrointestinal and thyroid cancers.
• Syndrome is caused by mutations in the MUTYH gene.

Criteria for genetic examination of patients with suspected Lynch syndrome, developed by the Federal State Budgetary Institution «State Scientific Center of Coloproctology named after A.N. Ryzhykh» for Russian patients

1. A patient with colorectal cancer under the age of 43.
2. Along with colorectal cancer, 2 or more cases of malignant tumors of any localization in the patient himself or in blood relatives, regardless of age.