Hereditary and familial colorectal cancer Pathophysiology

Genetics

Associated conditions[edit | edit source]

Approximately 5% of all the cases are associated with highly penetrant inherited mutations.

Lynch syndrome:

• Endometrial cancer is the most common extra-colonic malignancy associated with this syndrome. (Lynch syndrome causes approximately 2% of all endometrial cancers)^[1]
• Other cancers associated with Lynch syndrome: gastric, ovarian, hepatobiliary tract, upper urinary tract, small bowel, brain (glioblastoma) and pancreatic ^{[2] [3]}.
• Other: keratoacanthomas, sebaceous adenomas/carcinomas.

Familial adenomatous polyposis (FAP)

• Polyps of the Upper gastrointestinal tract.
  • Gastric fundic gland polyps: found in approximately 50% of individuals,and can be profuse ^[4]
  • Adenomatous polyps in the stomach: usually located in the antrum, less common than fundic gland polyps.
  • Dysplastic changes in fundic gland polyps: common, no concern unless dysplasia is severe^[5]
  • Adenomatous polyps in the duodenum: found in approximately 50% of individuals, commonly found in the second and third portions of duodenum. (Duodenal cancer is the second most common malignancy in FAP or attenuated FAP ^[6].
• Additional cancers: colon, duodenum, periampullary, stomach, thyroid, hepatoblastoma, medulloblastoma.
• Other: osteomas (skull and mandible), congenital hypertrophy of the retinal pigment epithelium (CHRPE), epidermoid cysts, fibromas, dental abnormalities, and desmoids ^[7].

MUTYH-associated polyposis

• Gastric and duodenal polyps (11% and 17% of patients)
• Duodenal cancer
• Other: ovarian, bladder, skin, sebaceous gland tumors and possibly breast cancer.

Hamartomatous polyposis conditions:

• Peutz-Jeghers syndrome (PJS)
  • Cancer: Breast, colon, pancreas, stomach, ovary, lung, small bowel, uterine, cervix, testicle.
  • Other: mucocutaneous pigmentation, gastrointestinal hamartomatous polyps.
• Juvenile polyposis syndrome (JPS)
  • Cancer: colon, stomach, pancreas, small bowel.
  • Other: gastrointestinal hamartomatous (juvenile) polyps, HHT, congenital defects.

Hyperplastic polyposis (HPP)

• Cancer: colon
• Other:Hyperplastic polyps, sessile serrated polyps, traditional serrated adenomas and mixed adenomas.

References[edit | edit source]

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Gross Pathology[edit | edit source]

Microscopic Pathology[edit | edit source]

• Lynch syndrome

Often poorly differentiated, mucinous, and have large numbers of tumor-infiltrating lymphocytes.^[1]

• Familial adenomatous polyposis (FAP): FAP and attenuated FAP

Polyp histologic type.

• MUTYH-associated polyposis

Polyp histologic type.

• Hamartomatous polyposis conditions:

Small bowel, histologically distinctive hamartomatous polyps.^[2]

• Hyperplastic polyposis (HPP)

Polyp histologic type.

References[edit | edit source]

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Genetics[edit | edit source]

• Lynch syndrome

Germline mutation in a class of genes involved in DNA MMR, including: hMSH2, hMLH1, hMSH6, and hPMS2.

DNA MMR: necessary to maintain genomic stability by correcting single-base mistmatches and insertion-deletion loops that form during DNA replication.

Mutations in hMSH2 and hMLH1: 90% of Lynch syndrome cases

Mutations in hMSH6: 10% of Lynch syndrome cases

Mutations in hPMS2: rare ^{[1] [2]}.

Other: germline deletions in the EpCAM (epithelial cell adhesion molecule) gene, also known as TACSTD1 ^[3] 19098912.

• Familial adenomatous polyposis (FAP): FAP and attenuated FAP

Germline mutations in APC.

APC encodes a tumor suppressor that is part of the WNT signaling pathway.

APC mutations (New or de novo): 25% of FAP cases.

Somatic mosaicism: 20% of individuals with an apparent de novo APC mutation^[4].

• MUTYH-associated polyposis

MUTYH gene product: part of the base-excision repair pathway, involved in defending against oxidative DNA damage. (Helps to prevent G:C to T:A transversions caused by oxidative stress to highly mutagenic DNA bases). Genetic testing for MAP is warranted in individuals with greater than 10 colorectal adenomas but without an identifiable mutation in APC. Siblings of individuals with biallelic MUTYH mutations have a 25% chance of having MAP.

• Hamartomatous polyposis conditions:

Peutz-Jeghers syndrome (PJS) Germline mutations in STK11 (LKB1) Disease-associated mutations: 70% of patients ^[5].

Juvenile polyposis syndrome (JPS) Mutations: SMAD4 or BMPR1A. Disease-associated mutations: 40% of patients.

• Hyperplastic polyposis (HPP)

Mutations: BRAF mutations Methylation of CpG islands Familial cases of HPP have been reported ^[6], but are rare. The reported family frequency varies from 0 to 63% ^[7]. Evidence supporting inheritance of HPP is weak.

References[edit | edit source]

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References[edit | edit source]

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