Hereditary and familial colorectal cancer Diagnosis

Diagnosis

• Lynch syndrome

Family history, tumor testing, mutation prediction models, and genetic testing.

- Family history: The Amsterdam criteria, The revised Bethesda guidelines

- Tumor testing: four antibodies specific for hMLH1, hMSH2, hMSH6 and hPMS2 proteins to evaluate tumors for MMR deficiency. Others include BRAF mutation and hMLH1 promoter methylation analyses .

- Commercial tests: analyze the distal portion of EpCAM and the 4 clinically relevant MMR genes.

- Genetic testing: mutations in hMLH1 and hMSH2

- Models for diagnosis: PREMM(1,2), MMRpro, and MMRpredict using family and personal history.

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

FAP: The diagnosis is made with the identification of at least 100 colonic adenomas; however, younger individuals with fewer polyps might also have FAP.

Extra-colonic lesions also contribute to the presumptive diagnosis. APC mutations confirm the diagnosis.

Attenuated FAP: Suspected when 10 or more, but fewer than 100 adenomas, are found in a person over 40 or 50 years of age . Can mimic FAP, MAP, or sporadic polyp.

Genetic testing is useful.

• MUTYH-associated polyposis

Clinical diagnostic criteria have not yet been fully established. Colonic phenotype may be considered similar to attenuated FAP. Genetic testing targets the specific ethnic allelic frequencies of MUTYH variants. Genetic testing is warranted in individuals with greater than 10 colorectal adenomas but without an identifiable mutation in APC.

• Hamartomatous polyposis conditions:

Peutz-Jeghers syndrome (PJS) A clinical diagnosis of PJS can be made when an individual has 2 or more of the following features: 2 or more Peutz-Jeghers polyps of the small intestine; typical mucocutaneous hyperpigmentation; and a family history of PJS.

Juvenile polyposis syndrome (JPS) Does not typically have obvious physical findings that facilitate diagnosis.A diagnosis is considered for anyone who has at least 3 juvenile polyps of the colon, multiple juvenile polyps throughout the GI tract, or any number of juvenile polyps and a family history of the condition.

• Hyperplastic polyposis (HPP)

Requires 20 - 30 cumulative hyperplastic polyps of any size distributed throughout the colon ; 5 or more hyperplastic polyps proximal to the sigmoid colon with at least 2 being greater than 10 mm in diameter; or at least 1 hyperplastic colonic polyp in an individual with a first-degree relative with HPP. Sessile serrated polyps also included.