Adenoma-Carcinoma sequence in Colorectal cancer.

CpG island Methylation

Occurs after chromosome instability, where methyl groups are added to the promotor region of genes.

TSA: traditional serrated adenoma Circled is ectopic crypts and eosinophilic columnar cells

What Cancer?

Serrated polyp pathway (RAS-RAF-MAP kinase) description

-20 to 30% of colorectal adenocarcinomas -polyps with glands/crypts and charactersitic saw-tooth outline.

Polyp (adenoma)

-pre-invasive neoplasm -Only small amounts of polyps progress to CRC malignancy -Risk begins at age 50, greater over the next 2 decades. -removal of polyps with incidence reduces CRC risk.

Serrated polyp pathway involved oncogenes

BRAF or KRAS is the mutated oncogene, prevent cell transformation. Inactivation of CpG island methylation, upregulation of cell cycle inhibitors such as p16 and p14.

Differences between SSA and TSA

TSA is more distal TSA has pronounced esoinohilia TSA has KRAF or BRAF mutations (BRAF is more aggressive)

Sessile serrated adenomas (SSA) BRAF mut, flat, lesions in PROXIMAL colon Enlarged, disordered crypts, can progress to dysplasia/cancer (unlike hyperplastic polyps) CpG island methylation inactivators tumor suppressor genes, including hMLH1.

What cancer?

Chrosome 18q

gene region deleted in approximately 75% of colon cancers, and 50% of advanced adeomas. Deletion involves tumor suppressor gene (DCC), SMAD4, SMAD2