Genetic Alterations In Hnpcc

Hereditary nonpolyposis colorectal cancer occurs due to inherited germline mutations in one of at least five mismatch repair (MMR) genes including hMLH1 at 3p21.3, hMSH2 at 2p22-p21, hMSH6 at 2p16, hPMS1 at 2q31-33, and hPMS2 at 7p22. The products of these five genes all participate in a multimeric DNA mismatch repair complex. Germline mutation of MMR genes results in the accumulation of somatic errors within the genome at an accelerated pace, leading to an increased risk and early age at onset of malignant neoplasm. A molecular hallmark of HNPCC is a high level of microsatellite instability (MSI), which is a variation in the length of short repeat

Table 1 Clinicopathological features of HNPCC-associated colorectal cancers

Characteristic clinical features:'14-1

- Early age of onset about 45 years

- 70% of tumors are proximal to splenic flexure

- Approximately one-third of all tumors occurring in the cecum

- Synchronous and metachronous lesions

- One in five patients diagnosed with HNPCC develops rectal cancer as the index colorectal lesion

- Improved survival compared with sporadic colorectal cancer

Distinct pathological (but not pathognomic) features:'14-

- High grade: mucinous and poor differentiation

- Prominent peritumoral lymphocytic infiltration

- Crohn's disease-like reaction

- Tumor infiltrating lymphocytes

- High level of microsatellite instability (MSI)

DNA sequences that results from this generalized genomic instability. High levels of MSI are found in the DNA from colorectal tumor tissue, but not in the adjacent normal colorectal mucosa, in approximately 90% of individuals with germline mutations in an HNPCC-associated gene, although high levels of MSI are also detected in about 15% of sporadic cases of colorectal cancer.[5]

Mutations in MLH1 and MSH2 account for the majority of cases of HNPCC.[6]

Mutations in MSH6 are thought to account for up to 10% of HNPCC families and are associated with higher frequency of endometrial cancer. Mutations in PMS1 and PMS2 have been reported to be associated with only a few HNPCC families.'7- Although the majority of mutations identified in MLH1 and MSH2 are small genomic insertions or deletions that result in a truncated protein product, it is estimated that up to 20% of families meeting the Amsterdam criteria may have large deletions or other genomic rearrangements in MLH1 or MSH2 that are not detectable by conventional testing techniques.'8-

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