MMP1-1,607 dupG and MMP9-1,562 C homozygotes demonstrated an increased risk of colorectal cancer regardless of ethnic differences, whereas other MMP and PAI1 polymorphisms did not. Nevertheless, specific MMP haplotypes on 11q22.1-23.3 and 20q12-13 seem to be implicated in susceptibility to colorectal cancer.

Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria.Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2).Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P ‫؍‬ 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P ‫؍‬ 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors.Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

Clinicopathologic features of sporadic colorectal adenocarcinomas were compared using integrated data from 244 patients subjected to curative resection. Individual steps in the tumorigenesis pathway, that is, adenomatosis polyposis coli (APC), Wnt-activated, base excision repair mutations, mismatch repair defects, RAF-mediated, transforming growth factor (TGF)-b-suppressed, bone morphogenic protein (BMP)-suppressed, and p53 alterations, were examined in terms of genetic and epigenetic changes, as well as protein expression. Genetic and molecular alterations of right colon cancers were distinct from those of left colon and rectal cancers. Rectal cancers showed the attenuated phenotype of left colon cancers. Tumors most frequently displayed either TGF-b-or BMP-suppressed alterations (81.2%), followed by RAF-mediated alterations (78.6%), and mismatch repair defects (38.4%), constituting a total of 24 integrated pathways. Tumors lacking APC mutations or carrying the RAF alteration (V600E) were frequently associated with lymphovascular invasion and lymph node metastasis (P < 0.05). Poorly differentiated or mucinous adenocarcinomas were generally associated with high level microsatellite instability, Axin2 suppression, TGF-b1 or BMPR1A suppression, loss of heterozygosity of D18S46 or D18S474, and absence of base excision repair mutations (P < 0.0001-0.05). T he classical pathway of colorectal tumorigenesis constitutes stepwise or consecutive genetic and molecular changes, commencing with adenomatosis polyposis coli (APC) alterations through RAS family genes, and concluding with p53.(1) Although this model provides a simplified explanation of pathogenesis, numerous crossover or alternative changes also occur in human colorectal cancer. These stepwise alterations are consistently observed in only 6.6% of all colorectal cancers.(2) Two types of molecular and biological characteristics have been identified in hereditary colorectal cancer. Hereditary non-polyposis colorectal cancer is associated with microsatellite instability (MSI), right-sided location, diploid DNA, transforming growth factor-β receptor 2 (TGFBR2) and Bc1-2-associated X protein mutations, and indolent behavior. In contrast, familial adenomatous polyposis displays chromosomal instability, left-sided location, aneuploid DNA, and pathogenic mutations in APC, KRAS, and p53, along with aggressive behavior. Previous investigations of sporadic hereditary colorectal cancer have disclosed various concurrent molecular and genetic changes, that is, APC and Wnt-activated mutations, mismatch repair (MMR) defects, and base excision repair (BER), RAFmediated, transforming growth factor (TGF)-β-and bone morphogenic protein (BMP)-suppressed, and p53 alterations. (3)(4)(5) These mutations are interconnected to generate diverse pathways of tumorigenesis and progression. For example, one study showed that both TGFBR2 mutations and MSI are approximately two-to threefold more prevalent in tumors displaying normal p53, APC, and RAS, compared to those with alterations in these ...

HAI alternating with systemic chemotherapy led to a promising response and hepatic progression-free survival, possibly reducing extrahepatic recurrence in colorectal cancer patients with non-resectable liver metastases.