Effect of COX2 -765G>C and c.3618A>G polymorphisms on the risk and survival of sporadic colorectal cancer.

BACKGROUND: The COX2 gene (also known as PTGS2) encodes one of the essential cyclooxygenases for the prostanoid synthesis, and its expression is tightly regulated at both transcriptional and posttranscriptional levels. COX2 overexpression has been detected in up to 90% of colon carcinomas, and its downregulation inhibits polyp formation. Several polymorphisms located in both 5'- and 3'- flanking regions of COX2 have been described, but their functional significance and their use as prognostic indicators are still unclear. METHOD: We analyzed in Spanish population the risk contribution and the prognostic significance for colorectal cancer (CRC) with five polymorphisms (rs20417, rs20426, rs5276, rs13306035 and rs4648298) located in the coding and regulatory regions of COX2. RESULTS: Only two variants appear in Spanish population: -765G>C (rs20417) located at the promoter and c.3618A>G (rs4648298) in the 3'UTR. None of the two polymorphisms associate with colon cancer risk (HR of 1.42; 95% CI = 0.46-4.47 and 0.62; 95% CI: 0.305-1.267, respectively). Moreover, the multifactor dimensionality reduction method does not detect high- or low-risk genotype combinations (training accuracy: 0.52; testing accuracy: 0.45; cross-validation consistency (CVC): 10/10; p = 0.37), indicating that there are no synergist interactions between these polymorphisms that alter the risk of cancer. However, the variant of the c.3618A>G polymorphism is associated with the presence of several clinicopathological features that have been shown to be good prognostic indicators. In addition, patients with the c.3618A>G polymorphism also show improved survival rates (log rank, p = 0.026). CONCLUSION: The current results suggested that c.3618A>G polymorphism in COX2 is a good prognostic indicator for patients with CRC. Genotyping this polymorphism may be useful for predicting the clinical outcome of sporadic CRC.

RIS1, a gene with trinucleotide repeats, is a target in the mutator pathway of colorectal carcinogenesis.

Microsatellite instability (MSI) due to mismatch repair system (MMR) alterations characterizes the mutator pathway implied in colorectal cancer development. In the present study, we have analyzed the gene RIS1 (Ras-induced senescence 1) in relation to loss of heterozygosity (LOH) and its frameshift mutations for an imperfect trinucleotide repeat (GCN) located at the 3'-OH end. Additionally, we have compared the status of RIS1 with a number of genetic and clinicopathological variables. RIS1 did not display LOH in any informative tumor of our series, but exhibited frameshift mutations in a high percentage (43.8%) of high-frequency MSI tumors (MSI-H), and its alteration was correlated with mutations in two target genes: BAX and TGFBR2. Moreover, mutations in RIS1 in MSI-H tumors correlated with the epigenetic silencing of MLH1 (P = 0.04). Finally, RIS1 seemed to be functionally involved in tumor development, as low-frequency MSI tumors (MSI-L) with RIS1 mutated usually were associated with a worse prognosis: 83% of them developed metastasis, and no patient with MSI-L tumor and RIS1 mutated (35.3% of MSI-L) survived >25 months after surgery (log rank P < 0.001). All these results indicate, according to the Bethesda criteria, that RIS1 is a target gene in the mutator pathway.

Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability.

The mutator pathway implied in the development of colorectal cancer is characterized by microsatellite instability (MSI), which is determined by alterations of mismatch repair (MMR) genes. Defects in MMR genes affect repetitive DNA tracts interspersed mostly between coding sequences, and therefore it cannot be expected that they play a role during tumor progression. Genes containing repetitive sequences within their coding regions could be targets for MSI tumorigenesis, but this does not necessarily imply a causal role for the affected gene, because most are probably passenger mutations. We analyzed MSI and TGFBR2 and BAX frameshift mutations to further clarify the relationships between inactivation of the two genes and genomic instability in sporadic colorectal cancer (CRC), and to address how mutations in these genes influence the development of tumors and, eventually, patient outcome. One hundred and fifty-five patients with sporadic CRC were classified according to their MSI status. Frameshift mutations in the two genes were recurrent in high-frequency MSI (MSI-H) tumors, but these tended to be more common in poorly differentiated tumors. A high rate of mutations of TGFBR2 was found in tumors at Dukes' B stage, showing a greater extent of vascular invasion. Finally, in MSI-H tumors, mutations of either gene were associated with a significant decrease in survival. Our results contribute to the understanding of how the TGFBR2 and BAX gene mutations contribute to tumor progression in the mutator phenotype pathway for MSI colorectal cancers.

Simultaneous mutations in K-ras and TP53 are indicative of poor prognosis in sporadic colorectal cancer.

Despite the fact that the mutations in K-ras codon 12 and TP53 are common abnormalities in colorectal cancer, the determination of K-ras mutation combined with TP53 gene mutation, with diagnostic and prognostic purposes is still controversial. We have analyzed K-ras and TP53 mutations in 77 sporadic colorectal adenocarcinomas by means of polymerase chain reaction and sequencing. We observed a negative correlation between both K-ras and TP53 mutations. Patients with mutations in K-ras but not in TP53 exhibited worse survival rates than those with mutations in TP53 and not in K-ras. Moreover, we found the worst outcome in patients with mutations in both K-ras and TP53. These results may relate to the previously published data about primary human and rodent cells, in which transformation by Ras require either a cooperating oncogene or the inactivation of tumor suppressors such as p53 or p16. In conclusion, simultaneous mutations in K-ras and TP53 are indicative of a worse prognosis in sporadic colorectal cancer.

Laparoscopic cholecystectomy and incidental carcinoma of the extrahepatic bilary tree.

BACKGROUND AND OBJECTIVES: Gallbladder carcinoma is found in 0.2% to 5% of patients undergoing cholecystectomy, and gallstones are found in 70% to 98% of patients with gallbladder carcinoma. Early diagnosis of carcinoma is difficult because of the absence of specific symptoms and the frequent association with chronic cholecystitis and gallstones. At present, laparoscopic cholecystectomy is the gold standard for the surgical treatment of symptomatic cholelithiasis and other benign gallbladder diseases. The aims of this study were to evaluate retrospectively the incidence of occasional and occult gallbladder carcinomas to ascertain the effect of laparoscopy on diagnosis and treatment of unexpected extrahepatic biliary tree carcinomas and to assess possible guidelines that can be taken into consideration when the problem is encountered. METHODS: Clinical records of 3900 patients undergoing laparoscopic cholecystectomy were reviewed. Patients with occasional (intraoperative = Group A) or occult (postoperative = Group B) diagnosis of gallbladder or common bile duct carcinoma entered the study group. Follow-up data were obtained in June 2000. RESULTS: A total of 14 patients (0.35%), 3 men and 11 women, mean age 60.8 years (range 37 to 73) with extrahepatic biliary tree carcinoma were found. Occasional carcinomas occurred in 8 patients, occult carcinomas in 6. No deaths occurred in either group. The overall survival at mean follow-up of 30.5 months is 50%. Five patients are disease free, and 2 are alive with evidence of recurrence. DISCUSSION: In 2 large series of unselected consecutive laparoscopic cholecystectomy, only 14 unsuspected malignant tumors of the extrahepatic biliary tree were found (0.35%). The limits of the preoperative workup and the difficult diagnosis of biliary tract carcinoma during laparoscopic cholecystectomy, has led to the present retrospective study and several significant recommendations.