Specific codon 13 K-ras mutations are predictive of clinical outcome in colorectal cancer patients, whereas codon 12 K-ras mutations are associated with mucinous histotype.

BACKGROUND: K-ras mutations, one of the earliest events observed in colorectal carcinogenesis, are mostly found in codons 12 and 13, and less frequently in codon 61, all three of which are estimated to be critical for the biological activity of the protein. Nevertheless the prognostic significance of such mutations remains controversial. Our purpose was to assess whether any or specific K-ras mutations in primary colorectal cancer had prognostic significance and were linked to clinico-pathological parameters. PATIENTS AND METHODS: Paired tumor and normal tissue samples from a consecutive series of 160 untreated patients (median of follow up 71 months), undergoing resective surgery for primary colorectal carcinoma, were prospectively studied for K-ras mutations by PCR/single strand conformation polymorphism sequencing. RESULTS: Seventy-four of the 160 (46%) primary colorectal carcinomas presented mutations in K-ras: 54% in codon 12, 42% in codon 13 (particularly G-->A transition) and 4% in both. Codon 12 K-ras mutations were associated with mucinous histotype (P <0.01), while codon 13 K-ras mutations were associated with advanced Dukes' stage (P <0.05), lymph-node metastasis (P <0.05) and high S-phase fraction (P <0.05). Multivariate analysis showed that codon 13 K-ras mutations, but not any mutation, were independently related to risk of relapse or death. CONCLUSIONS: Our results suggest that codon 12 K-ras mutations may have a role in the mucinous differentiation pathway, while codon 13 mutations have biological relevance in terms of colorectal cancer clinical outcome.     

Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years

Somatic mutation of K-ras is known to be a common event in colorectal cancer tumourigenesis however its association with age at onset has not been widely explored. In this study, we have analyzed tumours from a population-based study of colorectal cancer diagnosed before the age of 45 years, in which cases had been previously screened for germ-line mismatch repair gene mutations and for microsatellite instability. We used a micro-dissection and sequencing approach to search for somatic K-ras mutations in codons 12, 13 and 61 in 101 early-onset colorectal cancers. Six (6%) somatic K-ras mutations were detected; five in codon 12 (4 G>T transitions and 1 G>A) and one in codon 13 (G>A transition). All codon 12 mutations were identified in microsatellite stable tumours and the codon 13 mutation was identified in a MSI-high tumour. Four cases with K-ras mutations had no reported family history of colorectal cancer and two had some family history of colorectal cancer. None were known to carry a germ-line mutation in hMSH2, hMLH1, hMSH6 or hPMS2. The role of somatic K-ras mutations in early-onset colorectal cancer carcinogenesis appears to be minor, in contrast to its significant role in colorectal cancer of later age of onset.     

K-ras mutations and HLA-DR expression in large bowel adenomas.

A total of 72 sporadic colorectal adenomas in 56 patients were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene and for HLA-DR antigen expression related to clinicopathological variables. Forty K-ras mutations in 39 adenomas were found (54%): 31 (77%) in codon 12 and nine (23%) in codon 13. There was a strong relationship between the incidence of K-ras mutations and adenoma type, degree of dysplasia and sex. The highest frequency of K-ras mutations was seen in large adenomas of the villous type with high-grade dysplasia. Fourteen out of 15 adenomas obtained from 14 women above 65 years of age carried mutations. HLA-DR positivity was found in 38% of the adenomas, large tumours and those with high-grade dysplasia having the strongest staining. Coexpression of K-ras mutations and HLA-DR was found significantly more frequently in large and highly dysplastic adenomas, although two-way analysis of variance showing size and grade of dysplasia to be the most important variable. None of the adenomas with low-grade dysplasia showed both K-ras mutation and HLA-DR positivity (P = 0.004). K-ras mutation is recognised as an early event in colorectal carcinogenesis. The mutation might give rise to peptides that may be presented on the tumour cell surface by class II molecules, and thereby induce immune responses against neoplastic cells.     

结直肠癌K-ras基因突变与临床病理特征的相关性分析

 【摘要】 目的：研究结直肠癌组织中K-ras基因的突变情况与临床病理特性之间的相关性。 目的　研究结直肠癌组织中K-ras基因的突变情况与临床病理特性之间的相关性。方法　采用直接测序法对90例结直肠癌石蜡标本进行K-ras基因突变检测,并对K-ras基因的突变情况及其与结直肠癌患者临床病理特征的关系进行统计学分析。结果　90例结直肠癌患者组织中,K-ras基因12、13密码子总突变者31例,总突变率为34.4 %。12密码子单突变21例,突变率为23.3 %;双突变1例。13密码子突变者9例,突变率为10.0 %。结直肠癌K-ras基因突变率与肿瘤部位有明显相关性（P＝0.042）。12密码子单突变和13密码子突变与临床病理参数均无明显相关性（P＞0.05）。结论　不同肿瘤部位患者的K-ras基因突变率存在明显不同。     

The balanced induction of K-ras codon 12 and 13 mutations in mucosa differs from their ratio in neoplastic tissues

The aim of this study was to compare the ratio of K-ras codon 12 and 13 mutations in various tissues of colorectal cancer patients. Multiple samples of inconspicuous mucosa and a sample of carcinoma tissue were taken from 36 colorectal cancer patients (group I) and these results were compared with those from polyp and carcinoma tissues of another 48 colorectal cancer patients (group II). A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to detect the respective point mutations. The results of this assay were complemented by sequencing the K-ras mutations. In mucosa tissue, the ratio of codon 12 and 13 mutations was nearly equal (0.9:1) whereas the respective ratio in tumour tissue showed a strong preponderance of K-ras codon 12 mutations (14:1, p=0.004). In polyp tissue of patients from group II, the ratio was 2.7:1 and that in carcinomas was 19:1 (p=0.053). The prevalence of both types of mutation was 14.6% in all mucosa samples, corresponding to 30.6% of group I patients. The K-ras mutation rate in carcinoma tissue of the same patients was 38.9%. Similarly, 33.4% of all polyp and 41.7% of all carcinoma samples from group II harboured K-ras codon 12 and/or 13 mutations. Sequencing confirmed 59 of 60 K-ras codon 12 mutations, but due to the detection limit for sequencing (1:10(4)) only 10 of 20 K-ras codon 13 mutations were confirmed. It is concluded that after balanced induction K-ras codon 12 mutations increase in frequency relative to K-ras codon 13 mutations during tumour progression.     

结直肠癌中K-ras基因突变研究

目的研究K-ras基因突变表达与结直肠癌的相关性。方法采用实时荧光定量PCR方法检测89例患者结直肠癌组织中K-ras基因2号外显子12与13编码子突变情况,并结合病理资料进行分析。结果89例患者结直肠癌组织中K-ras基因突变者为37例,突变率为41．6％。其中12编码子突变为29例,突变率为32．6％。13编码子突变为8例,突变率为9．O％。K-ras基因突变与肿瘤位置、分化程度无明显相关性（P〉0．05）,与浸润深度、淋巴结转移、肝转移有相关性（P〈0．05）。淋巴结转移越多K-ras基因突变率越高,有肝转移者K-ras基因突变率高。结论K-ras基因突变在结直肠癌的发生、发展中起重要作用,与浸润深度、淋巴结转移和肝转移密切相关。     

Early detection of cancer-associated gene alterations in DNA isolated from rat feces during intestinal tumor-induction with 1,2-dimethylhydrazine

A highly sensitive mutation detection method was applied to reveal tarry K-ras alterations in exfoliated intestinal epithelium of Fischer-344 rats during the course of 1,2-dimethylhydrazine (DMH)-induced carcinogenesis. Ten weekly s.c. injections of DMH (50 mg/kg) in combination with consumption of a low-fiber diet resulted in 100% incidence of intestinal tumors at 20 weeks after initial DMH injection. Analysis of DNA extracted from fresh fecal samples obtained individually showed that proportion of codon 12 K-ras oncogene mutant alleles (G-->A transition at the second position of codon 12) was increased in some rats at 4 weeks and clearly in all rats at 8 weeks after initial DMH injection, i.e. much earlier than the first tumors appeared (14 weeks). A gradual increase of mutant K-ras fraction in DNA samples extracted from feces led to an extremely high level of the mutant reaching 10% of the oncogene alleles at the end of the experiment (20 weeks). K- and H-ras oncogene and p53 tumor suppressor gene mutations were analyzed in the resulting colon and duodenal tumors. 14 of 17 colon tumors had K-P as mutations (11 - G-->A transition at codon 12 second base; 3 - G-->A transition at codon 13 second base). G-->A transitions at codon 12 first base of H-ras were detected in 3 colon tumors. All 5 duodenal tumors induced in the experiment had G-->A transition at codon 12 second base of K-ras. 3 of these tumors also had H-ras mutations. No mutation was detected within exons 4-7 of p53 gene indicating that p53 alterations may not be involved in the rapid development of tumors induced by high doses of DMH. Our observations suggest that detection of K-ras mutations in stool samples are predictive of later tumor development from a very early stage.     

K-ras gene mutation in colorectal adenomas and carcinomas from familial adenomatous polyposis patients.

Colorectal adenomas and carcinomas from familial adenomatous polyposis (FAP) patients were screened for the presence of K-ras gene mutations at codon 12 using an in vitro amplification step (polymerase chain reaction) followed by dot blot analysis using oligonucleotide probes specific for different mutations at codon 12. We examined 28 colorectal adenomas and two colorectal carcinomas from 12 FAP patients and observed a mutation at codon 12 in seven adenomas and in both carcinomas. The frequency of K-ras gene mutations in colorectal tumours from FAP patients is similar to those in cases of sporadic adenomas and sporadic colorectal carcinomas indicating that the mechanisms involved in their development may be similar.     

K-ras mutation in colorectal carcinomas from singapore

54 sporadic colorectal cancers were analyzed for aberrations in the K-ras oncogene. DNA was extracted from frozen tissues obtained from surgical resection and analyzed for mutations in codons 12, 13 and 61 of the K-ras oncogene using single strand conformation polymorphism analysis (SSCP) and direct sequencing. Point mutations in the K-ras oncogene were found in 26/54 (48%) cases, all of which resulted in amino acid substitutions. No other types of mutations (e.g. insertions or deletions) were found. 4 of the mutations were at codon 12, 22 in codon 13 and only 1 was a codon 61 mutant. G-->A transitions were found to be predominant. A remarkable finding was the high preponderance of (13)Gly-(13)Ser mutations (54%). No correlation was observed between K-ras mutations and tumor location, Dukes' stage, differentiation levels, age or sex of the patient.     

The frequency and spectrum of K-ras mutations among Iraqi patients with sporadic colorectal carcinoma

Background: The epidemiology of colorectal cancers (CRC) is well known to differ in different geographical regions. K-ras mutations have been implicated in CRC carcinogenesis and they were extensively studied in developed countries; however, such studies are scarce from developing countries, like Iraq. Aim: To determine the frequency and spectrum of K-ras mutations among CRC Iraqi patients, and their clinico-pathological associations, if any. Materials and Methods: Fifty consecutive surgically resected sporadic CRC were evaluated. The evaluation included screening for ten K-ras mutations in codon 12 and 13 by mutant enriched polymerase chain reaction followed by reverse hybridization to oligospecific probes. Results: Out of the 50 enrolled patients, 24 (48%) had K-ras mutations. A total of 29 mutations were identified in the tumors of the latter 24 patients (20/24 tumors had single mutations, 3/24 had double mutations and 1/24 had triple mutations). The most frequently encountered mutations were the G>T transversions and G>A transitions (41.4% each). Codon 12 mutations constituted 89.7%, while codon 13 the remaining 10.3%. The most frequent mutation was GGT>GTT (Gly>Val) of codon 12 documented in 31%. No significant clinico-pathological correlations with K-ras mutational status were identified. Conclusion : The K-ras mutations are frequently encountered among Iraqi sporadic CRC patients, with relative higher frequencies of G>T transversions and Gly>Val codon 12 substitutions than encountered in their counterparts in developed countries. The latter is most likely to be related to differences in local carcinogens exposure, an aspect which requires further scrutiny.     

Detection of codon 61 point mutations of the K-ras gene in lung and colorectal cancers by enriched PCR

Mutation of the Kirsten ras (K-ras) gene is one of most common alterations in solid tumors including lung and colorectal cancers. We developed new enriched PCR-RFLP assay to detect mutations of K-ras codon 61 at the 1st and 2nd letters and non-enriched PCR-RFLP assay to detect the 3rd letter mutation. One mutant allele among 10(3) wild-type alleles was detected by enriched PCR-RFLP assay, while one mutant in 10 wild-type alleles was detected by non-enriched PCR-RFLP assay for codon 61 3rd letter. We then examined K-ras codon 12, 13 and 61 mutations in lung and colorectal cancers using these assays. K-ras codon 12 mutation was detected in 10 of 109 (9%) lung cancer and 19 of 83 (23%) colorectal cancer cases. K-ras codon 13 mutation was detected in 2 of 83 (2%) colorectal and 0 of 109 NSCLC cases, respectively. There was no K-ras codon 61 mutation in either type of cancer. Our results demonstrate that enriched PCR-RFLP is a sensitive assay to detect K-ras codon 61 mutation, however, it was extremely rare in lung and colorectal cancers, suggesting organ-specific pathways in mutagenesis of the ras gene family.     

Effects of N-methyl-N'-nitro-N-nitrosoguanidine on the human colorectal polyps consecutively maintained in SCID mice

N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) treatments for a long period induced morphological and molecular alterations in the benign human colorectal polyps which were maintained in the severe combined immunodeficient C.B17/N-scid/scid mice. Thirty four xenografts of colorectal polyps from five solitary polyp and three familial polyposis patients were examined for K-ras and p53 mutations. Six K-ras mutations were induced in 16 grafts treated with MNNG more than five times, while no K-ras mutations were detected in 14 untreated grafts (P<0.05). Additional and new K-ras mutations were also induced in two polyps in which K-ras mutation had pre-existed. p53 mutations were not observed in both MNNG-treated and untreated groups. The mutations in K-ras gene were induced at codon 12 (GGT-->GAT) except one at codon 13 (GGC-->GGT). The results indicate that K-ras mutation plays an important role in human colorectal carcinogenesis as is the case in experimental animals.     

Frequent detection of K-ras mutation in stool samples of colorectal carcinoma patients after improved DNA extraction: comparison with tissue samples

Fecal occult blood testing is widely used in the clinical screening of colorectal tumors. However, this method has so frequent false-positive results that more accurate screening-strategy should be established. Although the molecular screening using K-ras gene mutation in stools has been attempted to improve the results, the low rate of DNA extraction from stools leaves this measurement under utility value. In this study, we investigated whether or not our applied DNA extraction method from stools could produce enough DNA for the molecular screening of colorectal tumors by K-ras gene mutations in stools. We applied cetyltrimethylammonium bromide (CTAB) solution to improve human DNA extraction from stools and a mutant-allele-sensitive amplification (MASA) method to detect K-ras mutation within codon 12. We were able to confirm the stool DNA by identifying K-ras fragments in all the 20 patients. Tissue K-ras mutation was identified in 4 (2 cancers and 2 adenomas) of 20 patients. Stool K-ras mutations were found in 6 patients, 3 tissue K-ras mutation positive patients (2 cancers and an adenoma) and 3 tissue K-ras mutation negative patients. These results indicate that it is possible to extract enough DNA from human stool samples of all patients with colorectal tumors for K-ras mutation studies. K-ras mutations are more frequently detected in stools than in resected colorectal tumors. This study indicates that K-ras mutation screening in stools for colorectal cancer may include not only a primary colorectal cancer but also precancerous lesions in all parts of a gastrointestinal tract.     

K-ras mutations in colorectal adenocarcinomas and neighbouring transitional mucosa

The K-ras gene in codons 12 and 13 was investigated using allele-specific polymerase chain reaction in matched normal mucosa (n = 106), transitional mucosa (n = 69) and tumours (n = 149) from 149 patients with colorectal adenocarcinomas. K-ras mutations in codon 12 were detected in 41/149 (28%) of tumours and 4/69 (6%) of transitional mucosa samples, but not in the normal mucosa. Further, mutation rates were increased in younger patients (P = 0.001) and in mucinous carcinomas (50%) compared with well differentiated (17%), moderately differentiated (26%) or poorly differentiated (24%) tumours. Our findings indicate that mucinous carcinoma may represent a distinct genetic entity.     

Sensitive detection of K-ras mutations augments diagnosis of colorectal cancer metastases in the liver.

Postoperative survival of colorectal cancer patients is often delineated by metastases spreading to the liver. Current clinical diagnostic procedures are unable to discover micrometastases in this organ. Our aim was to develop a diagnostic tool for detecting micrometastases that are present at the time of surgery. Therefore, a PCR-RFLP assay was set up tracking point mutations of the K-ras oncogene at codons 12 and 13, based on mismatch primers and restriction enzymes BstXI and XcmI. The detection limit of this assay was one mutant in one million wild-type cells. One hundred forty-two patients with colorectal carcinoma were screened for these mutations in tissue samples from their tumor, proximally adjacent mucosa, and liver. Of these, 67 patients (46%) were positive for a K-ras mutation, of which 58 had codon 12 and 9 had codon 13 mutations. No patient without a K-ras-positive tumor showed a mutation in mucosa, but 11 patients with a K-ras-positive tumor (11 of 58; 19%) were found to bear a K-ras mutation in their mucosa, and in 21 patients (21 of 64; 33%), a K-ras mutation was detected in liver tissue. Sequencing of all mutated samples revealed a 92% confirmation of PCR-RFLP results. In summary, the assay is a useful tool for detecting K-ras codon 12 and 13 mutations and allows early proof of molecular determinants of liver metastases. Such knowledge will improve the staging of colorectal cancer patients and could beneficially influence their prognosis if followed by an effective therapy.     

Association of K-ras mutations with liver metastases from colorectal carcinoma

BACKGROUND: Colorectal carcinomas were studied regarding early proof of liver metastases through determination of K-ras mutations. PATIENTS AND METHODS: Seventy-seven colorectal carcinomas were investigated for the presence of point mutations in codon 12 and 13 of the K-ras gene, using single-strand conformation polymorphism (SSCP) analysis and direct sequencing. RESULTS: Twenty-six carcinomas were positive for K-ras mutations, of which 21 had codon 12 and 5 had codon 13 mutations. Twenty patients with K-ras-positive tumor (20 out of 26: 77%) developed liver metastases, of which 13 had simultaneous metastases and 7 had metachronous metastases. There was a significant association between K-ras mutations and liver metastases (p=0.03). A multivariate logistic regression model demonstrated that the involvement of lymph node (p<0.01) and K-ras mutations (p=0.02) were predictive factors for liver metastases from colorectal carcinoma. Sequencing in carcinomas without liver metastases showed the base change in the first position of codon 12, whereas with liver metastases it showed significantly frequent base change in the second position of codon 12 (p<0.01). CONCLUSION: It is suggested that the presence of K-ras mutation, especially base change in the second position of codon 12, may predict liver metastases from colorectal carcinoma.     

K-ras codon 12 and 13 mutations are correlated with differential patterns of tumor cell dissemination in colorectal cancer patients

The aim of this prospective study was to relate the incidences of cytokeratin 20 (CK20) and guanylylcyclase C (GCC) in lymph node, liver, and bone marrow specimens of 245 colorectal cancer (CRC) patients with the K-ras oncogene status of the corresponding primary tumor. Qualitative RT-PCR detection of CK20 and GCC mRNA was used as marker of circulating epithelial cells (CEC). Samples were considered positive for CEC only when both markers were detected concomitantly. For the detection of K-ras mutations, a PCR-RFLP assay was used. In the group with K-ras mutated primary carcinomas (n=92), CEC were detected in 62% of lymph node-, 43% of liver-, and 2% of bone marrow samples. No statistical significance was found when comparing these results with those from patients with K-ras wild-type carcinoma (59%, 46%, and 0%, respectively). In contrast to this combined evaluation, separate analysis of K-ras codons 12 (n=75, 82%) and 13 (n=17, 18%) revealed significantly differing CEC incidences. Lymph node specimens from corresponding K-ras codon 13 mutated carcinomas showed a significantly higher CEC incidence (82%) than the groups with codon 12 mutation (57%, p<0.05) or K-ras wild-type sequence (59%, p<0.05). Unlike these findings in lymph nodes, liver biopsies from corresponding carcinomas with K-ras codon 12 mutation or wild-type sequence were significantly more often positive for CEC (31% and 29%) than specimens from K-ras codon 13 mutated primary CRC (12%, p<0.04, respectively). In conclusion, colorectal carcinomas with K-ras codon 12 mutation showed the same pattern of tumor cell dissemination as their K-ras wild-type counterparts. Since K-ras codon 12 mutations prevailed 4-fold over codon 13 mutations, combined analysis of the two codons showed the same result. However, sub-analysis of patients with K-ras codon 13 mutation revealed that the respective CEC incidence was significantly increased in lymph nodes, but decreased in liver biopsies.     

Mutational activation of K-ras in nonneoplastic exocrine pancreatic lesions in relation to cigarette smoking status

BACKGROUND: Cigarette smoking is among the few unequivocal risk factors for the development of pancreatic ductal adenocarcinoma (PDAC). Activating mutations in codon 12 of the K-ras protooncogene is a frequent and early molecular event in the pathogenesis of PDAC and a variety of nonmalignant ductal pancreatic lesions. The molecular epidemiologic relation between heavy cigarette smoking and mutational activation of K-ras in PDAC has been examined to a limited extent. The authors have examined the mutational status of K-ras in nonneoplastic pancreata in relation to cigarette smoking status. METHODS: Archival formalin fixed paraffin embedded specimens of nonneoplastic pancreata (n = 39) were obtained from the American Cancer Society and evaluated histopathologically. Specimens from age- and gender-matched individuals were stratified into three groups: 1) those who never smoked cigarettes (n = 16), 2) those who smoked 1-2 packs/day for more than 20 years (n = 10 cases), and 3) those who smoked more than 2 packs/day for 20 or more years (n = 13). Cases were preselected from 77 specimens based on the quality, suitability, and cellularity of the archival tissues for analyses. Furthermore, none of the patients died of primary PDAC or had evidence of pancreatic metastases from an extrapancreatic primary tumor. Tissue sections were microdissected and deparaffinized, and genomic DNA was purified by standard proteinase K-phenol-chloroform extraction techniques. Genomic DNA was analyzed for mutations in codon 12 of the K-ras protooncogene by two mutant-allele-enriched polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assays and by multiplex PCR-based ligase chain reaction (LCR) analyses. RESULTS: Analyses of multiple microdissected pancreata specimens from 39 cases revealed wild-type K-ras codon 12 sequences in both nonsmoking individuals and those who smoked 1-2 packs/day for 20 or more years. K-ras codon 12 mutations were confirmed by PCR-RFLP and PCR-LCR assays in 5 of 13 pancreata cases (39%) obtained from individuals who smoked more than 2 packs of cigarettes/day for 20 years or more (P < 0.005). The K-ras mutation spectra revealed two G-->T transversions, one G-->C transversion and two G-->A transitions. There was no clear relation between the incidence or spectra of mutations and pancreatic histopathology, as overtly normal pancreata as well as pancreata with squamous metaplasia, periductal fibrosis, and ductal atypia revealed reproducible K-ras alterations. Similarly, among those 34 cases in which a wild-type K-ras sequence was revealed by both approaches, a similar histopathologic profile was evident. CONCLUSIONS: Mutational activation of codon 12 of the K-ras protooncogene was confirmed reproducibly by mutant allele-enriched PCR-RFLP and multiplex PCR-LCR analyses in 39% (5 of 13) of archival nonneoplastic pancreata from age- and gender-matched individuals who smoked more than 2 packs of cigarettes/day for 20 or more years. The presence of a mutated or wild-type or K-ras was independent of the histopathologic profile of the 39 cases examined. The data provide further suggestive molecular epidemiologic evidence of an association between a major and unequivocal risk factor for PDAC (heavy cigarette smoking) and mutations in a molecular target (K-ras), the activation of which is an important and early event both in the pathogenesis of PDAC and in the development of a variety of nonneoplastic ductal pancreatic lesions.     

K-ras activation in colorectal tumors from patients with familial polyposis coli

K-ras gene mutation in colorectal tumors from patients with familial polyposis coli were investigated using oligonucleotide probes specific for a mutation at codon 12, 13, or 61 of the K-ras gene. The authors examined 22 colorectal carcinomas and 51 colorectal adenomas from 41 familial polyposis coli patients and observed mutations at codons 12 and 13 in eight of 22 colorectal carcinomas (36%) and six of 51 colorectal adenomas (12%). Thus, the frequency and sites of K-ras gene mutation in colorectal carcinoma from familial polyposis coli patients are similar to those in cases of sporadic colorectal carcinoma and may not be the first genetic event linked to the tumorigenesis.     

Meat consumption and K-ras mutations in sporadic colon and rectal cancer in The Netherlands Cohort Study

Case-cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted incidence rate ratios and 95% confidence intervals were computed for colon and rectal cancer and for K-ras mutation status subgroups. Total fresh meat, most types of fresh meat and fish were not associated with colon or rectal cancer, neither overall nor with K-ras mutation status. However, several weak associations were observed for tumours with a wild-type K-ras, including beef and colon tumours, and an inverse association for pork with colon and rectal tumours; for meat products, an increased association was observed with wild-type K-ras tumours in the colon and possibly with G>A transitions in rectal tumours.