Kazuo Tamura

IL18 polymorphism is associated with an increased risk of Crohn’s disease

Background. The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn’s disease. Methods. To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure. Results. No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/ TCC at codon 35. In patients with Crohn’s disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (χ2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39–4.80). Also, the magnitude of the association was more remarkable in females (χ2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73–24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn’s disease, especially in females. Conclusions.IL18 is probably one of several genes that determine susceptibility to Crohn’s disease.

A clinical overview of familial adenomatous polyposis derived from the database of the Polyposis Registry of Japan

The clinical situation of familial adenomatous polyposis (FAP) in Japan has changed in the period since the last analysis of data of the Japanese Polyposis Center. To reevaluate our data and elucidate the changes we analyzed the records of the 1390 FAP patients in 900 families registered with the Polyposis Committee of the Japanese Society for Cancer of the Colon and Rectum. In the 13-year period 1990–2003, clinical differences between men and women with FAP diminished. The postoperative prognosis was substantially better in patients without advanced colorectal cancer (stage ≧ T2) than in those with early cancer or no cancer. Mean age at death improved from 42.5 years in the period before 1990 to 46.0 years, and it was a result of a decreased proportion of deaths from colorectal cancer. The distribution of colorectal cancer in FAP patients was similar to that in the general population. Desmoid tumors accounted for about 10% of deaths in the recent 13 years (1990–2003). The cumulative risk of rectal cancer in the preserved rectum was 12% at 10 years and 23% at 15 years. The registry system in Japan revealed a new clinical situation in FAP patients, and the findings of this study will be useful to improve the prognosis of patients with FAP.

Association between IL-18 gene promoter polymorphisms and inflammatory bowel disease in a Japanese population

Background: Interleukin‐18 (IL‐18) is a pleiotropic cytokine that induces the production of interferon (IFN)‐&ggr; and also to regulate Th2 cytokines. Recently, association studies between IL‐18 gene promoter polymorphisms and several Th1‐ or Th2‐mediated inflammatory diseases were reported. In inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohns disease (CD), recent evidence suggests that IL‐18 is involved in the pathogenesis. Methods: Using DNA direct sequencing, we investigated IL‐18 gene promoter polymorphisms at −607C/A and −137G/C. Allele, genotype, and haplotype frequencies were determined in 210 Japanese patients with UC, 205 patients with CD, and 212 controls. Results: In UC, the −137C allele frequency was significantly higher in the proctitis‐type patients than in controls (Pc = 0.0068). The −137 genotype frequency was also significantly different in the proctitis‐type patients than in controls (Pc = 0.032). No other allele and genotype frequencies were significantly associated with UC after Bonferroni correction. Furthermore, the frequency of haplotype 2 (−607A, −137C), which had a lower promoter activity and IFN‐&ggr; mRNA level than the other haplotypes as previously reported, was significantly higher in the proctitis‐type patients than in controls (Pc = 0.01). In CD, we could not find any significant differences. Conclusions: IL‐18 gene promoter polymorphisms may not be associated with disease susceptibility but related to the extent of disease in UC.

Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum

OBJECTIVE The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients. METHODS We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch repair gene mutations were diagnosed with suspected familial colorectal cancer type X. RESULTS We identified 69 patients with Lynch syndrome and 25 with suspected familial colorectal cancer type X. The frequencies of gastric and extracolonic Lynch syndrome-associated cancers were lower with suspected familial colorectal cancer type X than with Lynch syndrome. The number of organs with Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. The cumulative incidence of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. We estimated that the median cancer risk in 60-year-old patients with Lynch syndrome was 89, 36 and 24% for colorectal, endometrial and gastric cancers, respectively. Analyses of family members, including probands, revealed that the median age at diagnosis of extracolonic Lynch syndrome-associated cancer was significantly older with suspected familial colorectal cancer type X than with Lynch syndrome. The frequency of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. CONCLUSION A significant difference in extracolonic Lynch syndrome-associated cancer was evident between suspected familial colorectal cancer type X and Lynch syndrome.

Mechanism of carcinogenesis in familial tumors

It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson’s two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.

Germline p53 mutation at codon 133 in a cancer-prone family

Abstract We identified four families in which we suspected the presence of genetic factors predisposing them to cancer. We examined one family with features suggesting Li-Fraumeni syndrome for the presence of a germline p53 mutation in 13 of its members. To detect germline p53 mutations we performed polymerase chain reaction/nonradioisotopic single-strand conformation polymorphism and DNA sequencing analysis on exons 4–9 of the p53 gene. Mutated polymerase chain reaction–restriction fragment length polymorphism analysis was also performed on exon 5 to confirm the mutation identified by the sequencing analysis. A novel germline p53 mutation was identified at codon 133 (ATG→AGG) in exon 5, resulting in the substitution of arginine for methionine, in all four cancer-affected individuals and in three apparently healthy individuals. We also analyzed tumor specimens for additional p53 mutations in the wild-type alleles using the same methods. However, heterozygosity was retained, and no other additional mutations in the wild-type allele were identified in any of the tumor tissues. It is possible that additional mutations in the wild-type allele are not always necessary for the loss of tumor suppressor functions. This study presents serious clinical and ethical problems about the predictive value of identifying germline p53 mutations in presymptomatic carriers. However, accurate predictive testing will be very useful in identifying unaffected individuals who are at increased risk of developing cancer and in detecting cancer at an early stage.

Determination of splice-site mutations in Lynch syndrome (hereditary non-polyposis colorectal cancer) patients using functional splicing assay

Lynch syndrome (hereditary non-polyposis colorectal cancer) is an inherited disease caused by germ-line mutation in mismatch repair genes such as MLH1, MSH2, and MSH6. The mutations include missense and nonsense mutations, small insertions and deletions, and gross genetic alterations including large deletions and duplications. In addition to these genetic changes, mutations in introns are also involved in the pathogenesis. However, it is sometimes difficult to interpret correctly the pathogenicity of variants in exons as well as introns. To evaluate the effect of splice-site mutations in two Lynch syndrome patients, we carried out a functional splicing assay using minigenes. Consequently, this assay showed that the mutation of c.1731+5G>A in MLH1 led to exon15 skipping, and that the mutation of c.211+1G>C in MSH2 created an activated cryptic splice-site 17-nucleotides upstream in exon1. These aberrant splicing patterns were not observed when wild type sequence was used for the assay. We also obtained concordant results by RT-PCR experiments with transcripts from the patients. Furthermore, additional functional splicing assays using two different intronic mutations described in earlier studies revealed splicing alterations that were in complete agreement with the reports. Therefore, functional splicing assay is helpful for evaluating the effects of genetic variants on splicing.

Mucinous Carcinoma of the Duodenum Associated with Hereditary Nonpolyposis Colorectal Cancer: Report of a Case

We herein report a rare case of primary mucinous carcinoma of the duodenum associated with hereditary nonpolyposis colorectal cancer (HNPCC). A 50-year-old man known to have HNPCC based on the Amsterdam criteria I was admitted because of the presence of a duodenal tumor. Duodenoscopy revealed an ulcerated tumor in the posterior wall of the second portion of the duodenum and the malignancy was confirmed by a biopsy. He underwent a pylorus-preserving pancreaticoduodenectomy with a regional lymph node dissection. The histological diagnosis was mucinous carcinoma of the duodenum with lymph node metastasis. High-frequency microsatellite instability (MSI-H) was identified in both the colon and a duodenal specimen based on a microsatellite assay. A germline mutation in the hMSH2 gene was also identified. Even though extracolonic malignancies are associated with HNPCC, duodenal cancer is nevertheless very rare, and only two cases have been reported over the past 20 years. The present case is therefore only the third such case and the patient is herein described with a brief review of the literature.

Ovarian carcinoma in situ of presumable fallopian tube origin in a patient with Lynch syndrome: A case report

Highlights • Occult ovarian carcinoma of presumable fallopian tube origin in Lynch syndrome• Atypical endometrial hyperplasia during a 10-year follow-up period after colon cancer• Synchronous ovarian serous carcinoma in situ and borderline tumor in Lynch syndrome

Concomitant adenocarcinoma and colonic non-Hodgkin's lymphoma in a patient with ulcerative colitis: a case report and molecular analysis.

Ulcerative colitis (UC) complicated by colonic lymphoma is rare, although UC is often accompanied by adenocarcinoma of the colon. A concurrent existence of adenocarcinoma and lymphoma in a patient with UC is extremely rare, and has not yet been analyzed at the molecular level. We report a 64-year-old female patient with concomitant adenocarcinoma and diffuse large B-cell lymphoma (DLBCL) in the colon of UC. The genetic changes in these two neoplasms were analyzed. The colon adenocarcinomas had a mutation in MSH6 gene, DNA methylation in CDKN2A gene, and increased microsatellite instability (MSI), although these genetic changes were not recognized in either DLBCL or non-neoplastic UC mucosa. The DLBCL was diagnosed as primary colonic lymphoma, and confirmed Epstein-Barr virus (EBV) infection. The adenocarcinomas and the non-neoplastic UC mucosa were EBV-negative. Our case presented here clearly shows that the development of adenocarcinoma and lymphoma in the colon with UC was caused by individual mechanisms.