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In addition to BRCA1 and BRCA2, RAD51C,PALB2 and BRIP1 are known as breast cancer susceptibility genes. However, the mutation status of these genes in Japanese familial breast cancer cases has not yet been evaluated. To this end, we analyzed the exon sequence and genomic rearrangement of RAD51C,PALB2 and BRIP1 in 100 Japanese patients diagnosed with familial breast and ovarian cancer and without BRCA1 and BRCA2 mutations. We detected a large deletion from exons 6 to 9 in RAD51C, 4 novel BRIP1 missense variants containing 3 novel non‐synonymous variants, c.89A>C, c.736A>G and c.2131A>G, and a splice donor site variant c.918+2T>C. No deleterious variant of PALB2 was detected. The results of pedigree analysis showed that the proband with a large deletion on RAD51C had a family history of both breast and ovarian cancer, and the families of probands with novel BRIP1 missense variants included a male patient with breast cancer or many patients with breast cancer within the second‐degree relatives. We showed that the mutation frequency of RAD51C in Japanese familial breast cancer cases was similar to that in Western countries and that the prevalence of deleterious mutation of PALB2 was possibly lower. Furthermore, our results suggested that BRIP1 mutation frequency in Japan might differ from that in Western countries.

Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Objective: Inflammation bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancers. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. Method: Inflammatory colitis was induced by brief treatment of 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1-/-), Mlh1 heterozygous (Mlh1+/-) and wild-type (Mlh1+/+) mice at 10 weeks of age. Development of colon tumors was followed for subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, b-catenin and p53. Results: Male and female Mlh1-/- mice with DSS showed 63% and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1+/- and Mlh1+/+ mice. The mice without DSS treatment did not develop any tumors regardless of genotype. While aberrant expression of b-catenin was not detected in colonic neoplasms, p53 and iNOs expression was increased in 100% and 77%, respectively. These immunohistochemical changes were consistent with those of human ulcerative-colitis associated colon cancers. Conclusion: Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.

Deficiencies in DNA mismatch repair (MMR) result in replication errors within key tumor suppressor genes or oncogenes, and cause hereditary nonpolyposis colorectal cancer (HNPCC). Hematological malignancy with microsatellite instability is also associated with defective MMR, but little is known about the target genes for MMR. Here we identified Ikaros, a master transcription factor of lymphoid lineage commitment and differentiation, as a mutational target in spontaneous and radiation-induced T-cell lymphomas in Mlh1-deficient mice. Three quaters of lymphomas lacked Ikaros protein expression, which resulted from a frameshift mutation that created a stop codon. Mononucleotide repeat sequences at 1029-1034(C)6 and 1567-1572(G)6 in Ikaros were mutational hot spots with a one-base deletion occurring with a frequency of 45% and 50%, respectively. Point mutations and splicing alterations were also observed. In total, 85% of the lymphomas showed aberrations in Ikaros. The characteristics of Mlh1-deficient lymphomas is harboring of multiple mutations simultaneously in the same tumor, displaying a combination of two frameshift mutations at different repeats, frameshift and point mutations, and/or deletion mutations. This is the first report of Ikaros mutations coupled with Mlh1 deficiency in lymphomagenesis.

特集 イスラム史における地方権力(Local Authority in Islam)

Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.

多層プリント配線板のドリル穴あけ加工時に発生するスミアや穴内壁粗さは, 各層間の導通不良や絶縁不良の主な原因となっている。スミアや穴内壁粗さの発生は, 多層材料特性やドリル条件等に影響されるが, その発生機構や多層プリント配線板の特性との関係は明らかでない。そこで, スミアや穴内壁粗さと基板特性や基板に使用した樹脂特性との関係を明らかにすることを目的に, スミアについては, その発生機構をドリル摩耗や切粉形態, スミア発生過程の観察より推定し, 樹脂特性とスミアの関係を検討した。穴内壁粗さは, ガラス繊維と樹脂の界面接着特性をアコースティック・エミッション法で評価し, 穴内壁粗さとの関係を検討した。その結果, スミアの発生にはドリル摩耗の影響が大きく, 排出過程の微細な樹脂の切粉が銅箔切削面と摩耗したドリルのマージンとのすき間に侵入し, 押し付けられて付着し, スミアになると推定した。硬化後の臨界表面張力が大きい樹脂で作製した多層プリント配線板は, スミアレベルが良好であることを見いだした。穴内壁粗さは, 積層板のガラス繊維と樹脂の界面接着強度と良い相関を示し, 界面接着強度が高すぎる積層板は穴内壁粗さが大きくなることがわかった。