Koichi Bando

Identification of a 1-cM Region of Common Deletion on 4q35 Associated With Progression of Hepatocellular Carcinoma

To identify the location of one or more of the putative tumor suppressor genes (TSG) on chromosome arm 4q that may be involved in hepatocellular carcinoma (HCC), we examined 96 primary HCCs for their patterns of allelic loss at 39 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 71 (74%) HCCs. Detailed deletion mapping identified two distinct commonly deleted regions; one was located within a 1‐cM interval flanked by D4S1534 and D4S2929 at 4q21–22, the other in the 1‐cM interval flanked by D4S2921 and D4S2930 at 4q35. Of the tumors for which clinical data were available, allelic loss at 4q35 was more frequent in poorly or moderately differentiated tumors than in well‐differentiated tumors (3/15, 20%, vs. 14/21, 67%, P = 0.008); in tumors larger than 2 cm in size (2/11, 18%, vs. 34/62, 55%, P = 0.046); and in tumors that arose from liver cirrhosis as opposed to HCCs arising from chronic hepatitis (25/42, 60%, vs. 9/27, 33%, P = 0.048). The association of allelic losses on 4q35 with larger tumor size and aggressive histological type implies that loss or inactivation of TSG located within the 1‐cM interval of 4q35 identified here contribute to progression of HCCs. Genes Chromosomes Cancer 25:284–289, 1999.

PTEN/MMAC1 mutations in hepatocellular carcinomas: somatic inactivation of both alleles in tumors.

Allelic loss of loci on chromosome 10q occurs frequently in hepatocellular carcinomas. Somatic mutations of the PTEN/MMAC1 gene on this chromosome at 10q23 were recently identified in sporadic cancers of the uterus, brain, prostate and breast. To investigate the potential role of PTEN/MMAC1 gene in the genesis of hepatocellular carcinomas, we examined 96 tumors for allelic loss on 10q and also for subtle mutations anywhere within the coding region of PTEN/MMAC1 gene. Allelic loss was identified in 25 of the 89 (27%) tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in five of those tumors: three frameshift mutations, a 1‐bp insertion at codon 83–84 in exon 4 and two 4‐bp deletions, both at codon 318–319 in exon 8; two C‐to‐G transversion mutation, both at ‐9 bp from the initiation codon in the 5’non‐coding region of exon 1. No missense mutation was observed in this panel of tumors. In most of the informative tumors carrying intragenic mutations of one allele, we were able to detect loss of heterozygosity as well. These findings suggest that two alleles of the PTEN/MMAC1 gene may be inactivated by a combination of intragenic point mutation on one allele and loss of chromosomal material on the other allele in some of these tumors.

Identification of a 1-Mb common region at 16q24.1-24.2 deleted in hepatocellular carcinoma.

To identify the location of one or more putative tumor suppressor genes that may be involved in hepatocellular carcinoma (HCC), we examined 96 such tumors for their patterns of allelic loss at 21 microsatellite marker loci distributed along chromosome arm 16q. Allelic loss at one or more loci was observed in 58 (60%) of these tumors. Detailed deletion mapping identified a distinct commonly deleted region located within an interval flanked by D16S534 and D16S3091 at 16q24.1–24.2. By constructing a physical map consisting of a YAC contig across the region, the extent of the deleted region was determined to be less than 1 Mb. Among the tumors for which clinical data were available, allelic loss at 16q24.1–24.2 was more frequent in tumors arising from liver cirrhosis compared to HCCs arising from chronic hepatitis (30/42, 71%, vs. 13/33, 39%; P = 0.0054). Additionally, allelic loss at 16q24.1–24.2 was frequently observed in small tumors and early‐stage tumors as well as in tumors of more advanced phenotype. Genes Chromosomes Cancer 28:38–44, 2000.

Localization of a Target Region of Allelic Loss to a 1‐cM Interval on Chromosome 16p.13.13 in Hepatocellular Carcinoma

To identify the location of the putative tumor suppressor gene on chromosome 16p that may be involved in hepatocellular carcinoma (HCC), we examined 96 primary HCCs and evaluated their patterns of allelic loss at 10 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 46 (48%) of these tumors. Through detailed deletion mapping of tumors having partial or interstitial deletions, we identified a commonly deleted region at a 1‐cM interval, flanked by D16S519 and D16S3078 at 16p13.13, defining the location of a putative tumor suppressor gene for HCC. This region contains the gene for JAB (JAK‐binding protein), which is responsible for negative‐feedback regulation of the JAK‐STAT pathway induced by cytokine stimulation, raising the possibility that inactivation of this gene may participate in hepatocarcinogenesis via genetic and/or epigenetic changes.

Somatic mutation of the PTEN/MMAC1 gene in breast cancers with microsatellite instability

The extent to which microsatellite instability (MI) contributes to the etiology of breast cancer has not been established in any large-scale studies. We examined 528 samples of tumor DNA from patients with primary breast cancer for MI, using 14 polymorphic CA-repeat markers. The frequency of MI in these tumors was unexpectedly low (10/528, 1.9%). The ten MI+ tumors were analyzed for mutations in five potential target genes that contain simple repeat sequences (TGFBIIR, IGF2R, hMSH6, BAX and PTEN/MMAC1). A somatic insertion of an extra adenine in the (A)6 region at codon 321-323 (exon 8) of the PTEN/MMAC1 gene, leading to a frame-shift, was identified in one tumor. This observation represented the first documented instance of PTEN/MMAC1 alteration in a MI+ primary breast cancer.

New target region of allelic loss in hepatocellular carcinomas within a 1-cM interval on chromosome 6q23

BACKGROUND/AIMS Frequent allelic losses on the long arm of chromosome 16 in several types of human cancers have suggested that 16q harbors one or more genes that are important for suppressing tumorigenesis in the tissues in question. METHODS To identify the locations of putative tumor suppressor genes involved in hepatocellular carcinoma, we examined 96 primary hepatocellular carcinomas for their patterns of allelic loss at 18 microsatellite marker loci distributed along this chromosome arm. RESULTS Allelic loss at one or more loci was observed in 48 (50%) of these tumors. The highest frequency of loss of heterozygosity (42%) was observed with marker D6S311 on chromosome 6q23. Through detailed deletion mapping of tumors having partial or interstitial deletions, we identified two commonly deleted regions at 6q23 and at 6q26-27. CONCLUSIONS The common region at 6q23 lay within a 1-cM interval, flanked by D6S977 and D6S311. The previously documented deletion region that includes the M6P/IGF2R locus was confined to a 20-cM region at band 6q26-27 in our panel of tumors. The location we defined at 6q23 for a putative suppressor of hepatocellular carcinoma has not been reported before.

Silicon drain with channels along the sides for internal biliary stenting of hepaticojejunostomy in hepatic hilar malignancies.

Background:  We compared two types of stents in patients who underwent surgery for hepatic hilar malignancies.

Frequent Allelic Loss at 6q26-27 in Breast Carcinomas of the Solid-tubular Histologic Type

To characterize the effect that inactivation of a putative tumor suppressor gene on 6q appears to have on breast carcinogenesis, we examined loss of heterozygosity in 528 primary breast carcinomas with a polymorphic marker located at 6q26-27, a frequent target region of allelic loss in ovarian and breast cancers. Of the 56 informative tumors of the solid-tubular type, 29 (52%) showed allelic loss at 6q26-27; however, only 10 of 42 papillotubular carcinomas (23%) and 34 of 86 scirrhous carcinomas (39%) showed allelic loss (p=0.0215). These results are consistent with reported alterations at 6q26-27 in serous and mucinous types of ovarian cancers, in that they suggest that inactivation of one or more genes in that region may affect carcinogenic mechanisms in a histologic type-specific manner in neoplasms of the female reproductive organs.