Terumi Taniguchi

Promoter Hypermethylation in Cancer Silences LDHB, Eliminating Lactate Dehydrogenase Isoenzymes 1-4

Lactate dehydrogenase (LD; EC 1.1.1.27) isoenzymes are formed by the random combination of two different subunits encoded by two structurally distinct genes, LDHA and LDHB (1). Expression of mammalian LDHA and LDHB is regulated during development and is tissue specific (2)(3); therefore, alterations in the serum LD isoenzyme pattern serve as indicators of pathologic involvement and cancer development (3). In cancer patients, LD isoenzymes originate primarily from tumor tissues and partly from healthy tissues damaged by tumor expansion and invasion. Different phenotypes may originate from expression regulation by other regulatory genes and by the alteration of LDHA or LDHB caused by mutation; chromosomal deletion; duplication, or increase of copy number; and promoter methylation. The increase in LD1 correlates with the total copy number of the short arm of chromosome 12 in tumor cells (4). Recently, we found a high proportion of LD1 in a patient with retinoblastoma. The unique LD isoenzyme pattern was attributable to transcriptional silencing by promoter hypermethylation of LDHA (5). In mammals, DNA methylation usually occurs at CpG dinucleotides, which are cytosines located 5′ of guanines. Methylation is known to play a role in regulating gene expression during cell development, X chromosome inactivation, genomic imprinting, and carcinogenesis (6)(7). In neoplastic cells, some CpG islands in the promoter region that are usually unmethylated become aberrantly methylated, and this leads to transcriptional silencing. Therefore, an epigenetic event is thought to be one mechanism for the inactivation of tumor suppressor genes (8). Human LDHB has a CpG-rich region in its promoter that is similar to that of human LDHA and LDHC (9). We found that five cancer cell lines had only LDHA mRNA (10). Most gastrointestinal cancer patients had electrophoretically slow-moving isoenzymes and the LD-A subunit in their sera (3). We predicted that this …

Investigation of unexpected serum CA19-9 elevation in Lewis-negative cancer patients

Background Cancer patients with a Lewis (a−b−) phenotype have no carbohydrate antigen 19-9 (CA19-9) in their serum. However, we found a small but distinct elevation in the serum CA19-9 level in three cancer patients with the Lewis-negative phenotype. Here, we investigated the reason of such phenomena. Methods Six cancer patients with a Lewis-negative phenotype were selected by very low CA19-9 concentrations: three showed a small elevation (Group A) and the other three showed no elevation (Group B) in the serum CA19-9. We investigated the difference by analyzing the Lewis/Secretor genotypes. Results All of the six patients with a Le (a−b−) phenotype were genuine Le-negative genotypes: four individuals were homozygous for le1 (le59,508 ), one patient was compound heterozygous for le1 (le59,508 ) and le2 (le59,1067 ) and one patient was compound heterozygous for le1 and le202,314 . As for the Secretor gene, the three patients in Group B were homozygous for Se2 (one patient) or compound heterozygous for Se2 and sej (two patients), while the patients in Group A were all homozygous for sej genotypes. Conclusions Even genuinely Le-negative patients, who genetically lack the Le enzyme and theoretically never produce CA19-9, occasionally show a slight increase in serum CA19-9 level when they are homozygous for Se-negative genotypes and suffer from advanced cancer with overproduction of glycans as precursors of CA19-9. Although such cases are not frequent, we should be acquainted with the correlation between serum CA19-9 values and genotypes of Lewis and Secretor genes.

DNA methylation analysis in malignant pheochromocytoma and paraganglioma

Highlights • We tried to establish the epigenetics of malignant transformation in PCC/PGLs.• Benign and malignant PCC/PGLs were examined using whole genomic methylation analysis.• Selected candidate CpGs were narrowed down by analysis of individual genomic regions.• Two were left as the final candidates, related to ACSBG1 and MAST1 respectively.• Epigenetics in these genes might be involved in malignant transformation of PCC/PGLs.