The first case report of polymerase proofreading-associated polyposis in POLD1 variant, c.1433G>A p.S478N, in Japan.

Polymerase proofreading-associated polyposis, caused by germline variants in the exonuclease domains of POLD1 and POLE, is a dominantly inherited rare condition characterized by oligo-adenomatous polyposis and increased risk of colorectal cancer, endometrial cancer and brain tumours. We report the first Japanese case of polymerase proofreading-associated polyposis carrying a POLD1 variant. The proband was a Japanese woman who had undergone resections of early colorectal carcinomas repeatedly and a hysterectomy with bilateral oophorectomy for endometrial cancer, all of which were diagnosed within 2 years after the first colectomy at 49 year old. Colonoscopic examinations demonstrated at least 14 non-cancerous polypoid lesions, some of which were histologically confirmed to be adenoma. Multigene panel sequencing identified a missense variant in POLD1 (c.1433G>A). Although her relatives did not undergo genetic testing, her father and paternal grandfather died of brain tumours at 53 and ~30 years of age, respectively.

Prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancers in the Japanese population have scarcely been investigated. METHODS: Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary epithelial ovarian cancers in patients who underwent oophorectomy at our institution between April 2005 and September 2014. Genetic and/or epigenetic alterations of the mismatch repair genes were investigated in patients with loss of any mismatch repair proteins in the tumor. RESULTS: There were 305 patients with a median age of 54 years (range, 18-83 years). Loss of expression in the ovarian tumor of one or more mismatch repair proteins was observed in 3 of the 305 patients (0.98%): 2 patients MLH1/PMS2 loss and 1 patient showed MSH2/MSH6 loss. Genetic testing of these three patients failed to reveal any pathogenic germline mutations of MLH1 or MSH2. One patient with MLH1/PMS2 loss showed hypermethylation of the promoter region of MLH1. Somatic mutations were found in each of the alleles of MLH1 (c.545dupG and deletion of exons 2-19) in the other patient with MLH1/PMS2 loss. In the patient with MSH2/MSH6 loss, two somatic mutations were detected in MSH2 (c.229_230delAG and c.1861C>T), although we could not determine whether these mutations were biallelic or not. CONCLUSIONS: The prevalence of defective mismatch repair epithelial ovarian cancer in the Japanese hospital-based population was extremely low. Molecular mechanism involved in such defective mismatch repair ovarian cancers seems to be epigenetic events through MLH1 promotor hypermethylation or somatically mutated mismatch repair genes without germline mismatch repair mutation.

Long noncoding RNA variations in cardiometabolic diseases.

Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus, dyslipidemia, hypertension and abdominal obesity. This cluster of abnormalities individually and interdependently leads to atherosclerosis and CVD morbidity and mortality. In the past decade, genome-wide association studies (GWASs) have identified a series of cardiometabolic disease-associated variants that can collectively explain a small proportion of the variability. Intriguingly, the susceptibility variants imputed from GWASs usually do not reside in the coding regions, suggesting a crucial role of the noncoding elements of the genome. In recent years, emerging evidence suggests that noncoding RNA (ncRNA) is functional for physiology and pathophysiology of human diseases. These include microRNAs and long noncoding RNAs (lncRNAs) that are now implicated in human diseases. The ncRNAs can interact with each other and with proteins, to interfere gene expressions, leading to the development of many human disorders. Although evidence suggests the functional role of lncRNAs in cardiometabolic traits, the molecular mechanisms of gene regulation underlying cardiometabolic diseases remain to be better defined. Here, we summarize the recent discoveries of lncRNA variations in the context of cardiometabolic diseases.

Associations between the CDKN2A/B, ADTRP and PDGFD polymorphisms and the development of coronary atherosclerosis in Japanese patients.

AIM: Genome-wide association studies have identified a series of susceptibility loci for coronary artery disease(CAD). The present study attempted to replicate the results for eight of these loci, CDKN2A/B(rs1333049), ADTRP(rs6903956), PDGFD(rs974819), TCF21(rs12190287), COL4A1-A2(rs4773144), HHIPL1(rs2895811), ADAMTS7(rs4380028) and UBE2Z(rs46522), in patients with pathologically defined atherosclerosis of the coronary arteries. METHODS: Autopsy cases of elderly Japanese subjects were enrolled in the JG-SNP study(n=1,536). Polymorphisms were genotyped, and their associations with the coronary stenosis index(CSI) and incidence of pathological myocardial infraction(MI) were investigated. The potential combinatorial effects of the susceptibility loci were also assessed. RESULTS: Among the eight loci tested, three exhibited signs of positive associations. CDKN2A/B showed the most robust associations with CSI and MI(p=0.007 and OR=1.843, 95% CI 1.293-2.629, p=0.001, for CC＋CG vs. GG). In addition, ADTRP demonstrated associations with CSI and MI, although the risk allele was opposite from that observed in the original report(p=0.008 and OR=1.652, 95% CI 1.027-2.656, p=0.038 for GG vs. AA＋AG). Meanwhile, PDGFD displayed a suggestive association with CSI in women, but not men(p=0.023). CDKN2A/B and ADTRP were also found to be significantly associated with the severity of the CSI in a case-control setting. The cumulative risk allele counting of CDKN2A/B, ADTRP and PDGFD indicated an increased number of risk alleles to be associated with a higher CSI(p=4.61E-05). CONCLUSIONS: The present study confirmed the association between CDKN2A/B and CAD and identified a different associated risk allele of ADTRP. PDGFD was found to exhibit a gender-specific association with CAD. The combination of multiple risk alleles may be associated with a higher risk of CAD.