Aberrant methylation of H19-DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith-Wiedemann syndrome.

Gain of methylation (GOM) at the H19-differentially methylated region (H19-DMR) is one of several causative alterations in Beckwith-Wiedemann syndrome (BWS), an imprinting-related disorder. In most patients with epigenetic changes at H19-DMR, the timing of and mechanism mediating GOM is unknown. To clarify this, we analyzed methylation at the imprinting control regions of somatic tissues and the placenta from two unrelated, naturally conceived patients with sporadic BWS. Maternal H19-DMR was abnormally and variably hypermethylated in both patients, indicating epigenetic mosaicism. Aberrant methylation levels were consistently lower in placenta than in blood and skin. Mosaic and discordant methylation strongly suggested that aberrant hypermethylation occurred after implantation, when genome-wide de novo methylation normally occurs. We expect aberrant de novo hypermethylation of H19-DMR happens to a greater extent in embryos than in placentas, as this is normally the case for de novo methylation. In addition, of 16 primary imprinted DMRs analyzed, only H19-DMR was aberrantly methylated, except for NNAT DMR in the placental chorangioma of Patient 2. To our knowledge, these are the first data suggesting when GOM of H19-DMR occurs.

Cancer Prevalence in Aichi, Japan for 2012: Estimates Based on Incidence and Survival Data from Population-Based Cancer Registry

Background: Cancer is the leading cause of death among both men and women in Japan. Monitoring cancer prevalence is important because prevalence data play a critical role in the development and implementation of health policy. We estimated cancer prevalence in 2012 based on cancer incidence and 5-year survival rate in Aichi Prefecture using data from a population-based cancer registry, the Aichi Cancer Registry, which covers 7.4 million people. Methods: The annual number of incident cases between 2008 and 2012 was used. Survival data of patients diagnosed in 2006­2008 and followed up until the end of 2012 were selected for survival analysis. Cancer prevalence was estimated from incidence and year-specific survival probabilities. Cancer prevalence was stratified by sex, cancer site (25 major cancers), and age group at diagnosis. Results: The estimated prevalence for all cancers in 2012 was 68,013 cases among men, 52,490 cases among women, with 120,503 cases for both sexes. Colorectal cancer was the most incident cancer with 6,654 cases, accounting for 16.0% of overall incident cases, followed by stomach cancer with 5,749 cases (13.8%) and lung cancer with 5,593 cases (13.4%). Prostate cancer was the most prevalent among men, accounting for 21.5%, followed by colorectal and stomach cancers. Breast cancer was the most prevalent among women, accounting for 28.6%, followed by colorectal, stomach, and uterine cancers. Conclusion: This study provides cancer prevalence data that could serve as useful essential information for local governments in cancer management, to carry out more practical and reasonable countermeasures for cancer.

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome.

Perlman syndrome is a rare, autosomal recessive overgrowth disorder. Recently, the deletion of exon 9 and other mutations of the DIS3L2 gene have been reported in patients; however, the mechanism behind this deletion is still unknown. We report the homozygous deletion of exon 9 of DIS3L2 in a Japanese patient with Perlman syndrome. We identified the deletion junction, and implicate a non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements as the causative mechanism. Furthermore, the deletion junctions were different between the paternal and maternal mutant alleles, suggesting the occurrence of two independent NAHR events in the ancestors of each parent. The data suggest that the region around exon 9 might be a hot spot of L1-mediated NAHR.

Engraftment and dissemination of T lymphocytes from primary haemophagocytic lymphohistiocytosis in scid mice.

Although primary haemophagocytic lymphohistiocytosis (HLH) is a genetic disorder of T lymphocytes, it remains unclear why T lymphocytes of primary HLH patients preferentially infiltrate the central nervous system and peripheral blood, in addition to the reticuloendothelial systems. We engrafted Herpesvirus saimiri (HVS)-immortalized T-lymphocyte lines established from primary HLH patients into severe combined immunodeficient (scid) mice and examined their capacity to infiltrate mouse organs. A diffuse infiltration of human T lymphocytes was detected in each organ of scid mice treated with 1 x 10(6) T lymphocytes from all four primary HLH patients assessed, whereas no infiltration of T lymphocytes from healthy individuals was observed in any organ. The infiltration of T lymphocytes was mainly observed in the lung, brain and peripheral blood, in association with haemophagocytosis. These cells were positive for HLA-DR, CD3 and either CD8 or CD4, but negative for CD68. Certain markers of proliferation and apoptotic activities were highly positive in these cells. There was no difference between the infiltration pattern of T lymphocytes of primary HLH patients with a perforin deficiency and those without. By Southern blot analysis, T lymphocytes infiltrating mouse organs were observed to be polyclonal. These findings suggest that our murine model implementing HVS-immortalized human T lymphocytes is suitable to clarify the pathogenesis of primary HLH.