Refinement and delineation of the breakpoint regions of a chromosome 1;22 translocation in a patient with Costello syndrome*

Altered plasma levels of lipids and lipoproteins, obesity, hypertension, and diabetes are major risk factors for atherosclerotic cardiovascular disease. To identify genes that affect these traits and disorders, we looked for association between markers in candidate genes (apolipoprotein AII (apo AII), apolipoprotein AI‐CIII‐AIV gene cluster (apo AI‐CIII‐AIV), apolipoprotein E (apo E), cholesteryl ester transfer protein (CETP), cholesterol 7α‐hydroxylase (CYP7a), hepatic lipase (HL), and microsomal triglyceride transfer protein (MTP)) and known risk factors (triglycerides (Tg), total cholesterol (TC), apolipoprotein AI (apo AI), apolipoprotein AII (apo AII), apolipoprotein B (apo B), body mass index (BMI), blood pressure (BP), leptin, and fasting blood sugar (FBS) levels.) A total of 1,102 individuals from the Pacific island of Kosrae were genotyped for the following markers: Apo AII/MspI, Apo CIII/SstI, Apo AI/XmnI, Apo E/HhaI, CETP/TaqIB, CYP7a/BsaI, HL/DraI, and MTP/HhpI. After testing for population stratification, family‐based association analysis was carried out. Novel associations found were: 1) the apo AII/MspI with apo AI and BP levels, 2) the CYP7a/BsaI with apo AI and BMI levels. We also confirmed the following associations: 1) the apo AII/MspI with Tg level; 2) the apo CIII/SstI with Tg, TC, and apo B levels; 3) the Apo E/HhaI E2, E3, and E4 alleles with TC, apo AI, and apo B levels; and 4) the CETP/TaqIB with apo AI level. We further confirmed the connection between the apo AII gene and Tg level by a nonparametric linkage analysis. We therefore conclude that many of these candidate genes may play a significant role in susceptibility to heart disease. © 2002 Wiley‐Liss, Inc.     

Molecular alterations of Ras‐Raf‐mitogen‐activated protein kinase and phosphatidylinositol 3‐kinase‐Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur,Malaysia

Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3‐kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real‐time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well‐differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki‐67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.     

Multiple and bilateral kidney tumors with clear cells of three different histotypes: A case report with clinicopathologic and molecular study

We describe a rare multicentric neoplastic disease arising bilteraly in the kidney. The patient was a 70‐year‐old man, who, during a period of 3 years, was treated for five independent tumors of three histotypes (three multilocular cystic clear cell renal cell neoplasms of low malignant potential, one clear cell renal cell carcinoma, and one clear cell papillary renal cell carcinoma, respectively). Pathologic diagnosis of the reported tumors was confirmed by immunohistochemical analyses, including CD10, CA IX, CK7, AMACR/RACEMASE, and 34 beta E12. Molecular detection of KRAS, BRAF, NRAS, PIK3CA, ALK, ERBB2, DDR2, MAP2K1, RET, and EGFR gene mutational analysis was also performed in all tumors.     

Tandem pore domain K+‐channel TASK‐3 (KCNK9) and idiopathic absence epilepsies

Recently, the gene coding for the tandem pore domain K⁺‐channel TASK‐3 (KCNK9) has been localized to the chromosomal region 8q24. Because mutations in ion channel genes have been recognized as an important factor in the etiology of abnormal neuronal excitability, TASK‐3 is an interesting candidate gene for epilepsies linked to 8q24. We therefore performed a mutation analysis of the TASK‐3 gene in 65 patients with childhood and juvenile absence epilepsy. Only one silent nucleotide exchange (636C/T) was detected in exon 2 of the TASK‐3 coding region. No evidence for an allelic association was found between the exon 2 polymorphism and absence epilepsy. Accordingly, genetic variation of the TASK‐3 coding region does not play a major role in the etiology of idiopathic absence epilepsies. © 2002 Wiley‐Liss, Inc.     

Getting comfortable with RH blood group system terminologies and databases

The RH blood group system is the most important protein blood group system. Due to the high interest, often discoveries occurred in parallel and different groups used different nomenclatures. ISBT overtook the task to create nomenclatures both for antigens and alleles. Nevertheless, knowledge of internet resources is important to find the way among these alleles. Both general resources such as RESPIRE and gnomAD, allele‐oriented resource such as bloodantigens, erythrogene and HGMDB as well as dedicated resources such as the RHCE allele listing and the Human RhesusBase are presented.     

Endometrial stromal sarcoma – the new genetic paradigm

Endometrial stromal sarcoma (ESS) is a gynaecological sarcoma that is composed of cells that resemble those of proliferative‐phase endometrial stroma. The 2014 World Health Organization tumour classification system separates ESS into low‐grade and high‐grade types, which are histologically, genetically and clinically distinct from undifferentiated uterine sarcoma (UUS). Low‐grade ESSs frequently contain chromosomal rearrangements that result in JAZF1–SUZ12 fusion or equivalent genetic fusions. Although most low‐grade ESSs show classic histological features that closely resemble those of proliferative‐phase endometrial stroma, there are several histological variants that are associated with the same genetic fusions as seen in the classic type. High‐grade ESS is defined by the presence of YWHAE–NUTM2A/B (YWHAE–FAM22A/B) fusions. High‐grade ESSs are clinically more aggressive than low‐grade ESSs, but are associated with a lower mortality rate than UUSs. The histological and immunophenotypic features of these different types of ESS, and their diagnostic considerations, are the subjects of this review.     

Mutation screening and transmission disequilibrium study of ATP10C in autism

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11‐q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11‐q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15‐associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5′ flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family‐based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5′ flanking region and intron 2 splicing region may be evaluated in further studies. © 2002 Wiley‐Liss, Inc.