Nucleotide variants of the cancer predisposing gene CDH1 and the risk of non-syndromic cleft lip with or without cleft palate

The CDH1 gene plays an important role during carcinogenesis and craniofacial morphogenesis. Germline mutations in this gene have been described in families presenting syndromic diffuse gastric cancer and orofacial clefts. The aim of this study was to evaluate the association between nucleotide variants of CDH1 and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Six single nucleotide polymorphisms (SNPs) of the CDH1 gene (rs16260, rs9929218, rs7186053, rs4783573, rs16958383, and rs1801552) were genotyped using the TaqMan SNP genotyping assays in 250 patients with NSCL/P and 540 controls from the Polish population. Comparison between patient and control groups showed that the CDH1 rs1801552 variant, under the assumption of recessive model, was associated with a two-fold decrease in the risk of NSCL/P (OR_{TT vs CT + CC} = 0.481, 95 % CI 0.281–0.824, p = 0.007). This association remained statistically significant even after the multiple testing correction. No significant associations with NSCL/P risk were found for the other five tested SNPs. We found a strong association between the cancer predisposing gene CDH1 and the risk of NSCL/P in the Polish population. This result, together with previous observations of co-occurrence of orofacial clefts and a variety of cancer types, suggests the need for replication studies testing rs1801552 in NSCL/P cohorts with a known cancer history.     

Sensitive quantification of mosaicism using high density SNP arrays and the cumulative distribution function

Medicine is rapidly applying exome and genome sequencing to the diagnosis and management of human disease. Somatic mosaicism, however, is not readily detectable by these means, and yet it accounts for a significant portion of undiagnosed disease. We present a rapid and sensitive method, the Continuous Distribution Function as applied to single nucleotide polymorphism (SNP) array data, to quantify somatic mosaicism throughout the genome. We also demonstrate application of the method to novel diseases and mechanisms.     

Folate and choline metabolism gene variants and development of uterine cervical carcinoma

ObjectiveIt has been reported that aberrant DNA methylation can be associated with HPV infection and cervical tumorigenesis. The aim of this study was to evaluate the possibility that polymorphic variants of genes that may affect DNA methylation status are associated with the risk of cervical cancer in the Polish population.Design and methodEmploying PCR-RFLPs and HRM analyses, we examined the prevalence of BHMT Arg239Gln (rs3733890), MTR Asp919Gly (rs1805087), MTHFR Ala222Val (rs1801133), MTHFD1 Arg653Gln (rs2236225) and MTRR Ile22Met (rs1801394) genotypes and alleles in patients with advanced cervical cancer (n = 124) and controls (n = 168).ResultsThe odds ratio (OR) for BHMT Gln/Gln genotype was 0.433 (95% CI = 0.1780–1.054; p = 0.0602). The OR for patients having the BHMT Arg/Gln or Gln/Gln genotypes was 0.579 (95% CI = 0.3622–0.924; p = 0.0216). We also observed a significantly higher frequency of the BHMT 239Gln allele in controls than in patients, p = 0.0165. The genotype and allele frequencies of the MTR Asp919Gly, MTHFR Ala222Val, MTHFD1 Arg653Gln and MTRR Ile22Met gene variants did not display statistical differences between patients with cervical cancer and controls. We also did not find a significant association between the distribution of any genotypes or alleles and cancer characteristics.ConclusionOur results might suggest the protective role of the BHMT 239Gln variant in cervical cancer incidence.     

Breast cancer in a case of Shwachman Diamond syndrome

Shwachman Diamond syndrome (SDS) is a rare inherited bone marrow failure syndrome (IBMFS) characterized by neutropenia, exocrine pancreatic dysfunction, and cancer predisposition. Patients are at risk for myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) but, unlike other IBMFS, there have been no reported cases of solid tumors. We report a novel case of a solid tumor in a patient with SDS and biallelic mutations in the Shwachman Bodian Diamond Syndrome gene (SBDS). Whether the development of breast cancer in this patient is due to SDS or an isolated case due to unknown factors requires further study. Pediatr Blood Cancer 2012; 59: 945–946. © 2011 Wiley Periodicals, Inc.     

High‐resolution array CGH of metanephric adenomas: lack of DNA copy number changes

Szponar A, Yusenko M V & Kovacs G
(2010) Histopathology 56, 212–216 High‐resolution array CGH of metanephric adenomas: lack of DNA copy number changes Aims: Previous karyotyping and fluorescence in situ hybridization analysis of metanephric adenomas (MAs) has yielded controversial data. The aim of this study was to detect small genomic alterations, if any, specific to MAs by applying high‐resolution oligoarrays. Methods and results: DNA extracted from paraffin blocks of six metanephric adenomas was hybridized onto Agilent oligoarrays with ～43 000 in situ synthesized 60‐mer oligonucleotide probes that span coding and non‐coding sequences with an average spatial resolution of ～35 kb. None of the metanephric adenomas showed DNA copy number changes. To confirm our results, DNA extracted from the paraffin block of a chromophobe renal cell carcinoma (RCC) was simultaneously hybridized to one of the four arrays on the same slides as an internal control. The chromophobe RCC showed loss of several chromosomes but no alteration was seen in MAs. We have confirmed the negative results by dye‐swap and sex mismatch hybridization experiments. Conclusions: Our high‐resolution oligoarray analysis indicates that metanephric adenomas lack DNA copy number alterations. This finding may help to differentiate between metanephric adenomas from Wilms’ tumour and papillary renal cell adenoma with overlapping phenotype.     

Maternal MTR genotype contributes to the risk of non-syndromic cleft lip and palate in the Polish population

The aetiology of non-syndromic cleft lip with or without cleft palate (CL/P) is very complex. It has been shown that polymorphic variants of genes encoding key proteins of folate and methionine metabolism might be important maternal risk factors of having a child with this craniofacial anomaly. Therefore, in our study, mothers with CL/P children as well as control mothers were examined for prevalence of polymorphisms of genes that encode methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), 5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase and 10-formyltetrahydrofolate synthetase (MTHFD1) and reduced folate carrier 1 (RFC1). We observed that there were no statistical differences in allele and genotype frequencies of MTHFR c.677C>T, MTHFD1 c.1958G>A and RFC1 c.80G>A between mothers who had children with CL/P and control mothers. However, mothers with MTR c.2756AG or GG genotype displayed a 2.195-fold increased risk of having a child with CL/P (95% CI 1.189–4.050, p = 0.011). The mechanism by which polymorphic transition of MTR gene might increase the maternal risk of having CL/P progeny is unknown. Our observations are consistent with a significant role of the methyl cycle in the development of craniofacial structures in humans.