A single founder allele of the CHEK2 gene has been associated with predisposition to breast and prostate cancer in North America and Europe. The CHEK2 protein participates in the DNA damage response in many cell types and is therefore a good candidate for a multisite cancer susceptibility gene. Three founder alleles are present in Poland. Two of these result in a truncated CHEK2 protein, and the other is a missense substitution of an isoleucine for a threonine. We ascertained the prevalence of each of these alleles in 4,008 cancer cases and 4,000 controls, all from Poland. The majority of the common cancer sites were represented. Positive associations with protein-truncating alleles were seen for cancers of the thyroid (odds ratio [OR] 4.9; P=.0006), breast (OR 2.2; P=.02), and prostate (OR 2.2; P=.04). The missense variant I157T was associated with an increased risk of breast cancer (OR 1.4; P=.02), colon cancer (OR 2.0; P=.001), kidney cancer (OR 2.1; P=.0006), prostate cancer (OR 1.7; P=.002), and thyroid cancer (OR 1.9; P=.04). The range of cancers associated with mutations of the CHEK2 gene may be much greater than previously thought.

The population frequencies of the CDKN2A common variants remain undetermined. In Poland, there is a common variant of the CDKN2A: an alanine to threonine substitution (A148T), which has been detected in other populations. We have recently showed that it is significantly overrepresented among Polish melanoma patients when compared to general population. Herein, we ascertained the prevalence of the A148T variant in 3,583 unselected cancer cases and 3,000 random control subjects from the same Polish population. We evaluated eleven different malignancies, representing the majority of all common cancer sites. Positive association with A148T variant was observed for lung cancer (OR, 2.0; p 5 0.0052). A similar trend, although nonsignificant after the Bonferroni correction, was observed for colorectal cancer (OR, 1.5; p 5 0.5499). These results suggest that A148T variant may be associated with a multi-organ cancer risk in the Polish population. ' 2006 Wiley-Liss, Inc.Key words: CDKN2A; A148T variant; cancer risk The CDKN2A (OMIM 60160) is a tumor-suppressor gene that is regarded as a major malignant melanoma (MM) susceptibility gene. 1 The p16 protein is thought to be a cyclin-dependent kinase inhibitor that suppresses cell proliferation. 2 Thus far CDKN2A has been strongly implicated in predispositions to MM and pancreatic carcinoma. 3 Data from the literature indicate CDKN2A as a common MM/breast cancer susceptibility gene. 4 There is also some evidence to indicate a possible association between CDKN2A and head and neck cancer, 5 respiratory malignancies 6 and laryngeal cancer. 7 The p16 protein is expressed in a wide range of tissues, and the full range of cancers associated with CDKN2A mutations has yet to be determined.In Poland, there is one common variant of CDKN2A-an alanine to threonine substitution at codon 148 (A148T)-which has been estimated to be present in approximately 3-3.5% of the population. 8,9 Functional studies suggest that this variant is a polymorphism, which appears to have no major effect on p16 function. 10,11 Nevertheless, the A148T change has been found to be overrepresented in melanoma kindreds (3%) in comparison to the general population (1.8%). 12 In our population-based study, we found it to be associated with a significant increase in the risk of melanoma development (OR, 2.5; p 5 0.0003). We also observed that the A148T heterozygous carrier population was more likely to have a first-degree relative with cancer of any type compared to the non-carrier population: 57% versus 36%, respectively. 13 In our latest study, we reported significant overrepresentation of the A148T among breast cancer patients. 14 To determine whether this A148T change can be associated with an increased risk of malignancies at different sites of origin, we genotyped a series of 3,583 unselected cancer cases and compared the frequency of the change observed in this population to 3,000 controls in Poland. In this study, we examined eleven types of cancer, including seven of the most common in Poland, which represen...

Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes  and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.