Some Molecular and Clinical Aspects of Genetic Predisposition to Malignant Melanoma and Tumours of Various Site of Origin

Based on epidemiological data we can assume that at least some malignant melanoma (MM) and breast cancer cases can be caused by the same genetic factors. CDKN2A, which encodes the p16 protein, a cyclin-dependent kinase inhibitor suppressing cell proliferation, is regarded as a major melanoma susceptibility gene and the literature has also implicated this gene in predisposition to breast cancer. Genes also known to predispose to MM include XPD and MC1R. We studied CDKN2A/ARF, XPD and MC1R for their associations with melanoma and breast cancer risk in Polish patients and controls. We found that CDKN2A and ARF do not contribute significantly to either familial melanoma or malignant melanoma within the context of a cancer familial aggregation of disease with breast cancer. However, the common variant of the CDKN2A gene A148T, previously regarded as non-pathogenic, may predispose to malignant melanoma, early-onset breast cancer and lung cancer. Compound carriers of common XPD variants may be at slightly increased risk of breast cancer or late–onset malignant melanoma. Common recurrent variants of the MC1R gene (V60L, R151C, R163Q and R160W) may predispose to malignant melanoma. In general, the establishment of surveillance protocols proposed as an option for carriers of common alterations in CDKN2A, XPD or MC1R variants requires additional studies. It is possible that missense variants of genes for which truncating mutations are clearly pathogenic may also be deleterious, but with reduced penetrance. This may be overlooked unless large numbers of patients and controls are studied. A registry that includes 2000 consecutive breast cancer cases, 3500 early onset breast cancer patients, 500 unselected malignant melanoma and over 700 colorectal cancer patients has been established in the International Hereditary Cancer Centre and can contribute to these types of large association studies

Mutations in the von Hippel-Lindau Tumour Suppressor Gene in Central Nervous System Hemangioblastomas

Central nervous system hemangioblastomas (cHAB) are rare tumours which most commonly arise in the cerebellum. Most tumours are sporadic, but as many as one third of cHABs occur in the course of the hereditary disorder - von Hippel-Lindau disease (VHL). In order to diagnose new VHL families in Poland we performed sequencing of the entire VHL gene in archival material (paraffin embedded hemangioblastoma tissues) in a large series of 203 unselected patients with cHAB. VHL gene mutations were detected in 70 (41%) of 171 tumour samples from which DNA of relatively good quality was isolated. We were able to obtain blood samples from 19 of mutation positive cases. Eight (42%) of these harboured germline mutations in persons from distinct undiagnosed VHL families

Exploring the Link between Germline and Somatic Genetic Alterations in Breast Carcinogenesis

Recent genome-wide association studies (GWASs) have identified candidate genes contributing to cancer risk through low-penetrance mutations. Many of these genes were unexpected and, intriguingly, included well-known players in carcinogenesis at the somatic level. To assess the hypothesis of a germline-somatic link in carcinogenesis, we evaluated the distribution of somatic gene labels within the ordered results of a breast cancer risk GWAS. This analysis suggested frequent influence on risk of genetic variation in loci encoding for “driver kinases” (i.e., kinases encoded by genes that showed higher somatic mutation rates than expected by chance and, therefore, whose deregulation may contribute to cancer development and/or progression). Assessment of these predictions using a population-based case-control study in Poland replicated the association for rs3732568 in EPHB1 (odds ratio (OR) = 0.79; 95% confidence interval (CI): 0.63–0.98; Ptrend = 0.031). Analyses by early age at diagnosis and by estrogen receptor α (ERα) tumor status indicated potential associations for rs6852678 in CDKL2 (OR = 0.32, 95% CI: 0.10–1.00; Precessive = 0.044) and rs10878640 in DYRK2 (OR = 2.39, 95% CI: 1.32–4.30; Pdominant = 0.003), and for rs12765929, rs9836340, rs4707795 in BMPR1A, EPHA3 and EPHA7, respectively (ERα tumor status Pinteraction<0.05). The identification of three novel candidates as EPH receptor genes might indicate a link between perturbed compartmentalization of early neoplastic lesions and breast cancer risk and progression. Together, these data may lay the foundations for replication in additional populations and could potentially increase our knowledge of the underlying molecular mechanisms of breast carcinogenesis

The 3020insC Allele of NOD2 Predisposes to Cancers of Multiple Organs

The NOD2 gene has been associated with susceptibility to Crohn's disease and individuals with Crohn's disease are at increased risk for cancer at a number of organ sites. We studied the association between the 3020insC allele of the NOD2 gene and cancer among 2604 cancer patients and 1910 controls from Poland. Patients were diagnosed with one of twelve types of cancer in the Szczecin region between 1994 and 2004. Significant associations were found for colon cancer (OR = 1.8; 95% CI 1.2 to 2.6), for lung cancer (OR = 1.7; 95% CI = 1.1 to 2.5) and for ovarian cancer (OR = 1.6; 95% CI 1.1 to 2.3). In addition, a significant association was found for early-onset laryngeal cancer (OR = 2.9; 95% CI 1.4 to 6.2) and for breast cancer in the presence of DCIS (OR = 2.1 95% CI = 1.2 to 3.6). The NOD2 3020insC allele is relatively common (in Poland 7.3% of individuals) and may be responsible for an important fraction of cancer cases. We estimate that the lifetime cancer risk among carriers of this allele is 30% higher than that of individuals with two wild-type alleles