Localization of a novel melanoma susceptibility locus to 1p22

Over the past 20 years, the incidence of cutaneous malignant melanoma (CMM) has increased dramatically worldwide. A positive family history of the disease is among the most established risk factors for CMM; it is estimated that 10% of CMM cases result from an inherited predisposition. Although mutations in two genes, CDKN2A and CDK4, have been shown to confer an increased risk of CMM, they account for only 20%-25% of families with multiple cases of CMM. Therefore, to localize additional loci involved in melanoma susceptibility, we have performed a genomewide scan for linkage in 49 Australian pedigrees containing at least three CMM cases, in which CDKN2A and CDK4 involvement has been excluded. The highest two-point parametric LOD score (1.82; recombination fraction [theta] 0.2) was obtained at D1S2726, which maps to the short arm of chromosome 1 (1p22). A parametric LOD score of 4.65 (theta=0) and a nonparametric LOD score of 4.19 were found at D1S2779 in nine families selected for early age at onset. Additional typing yielded seven adjacent markers with LOD scores >3 in this subset, with the highest parametric LOD score, 4.95 (theta=0) (nonparametric LOD score 5.37), at D1S2776. Analysis of 33 additional multiplex families with CMM from several continents provided further evidence for linkage to the 1p22 region, again strongest in families with the earliest mean age at diagnosis. A nonparametric ordered sequential analysis was used, based on the average age at diagnosis in each family. The highest LOD score, 6.43, was obtained at D1S2779 and occurred when the 15 families with the earliest ages at onset were included. These data provide significant evidence of a novel susceptibility gene for CMM located within chromosome band 1p22.     

Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma

Germline mutations of the cell-cycle regulator p16 (also called "CDKN2A") in kindreds with melanoma implicate this gene in susceptibility to malignant melanoma. Most families with familial atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden dermatology clinic share the same p16-inactivating deletion (p16-Leiden). Incomplete penetrance and variable clinical expression suggest risk modification by other genetic and/or environmental factors. Variants of the melanocortin-1 receptor (MC1R) gene have been shown to be associated with red hair, fair skin, and melanoma in humans. Carriers of the p16-Leiden deletion in Dutch families with FAMMM show an increased risk of melanoma when they also carry MC1R variant alleles. The R151C variant is overrepresented in patients with melanoma who are from families with the p16-Leiden mutation. Although some of the effect of the R151C variant on melanoma risk may be attributable to its effect on skin type, our analyses indicate that the R151C variant contributes an increased melanoma risk even after statistical correction for its effect on skin type. These findings suggest that the R151C variant may be involved in melanoma tumorigenesis in a dual manner, both as a determinant of fair skin and as a component in an independent additional pathway.     

MC1R variation and melanoma risk in the Swedish population in relation to clinical and pathological parameters

The genetic background of cutaneous malignant melanoma (CMM) includes both germ line aberrations in high‐penetrance genes, like CDKN2A, and allelic variation in low‐penetrance genes like the melanocortin‐1 receptor gene, MC1R. Red‐hair colour associated MC1R alleles (RHC) have been associated with red hair, fair skin and risk of CMM. We investigated MC1R and CDKN2A variation in relation to phenotype, clinical factors and CMM risk in the Swedish population. The study cohort consisted of sporadic primary melanoma patients, familial melanoma patients and a control group. An allele‐dose dependent increase in melanoma risk for carriers of variant MC1R alleles (after adjusting for phenotype), with an elevated risk among familial CMM patients, was observed. This elevated risk was found to be significantly associated with an increased frequency of dysplastic nevi (DN) among familial patients compared to sporadic patients. MC1R variation was found to be less frequent among acral lentiginous melanomas (ALM) and dependent on tumour localisation. No association was found between CDKN2A gene variants and general melanoma risk. Two new variants in the POMC gene were identified in red haired individuals without RHC alleles.     

Reviews on sun exposure and artificial light and melanoma

Melanoma is the most common form of cancer among young adults aged 25-29 years and the second most common cancer in those aged 15-29 years. We reviewed all the evidence regarding risk factors for melanoma, looking in particular at childhood exposure to ultraviolet radiation (UV). UV radiation is clearly the predominant environmental and thus potentially modifiable risk factor for melanoma. All activities related to tan-seeking behaviour and history of sunburns were shown to be significantly associated to melanoma. Host factors, such as pigmentary characteristics, and genetic predisposition plays also an important role. UV exposure is not only due to the sun but also to indoor tanning devices that have been shown to lead to an elevated risk of melanoma. The strongest evidence for a link between artificial UV and melanoma is found among individuals who had their first exposure to indoor tanning before the age of 30: they have a 75% increase risk of developing melanoma than individuals who had no exposure to indoor tanning. Prevention is very important, especially for children and young adults, as childhood and adolescence are critical periods in the development of later melanoma. Indoor tanning is a widespread practice in most developed countries, particularly in Northern Europe and the USA. In the recent decades more and more people, especially teenagers and women, are exposed to substantially high radiant exposures of UV through artificial sources and these trends raised a considerable concern. In fact the International Agency for Research on Cancer concluded that the association between skin cancer and exposure to solar radiation and the use of UV-emitting tanning devices are causal. Interesting analyses carried out in Iceland showed that when interventions to discourage sunbed use were introduced the incidence of melanoma among women decreased. All this evidence encouraged many countries to introduce regulations on sunbed use to avoid exposure before the age of 18.     

Sunny Holidays before and after Melanoma Diagnosis Are Respectively Associated with Lower Breslow Thickness and Lower Relapse Rates in Italy

Background

Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort.

Methods

A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival.

Results

Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results.     

Synergistic effects of environmental risk factors and gene mutations in Parkinson's disease accelerate age-related neurodegeneration

As Parkinson's disease appears to be a multifactoral disorder, the use of animal models to investigate combined effects of genetic and environmental risk factors are of great importance especially in the context of aging which is the single major risk factor for the disorder. Here, we assessed the combined effects of neonatal iron feeding and environmental paraquat exposure on age-related nigrostriatal degeneration in transgenic mice expressing the A53T familial mutant form of human α-synuclein within these neurons. We report here that A53T α-synuclein mice exhibit greater susceptibility to paraquat. Increased oral intake of iron in the neonatal period leads to a progressive age-related enhancement of dopaminergic neurodegeneration associated with paraquat neurotoxicity. Furthermore, neurodegeneration associated with these combined genetic and environmental risk factors could be attenuated by systemic treatment with the bioavailable antioxidant compound EUK-189. These data suggest that environmental factors previously identified as contributors to neurodegeneration associated with sporadic Parkinson's disease may also be candidates for observed variations in symptoms and disease progression in monogenic forms and that this may mechanistically involve increased levels of oxidatively-induced post-translational nitration of α-synuclein.     

Environmental triggers of multiple sclerosis

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that develops in young adults with a complex genetic predisposition. Similar to other autoimmune disease, HLA-DR and -DQ alleles within the HLA class II region on chromosome 6p21 are by far the strongest risk-conferring genes. Less robust susceptibility effects have been reported for non-MHC related genetic variants. Improvements in the design of epidemiological studies helped to identify consistent environmental risk-associations such as the increased susceptibility for MS in individuals with a history of infectious mononucleosis, a symptomatic primary infection with the human γ-herpesvirus Epstein-Barr virus (EBV). Sun exposure and serum vitamin D levels are emerging non-infectious environmental risk factors that may have independent roles. The analysis of environmental effects will likely expand in the next few years and will allow for the generation of testable hypotheses as to how environmental insults interact with genetic factors to jointly determine the susceptibility to MS. Insights gained from these studies might facilitate the development of prevention strategies and more effective treatments for MS.     

Cloning of the human phospholipase A2 activating protein (hPLAP) gene on the chromosome 9p21 melanoma deleted region

Cutaneous malignant melanoma (CMM) is a common skin cancer. About 50% of CMM sporadic tumours have lost one copy of the chromosome 9p21 region. To identify genes involved in the initiation and/or progression of CMM we have characterised the 9p21 melanoma deleted region and screened the human expressed sequence tag (EST) databases (dbEST) to search for expressed genes. We have identified the gene that encodes the human orthologue of the rat phospholipase A2 activating protein (PLAP). PLAP was considered a potential candidate to be involved in malignant melanoma because it maps to the critical region for CMM and because the PLA2 gene has been identified as a modifier of the APC gene, responsible for the adenomatous polyposis phenotype in the mouse. PLAP encodes a protein of 738 amino acids and has a high DNA (90%) and protein (97%) sequence similarity with the rat and mouse PLAP protein. PLAP has a region of WD40 repeats in the amino-terminus, which allows us to include this protein in the superfamily of beta-transducin proteins. Northern blot hybridisation gave a fragment of 4.5 kb, with higher expression in heart compared to other tissues. PLAP was localised at chromosome 9p21, between marker AFM218xg11 and TEK. SSCP analysis of the coding region of PLAP revealed no variants in the studied samples, but one of six CMM samples analysed by RT-PCR showed specific inactivation of PLAP. Despite PLAP's important role in mediating several cellular responses and its localisation to the chromosome 9p21 region deleted in CMM, it is unlikely that point mutations or deletions in the coding region of PLAP are responsible for the initiation or progression of CMM. Further studies on PLAP inactivation should be performed to clarify its potential involvement in CMM.     

Acquired melanocytic nevi as risk factor for melanoma development. A comprehensive review of epidemiological data

Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus-prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.     

Genetic risk factors of venous thrombosis

Venous thrombosis, whose main clinical presentations include deep vein thrombosis and pulmonary embolism, represents a major health problem worldwide. Numerous conditions are known to predispose to venous thrombosis and these conditions are commonly referred to as risk indicators or risk factors. Generally accepted or "classically" acquired risk factors for venous thromboembolism include advanced age, prolonged immobilisation, surgery, fractures, use of oral contraceptives and hormone replacement therapy, pregnancy, puerperium, cancer and antiphospholipid syndrome. In addition to these well-established risk factors for venous thrombosis, several lines of evidence that have emerged over the past few decades indicate a role of novel genetic risk factors, mainly related to the haemostatic system, in influencing thrombotic risk. The most significant breakthrough has been the confirmation of the concept that inherited hypercoagulable conditions are present in a large proportion of patients with venous thromboembolic disease. These include mutations in the genes that encode antithrombin, protein C and protein S, and the factor V Leiden and factor II G20210 A mutations. Moreover, plasmatic risk indicators, such as hyperhomocysteinemia and elevated concentrations of factors II, VIII, IX, XI and fibrinogen, have also been documented. This extensive list of genetic and acquired factors serves to illustrate that a single cause of venous thrombosis does not exist and that this condition should be considered as a complex or multifactorial trait. Complex traits can be understood by assuming an interaction between different mutations in candidate susceptibility genes. The risk that is associated with each genetic defect may be relatively low in isolation but the simultaneous presence of several mutations may dramatically increase disease susceptibility. Moreover, environmental factors may interact with one or more genetic variations to add further to the risk. The analysis of genetic risk factors and plasmatic factors, together with private life style and environmental factors, has contributed significantly to our understanding of the genetic predisposition to venous thrombosis.     

Molecular epidemiology of hypospadias: review of genetic and environmental risk factors

Hypospadias is one of the most common congenital anomalies in the United States, occurring in approximately 1 in 125 live male births. It is characterized by altered development of the urethra, foreskin, and ventral surface of the penis. In this review, the embryology, epidemiology, risk factors, genetic predisposition, and likely candidate genes for hypospadias are described. Recent reports have identified increases in the birth prevalence of mild and severe forms of hypospadias in the United States from the 1960s to the present. Studies in consanguineous families and small case series have identified allelic variants in genes controlling androgen action and metabolism that cause hypospadias, but the relevance of these findings to the general population is unknown. Concern has also focused on whether exposure to endocrine disrupting chemicals (EDC) with antiandrogenic activity is the cause of this increase. Hypospadias is believed to have a multifactorial etiology in which allelic variants in genes controlling androgen action and metabolism predispose individuals to develop this condition. When genetic susceptibility is combined with exposure to antiandrogenic agents, a threshold is surpassed, resulting in the manifestation of this birth defect. A clear role for exposure to antiandrogenic environmental chemicals has yet to be established in the etiology of hypospadias, although results from laboratory animal models indicate that a number of environmental chemicals could be implicated. Molecular epidemiology studies that simultaneously examine the roles of allelic variants in genes controlling androgen action and metabolism, and environmental exposures are needed to elucidate the risk factors for these anomalies and the causes of the increased rate of hypospadias.     

Molecular Characterization of Melanoma Cases in Denmark Suspected of Genetic Predisposition

Both environmental and host factors influence risk of cutaneous melanoma (CM), and worldwide, the incidence varies depending on constitutional determinants of skin type and pigmentation, latitude, and patterns of sun exposure. We performed genetic analysis of CDKN2A, CDK4, BAP1, MC1R, and MITFp.E318K in Danish high-risk melanoma cases and found CDKN2A germline mutations in 11.3% of CM families with three or more affected individuals, including four previously undescribed mutations. Rare mutations were also seen in CDK4 and BAP1, while MC1R variants were common, occurring at more than twice the frequency compared to Danish controls. The MITF p.E318K variant similarly occurred at an approximately three-fold higher frequency in melanoma cases than controls. To conclude, we propose that mutation screening of CDKN2A and CDK4 in Denmark should predominantly be performed in families with at least 3 cases of CM. In addition, we recommend that testing of BAP1 should not be conducted routinely in CM families but should be reserved for families with CM and uveal melanoma, or mesothelioma.     

Complexities of cancer research: mouse genetic models

Cancer susceptibility is a complex interaction of an individual's genetic composition and environmental exposures. Huge strides have been made in understanding cancer over the past 100 yr, from recognition of cancer as a genetic disease, to identification of specific carcinogens, isolation of oncogenes, and recognition of tumor suppressors. A tremendous amount of knowledge has accumulated about the etiology of cancer. Cancer genetics has played a significant role in these discoveries. Analysis of high-risk familial cancers has led to the discovery of new tumor suppressor genes and important cancer pathways. These families, however, represent only a small fraction of cancer in the general population. Most cancer is instead probably the result of an intricate interaction of polymorphic susceptibility genes with the sea of environmental exposures that humans experience. Although the central cadre of cancer genes is known, little is understood about the peripheral genes that likely comprise the polymorphic susceptibility loci. The challenge for cancer genetics is therefore to move forward from the mendelian genetics of the rare familial cancer syndromes into the field of quantitative trait loci, susceptibility factors, and modifier genes. By identifying the genes that modulate an individual's susceptibility to cancer after an environmental exposure, researchers will be able to gain important insights into human biology, cancer prevention, and cancer treatment. This article summarizes the current state of quantitative trait genetic analysis and the tools, both proven and theoretical, that may be used to unravel one of the great challenges in cancer genetics.     

Inherited susceptibility to several cancers but absence of linkage between dysplastic nevus syndrome and CDKN2A in a melanoma family with a mutation in the CDKN2A (P16INK4A) gene

Genetic predisposition plays an important role in the development of nearly 10% of cases of cutaneous malignant melanoma (CMM). The CDKN2A gene has been described as responsible for melanoma susceptibility in a proportion of families with CMM linked to 9p. CDKN2A encodes a cyclin-dependent kinase inhibitor also implicated in the carcinogenesis of several sporadic tumors. Even though the incidence of other cancers is higher in CMM families, pancreatic adenocarcinoma is the only other well demonstrated cancer associated with CDKN2A mutations in some CMM pedigrees. We describe a family with four cases of CMM, eight patients affected by other cancers, and nine patients affected by dysplastic nevus (DN) syndrome. A CDKN2A frameshift mutation (358delG) was present in all the CMM patients, in at least three of the patients with other cancers (CDKN2A status is unknown in four patients), and in only two of the DN patients (CDKN2A status is unknown in one patient). An absence of linkage between chromosome 9p markers and the 358delG CDKN2A mutation and DN was detected, indicating genetic heterogeneity for DN and CMM in this family. The study strongly suggests that CDKN2A mutations are involved not only in the predisposition to CMM but also to several other types of cancer. Received: 2 June 1997 / Accepted: 11 August 1997     

Population aspects of cancer genetics

A number of relatively rare, high-risk genes have been identified which predispose to common cancers such as breast, colon, and melanoma. Although these are clearly important in the clinical setting, it is also relevant to discuss the impact of these genes at the population level and to contrast these with that which could be ascribed to more common genetic variants which only confer a modest increased risk of cancer. In this review, we examine inferences about the role of genetics in cancer from ecological studies of incidence patterns from a number of population-based studies of familial and attributable risk. The relationship between the genetic model (genotypic risk, allele frequency, mode of inheritance) and the expected impact in the population in terms of both attributable risk and familial risk is presented. The advantages and limitations of using cancer occurrence in twins to measure the genetic contribution to specific cancer sites is discussed. The potential role of lower-penetrance genes in the overall cancer burden may be significant but may pose significant problems in the public health arena.     

Xenogenetics in multifactorial disease susceptibility

Susceptibility to multifactorial disease includes both genetic and environmental components. These two aspects of susceptibility are interlinked through genetic control of an individual's response to the environment. As a first step in identifying disease susceptibility genes that influence the response of an individual to foreign compounds (xenobiotics), it is necessary to study disorders in which there is an identified environmental trigger. Establishing a DNA resource from individuals with known environmental exposure (‘a xenogenetic register’) for diseases with an established environmental aetiology is an essential step in beginning to understand how environmental factors contribute to the susceptibility to polygenic diseases. A complementary approach to identification of environmental factors is suggested using a comparison of genetically homogeneous subdivisions of individuals with polygenic disease where there is no clue to the environmental trigger.     

Viral triggers of multiple sclerosis

Genetic and environmental factors jointly determine the susceptibility to develop Multiple Sclerosis (MS). Collaborative efforts during the past years achieved substantial progress in defining the genetic architecture, underlying susceptibility to MS. Similar to other autoimmune diseases, HLA-DR and HLA-DQ alleles within the HLA class II region on chromosome 6p21 are the highest-risk-conferring genes. Less-robust susceptibility effects have been identified for MHC class I alleles and for non-MHC regions. The role of environmental risk factors and their interaction with genetic susceptibility alleles are much less well defined, despite the fact that infections have long been associated with MS development. Current data suggest that infectious triggers are most likely ubiquitous, i.e., highly prevalent in the general population, and that they require a permissive genetic trait which predisposes for MS development. In this review article, we illustrate mechanisms of infection-induced immunopathologies in experimental animal models of autoimmune CNS inflammation, discuss challenges for the translation of these experimental data into human immunology research, and provide future perspectives on how novel model systems could be utilized to better define the role of viral pathogens in MS.     

Fine mapping and positional candidate studies identify HLA-G as an asthma susceptibility gene on chromosome 6p21

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.