The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma.

In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10(-8), per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17-1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10(-14)) and rs12617313 (P = 7.48 × 10(-12)), both highly correlated with rs9679290 (r(2) > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r(2) < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10(-9), per-allele OR = 1.28, 95% CI: 1.18-1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.

A genome-wide association study identifies a novel susceptibility locus for renal cell carcinoma on 12p11.23.

Renal cell carcinoma (RCC) is the most lethal urologic cancer. Only two common susceptibility loci for RCC have been confirmed to date. To identify additional RCC common susceptibility loci, we conducted an independent genome-wide association study (GWAS). We analyzed 533 191 single nucleotide polymorphisms (SNPs) for association with RCC in 894 cases and 1516 controls of European descent recruited from MD Anderson Cancer Center in the primary scan, and validated the top 500 SNPs in silico in 3772 cases and 8505 controls of European descent involved in the only published GWAS of RCC. We identified two common variants in linkage disequilibrium, rs718314 and rs1049380 (r(2) = 0.64, D ' = 0.84), in the inositol 1,4,5-triphosphate receptor, type 2 (ITPR2) gene on 12p11.23 as novel susceptibility loci for RCC (P = 8.89 × 10(-10) and P = 6.07 × 10(-9), respectively, in meta-analysis) with an allelic odds ratio of 1.19 [95% confidence interval (CI): 1.13-1.26] for rs718314 and 1.18 (95% CI: 1.12-1.25) for rs1049380. It has been recently identified that rs718314 in ITPR2 is associated with waist-hip ratio (WHR) phenotype. To our knowledge, this is the first genetic locus associated with both cancer risk and WHR.

Von Hippel-Lindau (VHL) inactivation in sporadic clear cell renal cancer: associations with germline VHL polymorphisms and etiologic risk factors.

Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28-16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20-1.31) and current: OR = 0.56 (0.32-0.99); P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.

Systemic retinoids in the management of ichthyoses and related skin types.

The term retinoid includes both natural and synthetic derivatives of vitamin A. Retinoid-containing treatments have been used since ~1550BC by the early Egyptians. Treatment of ichthyosiform disorders with retinoids dates back at least to the 1930s. Early use of high-dose vitamin A demonstrated efficacy, but because vitamin A is stored in the liver, toxicity limited usefulness. Interest turned to synthetic retinoids in an effort to enhance efficacy and limit toxicity. Acetretin, isotretinoin and, in the past etretinate, have provided the most effective therapy for ichthyosiform conditions. They have been used for a variety of ages, including in newborns with severe ichthyosis and for decades in some patients. Careful surveillance and management of mucous membrane, laboratory, skeletal, and teratogenic side effects has made systemic retinoids the mainstay of therapy for ichthyosis and related skin types.

Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome.

Birt-Hogg-Dubé (BHD) syndrome is a rare inherited genodermatosis characterized by hair follicle hamartomas, kidney tumors, and spontaneous pneumothorax. Recombination mapping in BHD families delineated the susceptibility locus to 700 kb on chromosome 17p11.2. Protein-truncating mutations were identified in a novel candidate gene in a panel of BHD families, with a 44% frequency of insertion/deletion mutations within a hypermutable C(8) tract. Tissue expression of the 3.8 kb transcript was widespread, including kidney, lung, and skin. The full-length BHD sequence predicted a novel protein, folliculin, that was highly conserved across species. Discovery of disease-causing mutations in BHD, a novel kidney cancer gene associated with renal oncocytoma or chromophobe renal cancer, will contribute to understanding the role of folliculin in pathways common to skin, lung, and kidney development.

Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases.

There have been no prior large population-based studies focusing on cutaneous lymphomas (CL) in the United States. Using the Surveillance, Epidemiology and End Results (SEER) program data, we analyzed age-adjusted CL incidence rates (IRs) and survival rates by sex and race/ethnicity. There were 3884 CLs diagnosed during 2001-2005. Cutaneous T-cell lymphomas (CTCLs) accounted for 71% (age-adjusted incidence rate [IR] = 7.7/1 000 000 person-years), whereas cutaneous B-cell lymphomas(CBCLs) accounted for 29% (IR = 3.1/1 000 000 person-years). Males had a statistically significant higher IR of CL than females (14.0 vs 8.2/1 000 000 person-years, respectively; male-female IR ratio [M/F IRR] = 1.72; P < .001). CL IRs were highest among blacks and non-Hispanic whites (both 11.5/1 000 000 person-years), followed by Hispanic whites (7.9) and Asian/Pacific Islanders (7.1). The CTCL IR was highest among blacks (10.0/1 000 000 person-years), whereas the CBCL IR was highest among non-Hispanic whites (3.5). Over the past 25 years, the CL IR increased from 5.0/1 000 000 person-years during 1980-1982 to 14.3 during 2001-2003. During 2004-2005, the CL IR was 12.7. This recent apparent change could be incomplete case ascertainment or potential leveling off of IRs. CLs rates vary markedly by race and sex, supporting the notion that they represent distinct disease entities.

Revised nomenclature and classification of inherited ichthyoses: results of the First Ichthyosis Consensus Conference in Sorèze 2009.

BACKGROUND: Inherited ichthyoses belong to a large, clinically and etiologically heterogeneous group of mendelian disorders of cornification, typically involving the entire integument. Over the recent years, much progress has been made defining their molecular causes. However, there is no internationally accepted classification and terminology. OBJECTIVE: We sought to establish a consensus for the nomenclature and classification of inherited ichthyoses. METHODS: The classification project started at the First World Conference on Ichthyosis in 2007. A large international network of expert clinicians, skin pathologists, and geneticists entertained an interactive dialogue over 2 years, eventually leading to the First Ichthyosis Consensus Conference held in Sorèze, France, on January 23 and 24, 2009, where subcommittees on different issues proposed terminology that was debated until consensus was reached. RESULTS: It was agreed that currently the nosology should remain clinically based. "Syndromic" versus "nonsyndromic" forms provide a useful major subdivision. Several clinical terms and controversial disease names have been redefined: eg, the group caused by keratin mutations is referred to by the umbrella term, "keratinopathic ichthyosis"-under which are included epidermolytic ichthyosis, superficial epidermolytic ichthyosis, and ichthyosis Curth-Macklin. "Autosomal recessive congenital ichthyosis" is proposed as an umbrella term for the harlequin ichthyosis, lamellar ichthyosis, and the congenital ichthyosiform erythroderma group. LIMITATIONS: As more becomes known about these diseases in the future, modifications will be needed. CONCLUSION: We have achieved an international consensus for the classification of inherited ichthyosis that should be useful for all clinicians and can serve as reference point for future research.

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas.

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.

Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.

Germline mutations in the cylindromatosis (CYLD) gene have been described in families with cylindromas, trichoepitheliomas, and/or spiradenomas. Brooke-Spiegler syndrome (BSS) is the autosomal dominant predisposition to skin appendageal neoplasms including cylindromas, trichoepitheliomas, and/or spiradenomas. We review the clinical features, molecular genetics, and the animal models of BSS. To date, a total of 51 germline CYLD mutations have been reported, occurring in exons 9-20, in 73 families with diverse ethnic and racial backgrounds. Of 51 mutations, 86% are expected to lead to truncated proteins. The seven missense mutations reported to date occur only within the ubiquitin (Ub)-specific protease (USP) domain of the CYLD protein and most are associated exclusively with multiple familial trichoepithelioma (MFT). CYLD functions as a tumor suppressor gene. CYLD encodes a deubiquitinating (DUB) enzyme that negatively regulates the nuclear factor (NF)-kappaB and c-Jun N-terminal kinase (JNK) pathways. CYLD DUB activity is highly specific for lysine 63 (K63)-linked Ub chains but has been shown to act on K48-linked Ub chains as well. In 2008, the CYLD USP domain was crystallized, revealing that the truncated Fingers subdomain confers CYLD's unique specificity for K63-linked Ub chains. Recent work using animal models revealed new roles for CYLD in immunity, lipid metabolism, spermatogenesis, osteoclastogenesis, antimicrobial defense, and inflammation.

The folliculin mutation database: an online database of mutations associated with Birt-Hogg-Dubé syndrome.

The folliculin gene (FLCN), also known as BHD, is the only known susceptibility gene for Birt-Hogg-Dubé syndrome. BHDS is the autosomal dominant predisposition to the development of follicular hamartomas, lung cysts, spontaneous pneumothorax, and/or kidney neoplasms. To date, 53 unique germline mutations have been reported. FLCN mutation detection rate is 88%. FLCN encodes a predicted 579-amino acid protein, designated folliculin that is highly conserved between humans and homologs in mice, Drosophila, and C. elegans. We developed the first online database detailing all FLCN variants identified in our laboratory and reported in the literature. The FLCN database applies, and assists researchers in applying HGVS nomenclature guidelines. To date, the FCLN database includes 84 variants: 53 unique germline mutations and 31 SNPs. The majority of FLCN germline mutations are predicted to produce a truncated folliculin, resulting in loss of function. The FLCN mutations consist of: 45% (24/53) deletions, 32% (17/53) substitutions (10 putative-splice site, 5 nonsense, and 2 missense), 15% (8/53) duplications, 6% (3/53) insertion/deletions and 2% (1/53) insertions. The database strives to systematically unify current knowledge of FLCN variants and will be useful to geneticists and genetic counselors while also providing a rapid and systematic resource for investigators.

Transglutaminase-1 gene mutations in autosomal recessive congenital ichthyosis: summary of mutations (including 23 novel) and modeling of TGase-1.

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of rare cornification diseases. Germline mutations in TGM1 are the most common cause of ARCI in the United States. TGM1 encodes for the TGase-1 enzyme that functions in the formation of the cornified cell envelope. Structurally defective or attenuated cornified cell envelop have been shown in epidermal scales and appendages of ARCI patients with TGM1 mutations. We review the clinical manifestations as well as the molecular genetics of ARCI. In addition, we characterized 115 TGM1 mutations reported in 234 patients from diverse racial and ethnic backgrounds (Caucasion Americans, Norwegians, Swedish, Finnish, German, Swiss, French, Italian, Dutch, Portuguese, Hispanics, Iranian, Tunisian, Moroccan, Egyptian, Afghani, Hungarian, African Americans, Korean, Japanese and South African). We report 23 novel mutations: 71 (62%) missense; 20 (17%) nonsense; 9 (8%) deletion; 8 (7%) splice-site, and 7 (6%) insertion. The c.877-2A>G was the most commonly reported TGM1 mutation accounting for 34% (147 of 435) of all TGM1 mutant alleles reported to date. It had been shown that this mutation is common among North American and Norwegian patients due to a founder effect. Thirty-one percent (36 of 115) of all mutations and 41% (29 of 71) of missense mutations occurred in arginine residues in TGase-1. Forty-nine percent (35 of 71) of missense mutations were within CpG dinucleotides, and 74% (26/35) of these mutations were C>T or G>A transitions. We constructed a model of human TGase-1 and showed that all mutated arginines that reside in the two beta-barrel domains and two (R142 and R143) in the beta-sandwich are located at domain interfaces. In conclusion, this study expands the TGM1 mutation spectrum and summarizes the current knowledge of TGM1 mutations. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of 5' methylated CpG dinucleotides.

Prior history of non-melanoma skin cancer is associated with increased mortality in patients with chronic lymphocytic leukemia.

We investigated whether a previous diagnosis of non-melanoma skin cancer among chronic lymphocytic leukemia patients is a predictor of poor outcome. Using the Swedish Cancer Registry, we conducted a population-based study to evaluate the survival patterns among chronic lymphocytic leukemia patients with and without non-melanoma skin cancer. Cox proportional hazards regression models were used and Kaplan-Meier curves were constructed. Of a total of 12,041 chronic lymphocytic leukemia cases identified, 236 cases, including 111 squamous cell cancer, had a prior history of non-melanoma skin cancer. Chronic lymphocytic leukemia patients with a prior history of non-melanoma skin cancer had a 1.29-fold (95% CI 1.10-1.52; p=0.0024) increased risk of dying; and those with a history of squamous cell cancer had a further elevated 1.86-fold (95% CI 1.46-2.36; p<0.0001) risk of dying. Kaplan-Meier plots showed that patients with a history of non-melanoma skin cancer, particularly those with squamous cell cancer, had significantly poorer survival than chronic lymphocytic leukemia patients without non-melanoma skin cancer (p<0.0001; log-rank test). Non-melanoma skin cancer may be a novel clinical predictor of worse chronic lymphocytic leukemia outcome.

Improved identification of von Hippel-Lindau gene alterations in clear cell renal tumors.

PURPOSE: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics. EXPERIMENTAL DESIGN: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter. RESULTS: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC. CONCLUSION: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.

Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe.

An elevated familial relative risk may indicate either an important genetic component in etiology or shared environmental exposures within the family. Incidence rates of kidney cancer are particularly high in Central Europe, although no data were available on the familial aggregation or genetic background of kidney cancer in this region. We have, therefore, investigated the role of family history in first-degree relatives in a large multicenter case-control study in Central Europe. A total number of 1,097 cases of kidney cancer and 1,555 controls were recruited from 2000 to 2003 from seven centers in Czech Republic, Poland, Romania, and Russia. The risk of kidney cancer increased with the increasing number of relatives with history of any cancer [odds ratio (OR), 1.15; 95% confidence interval (95% CI), 1.00-1.31 per affected relative], and this association seemed to be more prominent among subjects with young onset (OR, 1.55; 95% CI, 1.09-2.20 per affected relative). Overall, the OR was 1.40 (95% CI, 0.71- 2.76) for the subjects who had at least one first-degree relative with kidney cancer after adjusting for tobacco smoking, body mass index, and medical history of hypertension, and this association was most apparent among subjects with affected siblings (OR, 4.09; 95% CI, 1.09-15.4). Based on the relative risk to siblings in our study population, we estimated that 80% of the kidney cancer cases are likely to occur in 20% of the population with the highest genetic risk, which indicate the importance of further investigation of genetic factors in cancer prevention for kidney cancer.

Topical cidofovir for the treatment of dermatologic conditions: verruca, condyloma, intraepithelial neoplasia, herpes simplex and its potential use in smallpox.

Cidofovir is a new antiviral drug that has a broad spectrum of activity against several DNA viruses. Many of the disorders caused by these viruses do not have satisfactory therapy, and given the efficacy of this agent in treating many of these conditions, it holds great promise. It is hoped that ongoing studies will confirm the initial anecdotal reports regarding its therapeutic efficacy and lack of systemic side effects. It is also hoped that the cost to formulate and use cidofovir topically will eventually decrease to a level that will allow more widespread use of this drug.

Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3.

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻8) and rs7579899 (P = 2.3 × 10⁻9), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹4). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻8). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.

Cutaneous appendageal carcinoma incidence and survival patterns in the United States: a population-based study.

OBJECTIVE: To examine incidence patterns of patients diagnosed as having cutaneous appendageal carcinoma (CAC). DESIGN: Population-based study using the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute data from 1978 through 2005. PARTICIPANTS: A total of 1801 subjects from SEER 16 registries (2001-2005) for incidence analyses, 2228 from SEER 9 registries (1987-2005) for trend analysis, and 1984 subjects (1992-2004) for survival analysis. MAIN OUTCOME MEASURE: Incidence rates (IRs) per 1 million person-years according to anatomic site, race, sex, age, and histologic type. RESULTS: Cutaneous appendageal carcinomas are uncommon (age-adjusted IR, 5.1 per 1 million person-years), with the IR among men statistically significantly higher than women (6.3 vs 4.2, respectively; male to female IR ratio 1.51; P < .001). Hispanic whites (IR, 3.7), blacks (IR, 3.5), and Asian/Pacific Islanders (IR, 2.5) all had significantly lower IRs than non-Hispanic whites (IR, 5.7) (P < .001). Apocrine-eccrine carcinoma overall was the most common category (IR, 2.6), and the IR was highest among non-Hispanic white (IR, 2.8) compared with other ethnic/racial groups (P < .001). Cutaneous appendageal carcinomas IRs rose 100-fold with age, from 0.37 among those aged 20 to 29 years to 37.3 among those 80 years or older. From 1978-1982 to 2002-2005, the CAC IRs increased 150%, from 2.0 to 5.0; the apocrine-eccrine carcinoma and the sebaceous carcinoma IRs rose 170%, from 1.0 to 2.7, and 217%, from 0.6 to 1.9, respectively. Five-year relative survival rates overall were 99% for localized and 43% for distant disease. CONCLUSIONS: Cutaneous appendageal carcinomas are rare tumors with IRs that vary by sex and racial/ethnic group. Cutaneous appendageal carcinoma IRs are increasing in the United States, especially for sebaceous carcinoma, perhaps related to improved recognition and classification, but factors such as UV exposure and immunosuppression may also play a role.