ABSTRACT
Cutaneous T-cell lymphoma (CTCL) patients have an increased risk of certain secondary cancers, the most common of which are lung cancers, especially small cell lung cancer. To reveal the molecular pathogenesis underlying CTCL-associated lung cancer, we analyzed genomic aberrations in CTCL-associated and reference lung cancer samples. DNA derived from microdissected lung cancer cells of five CTCL-associated lung cancers and five reference lung cancers without CTCL association was analyzed by comparative genomic hybridization (CGH). Fluorescent in situ hybridization (FISH), immunohistochemistry (IHC), and loss of heterozygosity (LOH) analysis were performed for selected genes. In CTCL-associated lung cancer, CGH revealed chromosomal aberrations characterizing both lung cancer and CTCL, but also losses of 1p, and 19, and gains of 4q and 7, hallmarks of CTCL. LOH for the CTCL-associated NAV3 gene was detected in two of the four informative primary lung cancers. FISH revealed increased copy number of the KIT gene in 3/4 of CTCL-associated lung cancers and 1/5 of primary lung cancers. PDGFRA and VEGFR2 copy numbers were also increased. IHC showed moderate KIT expression when the gene copy number was increased. CTCL-associated lung cancer shows chromosomal aberrations different from primary lung cancer, especially amplifications of 4q, a chromosome arm frequently deleted in the latter tumor type. Copy numbers and expression of selected genes in chromosome 4 differed between CTCL-associated and reference lung cancers. These preliminary observations warrant further prospective studies to identify the common underlying factors between CTCL and CTCL-associated lung cancer.
Subject(s)
Carcinoma, Small Cell/genetics , Chromosome Aberrations , Lung Neoplasms/genetics , Lymphoma, T-Cell, Cutaneous/genetics , Aged , Gene Dosage , Humans , In Situ Hybridization, Fluorescence , Male , Middle Aged , Nucleic Acid HybridizationABSTRACT
The PSORS1 locus is the consistently replicated genetic risk factor for psoriasis. Clinical associations with the main marker allele of PSORS1, HLA-Cw6, have been addressed in a number of studies, but clinical associations have not been used as a way to distinguish the effects of the neighbouring candidate genes in PSORS1. Our results show that HLA-Cw6 and CCHCR1 risk allele associations with clinical features of psoriasis are predictably highly similar in a Finnish nationwide cohort of 379 psoriasis patients. The clinical profiling of a small group of patients (n=34) who were HLA-Cw6- but CCHCR1*WWCC positive suggested that no great differences existed between them and HCR-Cw6- patients. HCR+ genotype (as well as Cw6+ genotype) correlated for the first time positively with female sex and, in contrast with previous studies, negatively with disease severity. Presence of psoriatic arthritis was more pronounced in HCR- psoriasis (as well as in Cw6- psoriasis). Clinical profiling may be a useful approach to distinguishing genetic effects of candidate genes even within a locus in sufficiently large cohorts.
Subject(s)
Arthritis, Psoriatic/genetics , HLA-C Antigens/genetics , Intracellular Signaling Peptides and Proteins/genetics , Psoriasis/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Arthritis, Psoriatic/pathology , Child , Child, Preschool , Genetic Predisposition to Disease , HLA-C Antigens/metabolism , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Middle Aged , Psoriasis/immunology , Psoriasis/pathology , Sex FactorsSubject(s)
Butterflies/immunology , Hypersensitivity/etiology , Insect Bites and Stings/immunology , Animals , Data Collection , Female , Finland/epidemiology , Hand Dermatoses/epidemiology , Hand Dermatoses/etiology , Hobbies , Humans , Hypersensitivity/epidemiology , Incidence , Insect Bites and Stings/epidemiology , Male , Protective Clothing , Risk Assessment , Surveys and QuestionnairesABSTRACT
The major susceptibility locus for psoriasis, PSORS1, resides on chromosome 6p and includes the candidate genes HLA-C, HCR, and CDSN. Based on a nationwide collection of psoriasis patients and genotyping for the PSORS1 susceptibility haplotype, we selected for a genome scan nine families who do not show association with PSORS1 to more easily detect minor loci for psoriasis susceptibility. In the genome scan, five loci gave initial evidence of linkage and were studied with a denser marker map. After fine mapping, only one locus on 18p11.23 showed suggestive evidence of linkage (nonparametric multipoint linkage analysis score, 3.58; p = 0.0038). The bootstrapping analysis showed that one large family contributed the majority of the linkage (p = 0.0039), but was supported by other families. Haplotype sharing between the linked families and haplotype association analysis gave additional support for the locus. Further, the 18p locus has shown nominal evidence of linkage with psoriasis in the British population. Taken together, these findings confirm the presence of a minor susceptibility locus for psoriasis on 18p11.
