Risk of basal cell carcinoma in Swedish organ transplant recipients: a population-based study.

BACKGROUND: Risk of basal cell carcinoma (BCC) has been reported to be several-fold increased among organ transplant recipients (OTRs). However, due to lack of reliable BCC registration, population-based risk estimates are scarce. OBJECTIVES: To characterize risk of BCC among OTRs compared with the general population, and contrast with risk of cutaneous squamous cell carcinoma (SCC). SUBJECTS AND METHODS: OTRs transplanted during 2004-2011 were identified through national healthcare registers and linked with the nationwide Swedish BCC Register initialized in 2004. Relative risk of BCC was expressed as standardized incidence ratios (SIR) with 95% confidence intervals (CI). RESULTS: Altogether, 4023 transplanted patients developed 341 BCCs during follow-up. Compared with the general population, the relative risk of BCC was increased sixfold (SIR 6·1, 95% CI 5·4-6·9). The risk was higher in kidney and heart/lung than in liver recipients (SIRkidney 7·2, 6·3-8·3; SIRheart/lung 5·8, 4·0-8·2; SIRliver 2·6, 1·7-4·0), and risk increased with time since transplantation (Ptrend < 0·01). The SCC to BCC ratio was 1 : 1·7 and BCC developed earlier after transplantation than SCC. Distribution of anatomical sites and histological types did not differ substantially between OTR- and population-BCCs. CONCLUSIONS: Risk of BCC was strikingly elevated in OTRs compared with the general population. Risk was higher in kidney recipients and increased with follow-up time. These findings support a tumour-promoting effect of immunosuppressive drugs in BCC development. The low SCC to BCC ratio was possibly attributed to short follow-up time.

Mutations in the human homologue of Drosophila patched (PTCH) in basal cell carcinomas and the Gorlin syndrome: different in vivo mechanisms of PTCH inactivation.

The nevoid basal cell carcinoma (Gorlin) syndrome (NBCCS) is an autosomal dominant disorder characterized by multiple developmental defects and cancer susceptibility, in particular to basal cell carcinoma. The human homologue of Drosophila patched (PTCH) was recently identified, mapped to the NBCCS locus on chromosome 9q22.3, and found mutated in patients with NBCCS and also in sporadic basal cell carcinomas. Here we show germ-line PTCH mutations in three families with NBCCS. We demonstrate that a germ-line PTCH frameshift deletion in one patient with NBCCS was accompanied by loss of the normal copy of PTCH in a tumor developed in the same patient. Another basal cell carcinoma from this patient did not show the loss of the normal copy of PTCH, instead a missense mutation in a highly conserved residue was identified in the nondeleted allele, illustrating two different mechanisms of PTCH inactivation in different tumors derived from the same NBCCS patient. We also show somatic PTCH mutations in 4 basal cell carcinomas identified by analyzing 18 non-NBCCS patients with sporadic tumors. These data provide further support for PTCH as an important tumor suppressor gene in the development of the most common human cancer.

Inter- and intra-individual differences in human stratum corneum lipid content related to physical parameters of skin barrier function in vivo.

For a full understanding of the properties of the human skin barrier, physical macroscopic parameters of barrier function must be correlated to the structural organization of the barrier on a molecular level. This study was undertaken to relate differences in the relative composition of the three main lipid classes of human stratum corneum, i.e., free fatty acids, cholesterol, and ceramides, to differences in transepidermal water loss, stratum corneum electrical impedance, and corneometer value. A new high performance liquid chromatography/light scattering detection-based analysis method recently developed was used for collection of quantitative lipid data in conjunction with gas chromatography/mass spectrometry/flame ionization detection measurements on the free fatty acid fraction. After subtraction of contaminating lipid fractions we have estimated the molar ratio of the human skin barrier lipid composition to be, respectively, 15% cholesterol esters, 16% saturated long chain free fatty acids, 32% cholesterol, and 37% ceramides. The inter-individual difference in the relative amount of free fatty acids, cholesterol, and ceramides, respectively, can be >100% in the individual case. It was found that the relative amount of ceramides to cholesterol is larger in the wrist area, paralleled by a higher transepidermal water loss and corneometer value as well as different skin electrical impedance values as compared with the upper forearm area. We conclude that the site-dependent differences in the stratum corneum lipid composition are small compared with the large inter-individual variation. Interestingly, in the individual case, no correlation was registered between relative ceramide content and barrier properties.

Loss of heterozygosity at chromosome 9p21 (INK4-p14ARF locus): homozygous deletions and mutations in the p16 and p14ARF genes in sporadic primary melanomas.

Loss of heterozygosity (LOH) was determined in 45 sporadic primary melanomas at six polymorphic microsatellite markers that flank the INK4a (p16-p14ARF) locus on chromosome 9p21. We also determined allelic loss at two markers on chromosome 9q and two markers at the Rb locus on chromosome 13. Homozygous deletion of the p16 and p14ARF genes was determined by a fluorescent-based quantitative multiplex polymerase chain reaction method. LOH at one or more polymorphic microsatellite markers on locus 9p21 was found in 32 of the melanomas (71%). The highest proportion of LOH was found at markers D9S736 and D9S104, which are telomeric and centromeric to the INK4 locus, respectively. Five melanomas showed LOH at all the analysed markers located on chromosome 9p21. LOH at markers D9S942 and D9S974, which are located close to the p16 and p14ARF genes, was found in 39% and 46% of melanomas, respectively. Analysis of the marker D9S257 on 9q22.1 showed LOH in 13 melanomas (44% of the informative cases). A subset of melanomas with LOH at the INK4 locus also carried inactivating mutations within the p16 coding sequence. Four melanomas carried homozygous deletions at the p16-p14ARF locus. Our results suggest, besides the involvement of the INK4 locus in sporadic melanomas, the possibility of the existence of additional tumour suppressor loci on chromosome 9.

Mutations in the CDKN2A (p16INK4a) gene in microdissected sporadic primary melanomas.

The role of the CDKN2A (p16INK4a) gene in sporadic primary melanomas has remained unclear due to the inadequate number of mutational studies. In the present study, we analyzed the entire coding region of the CDKN2A gene in microdissected sporadic primary melanomas, for the presence of mutations and polymorphisms, using 2 independent methods of mutation detection, SSCP and CMC. We found 11 intragenic mutations in 8 melanomas out of 31 (26%) and the majority of mutations were located in exon 1, with 2 cases harbouring multiple mutations. Of the mutations detected, 6 were C-to-T transitions, 4 involving CC sites; 2 melanomas showed a novel deletion of one of the two 24-bp repeat units located at the 5' end of exon 1. There was also a high frequency of C-to-G and C-to-T polymorphisms at the nucleotides 540 (frequency of G allele: 0.18) and 580 (frequency of T allele: 0.13) in the 3' untranslated region.

Correlation of impedance response patterns to histological findings in irritant skin reactions induced by various surfactants.

We have explored the use of measurements of electrical impedance to discriminate between the effects of different irritant substances upon the skin, and have studied the relationships between impedance and histopathological change. Three compounds with different chemical profiles were tested on volunteers: sodium lauryl sulphate, benzalkonium chloride and nonanoic acid. The concentrations selected were such that each irritant produced responses of a similar order, as judged by visual scores. The magnitude and phase of electrical impedance were measured and, for comparison, also the transepidermal water loss. Four physically distinct aspects (indices) were devised from the impedance data, and the values obtained were statistically analysed. The three irritants produced different effects, giving distinctive impedance patterns. These were also found to be reflected by three different types of histopathological skin response. Our results suggest that the indices can be used to classify irritant contact reactions, which it is difficult or impossible to achieve by other non-invasive techniques.

Tissue concentrations of tissue polypeptide antigen (TPA) and prostatic specific antigen (PSA) in 42 patients with prostatic carcinoma.

BACKGROUND: Following development of methods to quantitate biochemical markers in aspiration biopsies we showed that tissue concentration of prostate specific antigen (T-PSA) decreased with increasing malignancy while serum PSA increased. We also found that T-PSA predicts the clinical outcome better than earlier used prognostic markers. METHODS: In order to further study biochemical markers in prostatic cancer a membrane protein, tissue polypeptide antigen (TPA), which is a complex of polypeptide fragments of cytokeratins 8, 18, and 19, was quantitated in 42 patients with newly diagnosed carcinoma of the prostate. The samples had previously been analyzed for T-PSA. RESULTS: Correlation to TGM classification showed that higher malignancy is correlated to lower tissue TPA values. There is a significant positive correlation (r(s) = 0.49, P < 0.01) between T-TPA and T-PSA. Pretreatment values of T-PSA, but not T-TPA, had association to time to progression or time to death. CONCLUSIONS: Increasing prostatic malignancy is correlated to decreasing values of T-TPA. This indicates that the concentrations of membrane and secretory proteins are changed in the same direction in tissue during cancer development. Tissue TPA seem to have no prognostic value in endocrine treatment of prostatic carcinoma.

Mutation analysis of the human homologue of Drosophila patched and the xeroderma pigmentosum complementation group A genes in squamous cell carcinomas of the skin.

The human homologue of Drosophila patched (PTCH), located at chromosome 9q22.3, was recently identified as a candidate tumor suppressor gene for familial and sporadic basal cell carcinomas. Squamous cell carcinomas (SCCs) of the skin display allelic loss in this chromosomal region, which, in addition to the PTCH gene, contains the DNA repair gene xeroderma pigmentosum complementation group A (XPA). Patients with xeroderma pigmentosum are predisposed to non-melanoma skin tumors because of deficient excision repair of ultraviolet-induced DNA damage. Mutation analysis by single-strand conformation analysis and direct DNA sequencing of all 23 exons of the PTCH gene and all six exons of the XPA gene in 14 SCCs did not reveal structural alterations in any of these genes. Additionally, analysis of PTCH expression by in situ hybridization in SCCs revealed no evidence of upregulation of PTCH mRNA, confirming the lack of mutations in this gene. These findings suggest that another, yet to be identified gene or genes on chromosome 9q are involved in SCC tumorigenesis.