Breastfeeding decreases the risk of developing psoriasis through to early adulthood.

BACKGROUND: Psoriasis is a genetically determined systemic skin disease, although environmental trigger factors are required for disease manifestation. Some of these triggers, such as stress, infections and drug exposure, have been identified. OBJECTIVES: To explore the role of early nutrition as a risk factor for the development of psoriasis. METHODS: Parents in the All Babies in Southeast Sweden (ABIS) prospective birth cohort (n = 16 415) answered questionnaires at birth and when their children were aged 1 and 3 years. A diagnosis of psoriasis was determined from the Swedish National Patient Register and National Drug Prescription Register. Statistical analyses were conducted using custom-written R scripts. RESULTS: Individuals breastfed for < 4 months and who received infant formula before 4 months of age had a higher risk of psoriasis [odds ratio (OR) 1.84 (P = 0.02) and OR 1.88 (P = 0.02), respectively]. At the 3-year follow-up, the increased consumption of fish, especially from the Baltic Sea, increased the risk of psoriasis (OR 9.61; P = 0.003). In addition, the risk of psoriasis increased following the consumption of a large volume of milk (OR 2.53; P = 0.04). CONCLUSIONS: Our study underscores, for the first time, the impact of very early nutrition on the manifestation of psoriasis through early adulthood. Exclusive breastfeeding for 4 months appears to be protective.

Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis.

Psoriasis is a chronic inflammatory disease characterised by sharply demarcated erythematous and scaly skin lesions accompanied by systemic manifestations. Classified by WHO as one of the most serious non-infectious diseases, psoriasis affects 2-3% of the global population. Mechanistically, psoriatic lesions result from hyperproliferation and disturbed differentiation of epidermal keratinocytes that are provoked by immune mediators of the IL-23 and IL-17 pathway. Translational immunology has had impressive success in understanding and controlling psoriasis. Psoriasis is the first disease to have been successfully treated with therapeutics that directly block the action of the cytokines of this pathway; in fact, therapeutics that specifically target IL-23, IL-17, and IL-17RA are approved for clinical use and show excellent efficacy. Furthermore, inhibitors of IL-23 and IL-17 intracellular signalling, such as TYK2 or RORγt, are in clinical development. Although therapies that target the IL-23 and IL-17 pathway also improve psoriatic arthritis symptoms, their effects on long-term disease modification and psoriasis-associated comorbidities still need to be explored.

The Act1 D10N missense variant impairs CD40 signaling in human B-cells.

The TRAF3IP2 gene resides within one of at least 63 psoriasis susceptibility loci and encodes Act1, an adapter protein involved in IL-17 receptor and CD40 signaling pathways. TRAF3IP2 is distinctive (among <10% of candidate susceptibility genes) in that a strongly disease-associated variant encodes a missense SNP predicted to be functionally relevant (SNP rs33980500 C/T encoding Act1 pD10N). As assessed by flow cytometry, Act1 protein was expressed at the highest levels in monocytes, with lower levels in T-cells and B-cells. However, monocytes, T-cells and B-cells failed to respond to IL-17A stimulation of PBMC, as measured by flow cytometric determination of NF-κB phospho-p65. As an alternative stimulus, we treated PBMCs with trimerized recombinant human CD40L and assessed p65, p38 and Erk phosphorylation in CD19+ B-cells as a function of D10N genotype. The increase of phosphorylated p65, p38, and Erk was well-correlated across individuals, and CD40L-induced phosphorylation of p65, p38, and Erk was significantly attenuated in B-cells from Act1 D10N homozygotes, compared to heterozygotes and nullizygotes. Our results indicate that the Act1 D10N variant is a relevant genetic determinant of CD40L responsiveness in human B-cells, with the risk allele being associated with lower B-cell responses in an acute signaling context.

Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling.

Psoriasis is a common inflammatory skin disorder for which multiple genetic susceptibility loci have been identified, but few resolved to specific functional variants. In this study, we sought to identify common and rare psoriasis-associated gene-centric variation. Using exome arrays we genotyped four independent cohorts, totalling 11 861 psoriasis cases and 28 610 controls, aggregating the dataset through statistical meta-analysis. Single variant analysis detected a previously unreported risk locus at TNFSF15 (rs6478108; P = 1.50 × 10-8, OR = 1.10), and association of common protein-altering variants at 11 loci previously implicated in psoriasis susceptibility. We validate previous reports of protective low-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (encoding a Janus kinase), in each case establishing a further series of protective rare variants (minor allele frequency < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 × 10-7, OR = 0.707; TYK2: pburden = 6.17 × 10-4, OR = 0.744). Both genes play significant roles in type I interferon (IFN) production and signalling. Several of the protective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highlighting potential mechanisms through which their effect may be exerted.

The Importance of Achieving Clear or Almost Clear Skin for Patients: Results from the Nordic Countries of the Global.

Psoriasis is a stigmatizing chronic skin condition in which impairment of quality of life is associated with visibility of skin lesions, disease activity and severity. The ultimate goal of treatment is complete clearance of skin symptoms. The worldwide "Clear About Psoriasis" survey explored patients' perspectives on clear/almost clear skin and the impact of psoriasis on daily life. We report here results from the Nordic countries (n = 609). Of respondents, 44% achieved clear/almost clear skin with their current treatment, of which 71% were comfortable discussing this expectation with their physician, compared with only 46% of patients who had not achieved clear/almost clear skin. Of patients who achieved clear/almost clear skin, 85% reported treatment satisfaction vs. 39% who had not. Psoriasis profoundly affected daily life, with 88% of respondents reporting discrimination/humiliation and 61% reporting an impact on their professional life. This report highlights stigmatization among Nordic patients with psoriasis and the potential to improve physician-patient communication.

Genome-wide Association Analysis of Psoriatic Arthritis and Cutaneous Psoriasis Reveals Differences in Their Genetic Architecture.

Psoriasis vulgaris (PsV) is a common inflammatory and hyperproliferative skin disease. Up to 30% of people with PsV eventually develop psoriatic arthritis (PsA), an inflammatory musculoskeletal condition. To discern differences in genetic risk factors for PsA and cutaneous-only psoriasis (PsC), we carried out a genome-wide association study (GWAS) of 1,430 PsA case subjects and 1,417 unaffected control subjects. Meta-analysis of this study with three other GWASs and two targeted genotyping studies, encompassing a total of 9,293 PsV case subjects, 3,061 PsA case subjects, 3,110 PsC case subjects, and 13,670 unaffected control subjects of European descent, detected 10 regions associated with PsA and 11 with PsC at genome-wide (GW) significance. Several of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A, NFKBIA for PsC) have not previously achieved GW significance. After replication, we also identified a PsV-associated SNP near CDKAL1 (rs4712528, odds ratio [OR] = 1.16, p = 8.4 × 10(-11)). Among identified psoriasis risk variants, three were more strongly associated with PsC than PsA (rs12189871 near HLA-C, p = 5.0 × 10(-19); rs4908742 near TNFRSF9, p = 0.00020; rs10888503 near LCE3A, p = 0.0014), and two were more strongly associated with PsA than PsC (rs12044149 near IL23R, p = 0.00018; rs9321623 near TNFAIP3, p = 0.00022). The PsA-specific variants were independent of previously identified psoriasis variants near IL23R and TNFAIP3. We also found multiple independent susceptibility variants in the IL12B, NOS2, and IFIH1 regions. These results provide insights into the pathogenetic similarities and differences between PsC and PsA.

Decreased Systemic Levels of Endocan-1 and CXCL16 in Psoriasis Are Restored following Narrowband UVB Treatment.

BACKGROUND: In psoriasis, a common immune-mediated disease affecting 2-3% of the population worldwide, there is an increased prevalence of extracutaneous diseases including obesity, the metabolic syndrome, and cardiovascular disease. This is believed to be linked to systemic inflammation. In previous studies, we have explored various markers in plasma and serum to characterize the ongoing systemic inflammation in psoriasis patients compared to controls. We have identified several markers that were altered in psoriasis patients, but which all were unresponsive to narrowband UVB (NB-UVB) treatment. OBJECTIVE: The objective of the study was to evaluate the effect of NB-UVB treatment on markers of cardiovascular risk and systemic inflammation in psoriasis. METHODS: The levels of 17 potential biomarkers with an association with cardiovascular risk were quantitated in plasma from 37 age- and gender-matched psoriasis patients and controls at baseline and in 21 psoriasis patients after 12 weeks of NB-UVB treatment to identify a systemic treatment response. RESULTS: We identified the mediators endocan-1, CXCL16, and sVEGFR1, which were systemically decreased in psoriasis at baseline, as well as FABP3, FABP4, and sIL-1R1, which showed normal baseline levels. After 10-12 weeks of NB-UVB treatment, endocan-1 and CXCL16 were restored to normal levels, while sVEGFR1, FABP3, FABP4, and sIL-1R1 showed a significant reduction. CONCLUSION: The current study expands the number of potential biomarkers in psoriasis by including a greater number and variety of mediators, approaching the systemic inflammation from additional vantage points, including soluble immune receptors and adipocyte contribution, to provide a more complete picture of the systemic inflammatory state in psoriasis.

Involved and Uninvolved Psoriatic Keratinocytes Display a Resistance to Apoptosis that may Contribute to Epidermal Thickness.

Psoriasis is a common autoimmune skin disease. The aim of this study was to investigate whether the apoptotic process is disturbed in psoriatic keratinocytes. In vitro culture of keratinocytes derived from both involved and uninvolved psoriatic skin, revealed higher viability and resistance to apoptosis following exposure to ultraviolet B, compared with cells from healthy controls. The position of apoptotic dysregulation was found to be upstream of cytochrome c release in the mitochondrial apoptotic pathway. Microarray transcriptome analysis revealed that 87 genes were differentially expressed in both involved and uninvolved psoriatic keratinocytes compared with controls. Among these, a general upregulation of anti-apoptotic genes and downregulation of pro-apoptotic genes were identified. This distinct apoptosis-resistant phenotype, unrelated to the inflammatory component of the disease, implies that intrinsic abnormalities in keratinocytes may contribute to the pathogenesis of psoriasis.

Overexpression of Psoriasin (S100A7) Contributes to Dysregulated Differentiation in Psoriasis.

Psoriasin, which is highly expressed in psoriasis, is encoded by a gene located within the epidermal differentiation complex. The aim of this study was to investigate the effect of endogenous psoriasin on disturbed keratinocyte differentiation in psoriasis. Immunohistochemical staining revealed a gradient of psoriasin expression in the psoriatic epidermis with highest expression in the suprabasal, differentiated layers. Induction of keratinocyte differentiation caused concurrent expression of psoriasin and the differentiation marker involucrin. The differentiation-induced psoriasin expression was found to be mediated by the protein kinase C pathway. The downregulation of psoriasin expression by small interfering RNA revealed that psoriasin mediates the expression of involucrin, desmoglein 1, transglutaminase 1 and CD24 in normal differentiation. The lentivirus-mediated overexpression of psoriasin, mimicking the psoriatic milieu, gave rise to an altered regulation of differentiation genes and an expression pattern reminiscent of that in psoriatic epidermis. These findings suggest that psoriasin contributes to the dysregulated differentiation process in the psoriasis epidermis.

Deletion of the MGMT gene in familial melanoma.

The DNA repair gene MGMT (O-6-methylguanine-DNA methyltransferase) is important for maintaining normal cell physiology and genomic stability. Alterations in MGMT play a critical role in the development of several types of cancer, including glioblastoma, lung cancer, and colorectal cancer. The purpose of this study was to explore the function of genetic alterations in MGMT and their connection with familial melanoma (FM). Using multiplex ligation-dependent probe amplification, we identified a deletion that included the MGMT gene in one of 64 families with a melanoma predisposition living in western Sweden. The mutation segregated with the disease as a heterozygous deletion in blood-derived DNA, but a homozygous deletion including the promoter region and exon 1 was seen in tumor tissue based on Affymetrix 500K and 6.0 arrays. By sequence analysis of the MGMT gene in the other 63 families with FM from western Sweden, we identified four common polymorphisms, nonfunctional, as predominantly described in previous studies. We conclude that inherited alterations in the MGMT gene might be a rare cause of FM, and we suggest that MGMT contributes to melanoma predisposition.

Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis.

BACKGROUND: Psoriasis is associated with a systemic inflammation and an increased frequency of the metabolic syndrome, both of which are believed to link psoriasis to an increased risk of cardiovascular disease. OBJECTIVE: The study aimed to investigate the systemic expression of markers of cardiovascular risk and determine their response to ultraviolet B therapy and treatment with the tumor necrosis factor-alfa inhibitor, etanercept. METHODS: Six markers of cardiovascular risk were measured in 28 patients with psoriasis and 28 control subjects. RESULTS: Five of the 6 investigated markers were elevated in patients with psoriasis. Four of these correlated to the body mass index and waist-hip ratio, suggesting a link to the metabolic syndrome. Total plasminogen activator inhibitor-1 remained elevated independently of these factors. The levels of the investigated risk markers decreased considerably after tumor necrosis factor-alfa inhibitor treatment but remained unaffected by ultraviolet therapy. LIMITATIONS: A relatively limited study population and nonrandomization are limitations. CONCLUSION: These findings suggest that the choice of treatment in psoriasis may influence the cardiovascular risk in patients with psoriasis and the metabolic syndrome.

NOS2-derived low levels of NO drive psoriasis pathogenesis.

Psoriasis is an IL-23/Th17-mediated skin disorder with a strong genetic predisposition. The impact of its susceptibility gene nitric oxide synthase 2 (NOS2) remains unknown. Here, we demonstrate strong NOS2 mRNA expression in psoriatic epidermis, an effect that is IL-17 dependent. However, its complete translation to protein is prevented by the IL-17-induced miR-31 implying marginally upregulated NO levels in psoriatic skin. We demonstrate that lower levels of NO, as opposed to higher levels, increase keratinocyte proliferation and mediate IL-17 downstream effects. We hypothesized that the psoriatic phenotype may be alleviated by either eliminating or increasing cellular NO levels. In fact, using the imiquimod psoriasis mouse model, we found a profound impact on the psoriatic inflammation in both IMQ-treated NOS2 KO mice and wild-type mice treated with IMQ and the NO-releasing berdazimer gel. In conclusion, we demonstrate that IL-17 induces NOS2 and fine-tunes its translation towards a window of proinflammatory and hyperproliferative effects and identify NO donor therapy as a new treatment modality for psoriasis.

High levels of γ-glutamyl hydrolase (GGH) are associated with poor prognosis and unfavorable clinical outcomes in invasive breast cancer.

BACKGROUND: Previously, we performed analysis of gene expression in 46 axillary lymph node negative tumors and identified molecular gene signatures that resulted in different clinical outcomes. The aim of this study was to determine the correlation of γ-glutamyl hydrolase (GGH), fatty acid amide hydrolase (FAAH), Pirin (PIR) and TAF5-like RNA polymerase II, p300/CBP-associated factor (PCAF)-associated factor, 65 kDa (TAF5L), selected from identified gene signatures, with clinical outcomes as well as classical clinicopathological characteristics in primary invasive breast cancer patients. METHODS: The protein levels of GGH, FAAH, PIR and TAF5L were assessed by immunohistochemistry (IHC) on a panel of 80 primary invasive breast tumors. Quantitative real-time PCR (qRT-PCR) and western blot analysis were performed to verify the expression levels of the candidate biomarkers. Patient disease-specific survival (DSS) and recurrence-free survival (RFS) were evaluated using the Kaplan-Meier method. The prognostic biomarkers were identified by univariate analysis with a log-rank test and by multivariate analysis with Cox proportional hazards regression models. RESULTS: The GGH and FAAH protein levels were significantly up-regulated in invasive breast cancer tumors compared with adjacent non-cancerous tissues. Furthermore, the protein levels of GGH and FAAH were significantly correlated in tumor tissues. Tumoral GGH protein expression was significantly correlated with shorter DSS and RFS. Furthermore, the protein expression of GGH was positively correlated with undifferentiated tumors (BRE grade III) and ER/PR expressing tumors. Multivariate regression analysis showed that only GGH protein expression independently predicts DSS. No such correlations were found for FAAH, PIR and TAF5L protein expression. However, elevated protein levels of FAAH were positively associated with high number of lymph node involvement and upregulated levels of PIR were positively related with lymph node metastasis. The TAF5L was pronouncedly down-regulated in primary invasive breast cancer tissues compared to matched adjacent non-cancerous tissues. CONCLUSION: These data show for the first time that cytoplasmic GGH might play a relevant role in the development and progression of invasive breast cancer, warranting further investigations. Our findings suggest that GGH serve as a potential biomarker of unfavorable clinical outcomes over short-term follow-up in breast cancer. The GGH may be a very attractive targeted therapy for selected patients.

Systemically elevated Th1-, Th2- and Th17-associated chemokines in psoriasis vulgaris before and after ultraviolet B treatment.

Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation.

Psoriasin (S100A7), originally identified in psoriasis, is a calcium-binding protein belonging to the multigenic S100 family. In high-grade ductal carcinoma in situ, psoriasin was identified as one of the most abundant transcripts. We have previously shown that psoriasin was induced by reactive oxygen species (ROS). Moreover, the downregulation of psoriasin by short hairpin RNA (shRNA) led to the reduced expression of vascular endothelial growth factor (VEGF) and inhibited tumor growth in vivo. The aim of the present study was to investigate whether psoriasin could have direct effects on endothelial cells. In this study we demonstrated that psoriasin increased VEGF expression in mammary epithelial cells. The treatment of endothelial cells with recombinant psoriasin increased proliferation comparable to that of recombinant VEGF protein. No change in proliferation was seen when endothelial cells were infected with psoriasin-expressing adenoviruses, suggesting that the proliferative effect of psoriasin was mediated by a specific receptor. Treatment with sRAGE, targeting the receptor for advanced glycation end products (RAGE), thus inhibited endothelial cell proliferation and tube formation enhanced by recombinant psoriasin. We showed that VEGF expression was not induced by hydrogen peroxide, when psoriasin was silenced by shRNA, which led to the hypothesis that psoriasin induces ROS. Indeed, psoriasin was shown to induce ROS in both endothelial and epithelial cells. Moreover, sRAGE inhibited the psoriasin-dependent generation of ROS in endothelial cells. Finally, treatment with antioxidant Bcl-2 protein abolished the effect of psoriasin on endothelial cell proliferation. Our data suggest that psoriasin expression in mammary epithelial cells leads to increased endothelial cell proliferation in a paracrine manner through RAGE. Psoriasin may therefore play a role in breast cancer progression by promoting oxidative stress response and angiogenesis.

Genetic support for the role of the NLRP3 inflammasome in psoriasis susceptibility.

NACHT leucine-rich repeat- and PYD-containing (NLRP)3 protein controls the inflammasome by regulating caspase-1 activity and interleukin (IL)-1ß processing. The contribution of IL-1ß in the pathogenesis of psoriasis is well recognized. Polymorphisms in NLRP3 and caspase recruitment domain-containing protein (CARD)8, a negative regulator of caspase-1 activity, have been associated with susceptibility to common inflammatory diseases, such as Crohn's disease and rheumatoid arthritis. To investigate the role for genetic variants in the NLRP3 inflammasome in psoriasis susceptibility. In a patient sample comprising 1988 individuals from 491 families and 1002 healthy controls, genotypes for four selected single-nucleotide polymorphisms (SNPs) in NLRP3 (three SNPs) and CARD8 (one SNP) were determined by TaqMan(®) Allelic Discrimination. Using the transmission disequilibrium test (TDT), a significant increase in the transmission of the NLRP3 rs10733113G genotype to a subgroup of patients with more widespread psoriasis was demonstrated (P = 0.015). Using logistic regression analysis in 741 patients with psoriasis and 1002 controls, the CARD8 rs2043211 genotype was significantly different in cases and controls in overall terms [OR 1.3 (1.1-1.5), P = 0.004] and for both genders. Our data support the hypothesis that the inflammasome plays a role in psoriasis susceptibility.

Soluble biomarkers in psoriasis.

Psoriasis is a common, chronic, recurrent skin disorder, characterized by keratinocyte proliferation, T-cell activation and angiogenesis. The results of various clinical and experimental studies indicate that psoriasis is a complex, multifactorial disease with a genetic predisposition. During the past few years, many studies related to psoriasis biomarkers have been conducted. Biomarkers can relate to diagnosis, pathogenesis, prognosis, or therapeutic response. They could provide insight into disease susceptibility and natural history. The identification of biomarkers related to co-morbidities in psoriasis, such as arthritis, cardiovascular disease and the metabolic syndrome, has attracted special interest. This review presents current knowledge of soluble biomarkers in psoriasis, including cytokines, chemokines, pro-angiogenic mediators, growth factors, antimicrobial proteins, neuropeptides and markers of oxidative stress.

Enhanced Inflammasome Activity in Patients with Psoriasis Promotes Systemic Inflammation.

Psoriasis is linked to systemic inflammation and cardiovascular comorbidities, but studies of the underlying cellular mechanisms are lacking. The NLRP3 inflammasome is genetically associated with psoriasis, and its activation is increasingly linked with cardiovascular disease. In this study, we show that patients with psoriasis exhibited higher plasma levels of inflammasome-generated IL-1ß and IL-18, without any correlation to skin lesion severity. Increased constitutive expression of the inflammasome sensors NLRP3, NLRP1, and AIM2 was found in peripheral blood cells of the patients and also of those with mild disease, and this was accompanied by an increased caspase-1 reactivity in the myeloid blood subsets. TNF-α was found to activate selectively the NLRP3 inflammasome without the requirement for a priming signal. TNF-α was found to signal through the TNFR‒caspase-8‒caspase-1 alternative inflammasome pathway, which proceeds independently of pyroptosis. Patients who received anti-TNF therapy had normalized plasma IL-1ß and IL-18 levels as well as normalized caspase-1 reactivity. This was in contrast to the patients treated with methotrexate who exhibited persistent, increased caspase-1 reactivity. Thus, we show that the TNF-α-mediated activation of NLRP3 inflammasomes in patients with psoriasis may contribute to systemic inflammation. Anti-TNF therapy normalized inflammasome function, suggesting a mechanism for the cardiovascular risk‒reducing effect.

MTH1 Inhibitors for the Treatment of Psoriasis.

Inflammatory diseases, including psoriasis, are characterized by changes in redox regulation. The MTH1 prevents the incorporation of oxidized nucleotides during DNA replication. Using MTH1 small-molecule inhibitors, we found induced apoptosis through 8-oxodeoxyguanosine triphosphate accumulation and DNA double-strand breaks after oxidative stress in normal and malignant keratinocytes. In psoriasis, we detected increased MTH1 expression in lesional skin and PBMCs compared with that in the controls. Using the imiquimod psoriasis mouse model, we found that MTH1 inhibition diminished psoriatic histological characteristics and normalized the levels of neutrophils and T cells in the skin and skin-draining lymph nodes. The inhibition abolished the expression of T helper type 17‒associated cytokines in the skin, which was in line with decreased levels of IL-17-producing γδ T cells in lymph nodes. In human keratinocytes, MTH1 inhibition prevented the upregulation of IL-17‒downstream genes, which was independent of ROS-induced apoptosis. In conclusion, our data support MTH1 inhibition using small molecules suitable for topical application as a promising therapeutic approach to psoriasis.

BRCA1 gene mutations may explain more than 80% of excess number of ovarian cancer cases after breast cancer - a population based study from the Western Sweden Health Care region.

AIM: In a previous cohort study, we showed that there was a significant variation in the frequency of ovarian cancer after having breast cancer in Sweden, with the highest risk occuring in the Western region. The present study aimed to evaluate whether the high prevalence of the founder mutation BRCA1 3171ins5 may explain the excess number of ovarian cancer. METHOD: Among more than 26 000 women with breast cancer in the Western Swedish Health Care Region, 159 cases were subsequently diagnosed with ovarian cancer, whereas the expected number was 96. Archived tissue material was analysed for six common Scandinavian BRCA1 and BRCA2 gene mutations. RESULTS: The excess number of cases was 63 (95% CI 47-77), based on person-years at risk and national incidence rates of ovarian cancer. A BRCA1 gene mutation was detected in 33 cases corresponding to 52% of the excess number. The founder mutation, BRCA1 3171ins5, was detected in 44% of the excess number. The identified mutations decreased from 45% in women less than 50 years of age at follow-up to 14% at 60+ years at follow-up. There was no obvious decrease in mutation frequency by excess numbers with age. Age at follow-up and first-degree relatives with breast and/or ovarian cancer were the best predictors of a mutation in this material. CONCLUSION: The founder mutation, BRCA1 3171ins5, explains the excess of ovarian cancer after breast cancer in the region. From the relative frequency of the studied mutations found at the cancer genetic counselling clinic, it is estimated that BRCA1 gene mutations are associated with about 80-85% of the excess cases. This means that a negative screening for these mutations in similar cases may have a predictive value and could strongly reduce the risk of ovarian cancer in relatives.