PALB2 Variants Extend the Mutational Profile of Hungarian Patients with Breast and Ovarian Cancer.

BACKGROUND: The pathogenic/likely pathogenic (P/LP) variant detection rate and profile of PALB2, the third most important breast cancer gene, may vary between different populations. METHODS: PALB2 was analyzed in peripheral blood samples of three independent cohorts: prospectively between September 2021 and March 2023 (i) in 1280 consecutive patients with breast and/or ovarian cancer (HBOC), (ii) in 568 patients with other cancers (controls), and retrospectively, (iii) in 191 young breast cancer (<33 years, yBC) patients. These data were compared with data of 134,187 non-cancer individuals retrieved from the Genome Aggregation Database. RESULTS: Altogether, 235 cases (235/1280; 18.3%) carried at least one P/LP variant in one of the HBOC susceptibility genes. P/LP PALB2 variants were identified in 18 patients (1.4%; 18/1280) in the HBOC and 3 cases (1.5%; 3/191) in the yBC group. In the control group, only one patient had a disease-causing PALB2 variant (0.17%; 1/568) as a secondary finding not related to the disease, which was similar (0.15%; 205/134,187) in the non-cancer control group. The NM_024675.4:c.509_510delGA variant was the most common among our patients (33%; 6/18). We did not find a significant difference in the incidence of PALB2 disease-causing variants according to age; however, the median age of tumor onset was lower in PALB2 P/LP carriers versus wild-type patients (44 vs. 48 years). In our cohort, the odds ratio for breast cancer risk in women with PALB2 P/LP variants was between 8.1 and 9.3 compared to non-HBOC cancer patients and the non-cancer population, respectively. CONCLUSIONS: PALB2 P/LP variants are not uncommon among breast and/or ovarian cancer patients. Their incidence was the same in the two breast cancer cohorts studied but may occur rarely in patients with non-breast/ovarian cancer. The c.509_510delGA variant is particularly common in the studied Hungarian patient population.

Cell facilitation promotes growth and survival under drug pressure in breast cancer.

The interplay of positive and negative interactions between drug-sensitive and resistant cells influences the effectiveness of treatment in heterogeneous cancer cell populations. Here, we study interactions between estrogen receptor-positive breast cancer cell lineages that are sensitive and resistant to ribociclib-induced cyclin-dependent kinase 4 and 6 (CDK4/6) inhibition. In mono- and coculture, we find that sensitive cells grow and compete more effectively in the absence of treatment. During treatment with ribociclib, sensitive cells survive and proliferate better when grown together with resistant cells than when grown in monoculture, termed facilitation in ecology. Molecular, protein, and genomic analyses show that resistant cells increase metabolism and production of estradiol, a highly active estrogen metabolite, and increase estrogen signaling in sensitive cells to promote facilitation in coculture. Adding estradiol in monoculture provides sensitive cells with increased resistance to therapy and cancels facilitation in coculture. Under partial inhibition of estrogen signaling through low-dose endocrine therapy, estradiol supplied by resistant cells facilitates sensitive cell growth. However, a more complete blockade of estrogen signaling, through higher-dose endocrine therapy, diminished the facilitative growth of sensitive cells. Mathematical modeling quantifies the strength of competition and facilitation during CDK4/6 inhibition and predicts that blocking facilitation has the potential to control both resistant and sensitive cancer cell populations and inhibit the emergence of a refractory population during cell cycle therapy.

A common genetic variation in GZMB may associate with cancer risk in patients with Lynch syndrome.

Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is a common genetic predisposition to cancer due to germline mutations in genes affecting DNA mismatch repair. Due to mismatch repair deficiency, developing tumors are characterized by microsatellite instability (MSI-H), high frequency of expressed neoantigens and good clinical response to immune checkpoint inhibitors. Granzyme B (GrB) is the most abundant serine protease in the granules of cytotoxic T-cells and natural killer cells, mediating anti-tumor immunity. However, recent results confirm a diverse range of physiological functions of GrB including that in extracellular matrix remodelling, inflammation and fibrosis. In the present study, our aim was to investigate whether a frequent genetic variation of GZMB, the gene encoding GrB, constituted by three missense single nucleotide polymorphisms (rs2236338, rs11539752 and rs8192917) has any association with cancer risk in individuals with LS. In silico analysis and genotype calls from whole exome sequencing data in the Hungarian population confirmed that these SNPs are closely linked. Genotyping results of rs8192917 on a cohort of 145 individuals with LS demonstrated an association of the CC genotype with lower cancer risk. In silico prediction proposed likely GrB cleavage sites in a high proportion of shared neontigens in MSI-H tumors. Our results propose the CC genotype of rs8192917 as a potential disease-modifying genetic factor in LS.

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization.

Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as a result of germline mutations in the APC gene. Despite a clear clinical diagnosis of FAP, a certain proportion of the APC variants are not readily detectable through conventional genotyping routines. We accomplished genome sequencing in duo of the disease-affected proband and non-affected sibling followed by in silico predictions and a series of RNA-based assays clarifying variant functionality. By prioritizing variants obtained by genome sequencing, we discovered the novel deep intronic alteration APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of 56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant splicing event was complete and its splice product was subject to nonsense-mediated decay. Co-segregation was observed between the variant carrier status and the disease phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic variant causative of the disease.

Is HLA type a possible cancer risk modifier in Lynch syndrome?

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.

Reclassification of Five BRCA1/2 Variants with Unknown Significance Using Complex Functional Study.

PURPOSE: While BRCA1/2 genes are commonly investigated, variants of unknown significance (VUS) and variants with potential splice effect are still being detected and they represent a substantial challenge in genetic counseling and therapy. MATERIALS AND METHODS: Out of genetically tested 3,568 hereditary breast and ovarian cancer probands five, functionally not investigated variants with potential splice-modifying effect were subjected to functional characterization. Transcript-level analysis on peripheral blood-derived RNA of the carriers was performed to test aberrant splicing. The completeness of the aberrant splicing event was also studied, existence and extent of nonsense-mediated decay was even addressed. Clinical and phenotype data, pedigree and co-segregation analyses were also done. Locus-specific loss of heterozygosity (LOH) in tumor tissues was additionally tested. RESULTS: In case of the BRCA1:c.4484+4dupA and the BRCA1:c.5407-10G>A variants functional results allowed us to reclassify them from VUS into likely pathogenic category. BRCA1:c.4358-31A>C, by producing incomplete aberrant splicing, was highlighted as strong VUS, but in lack of other supporting evidence, re-categorization was not possible. The likely pathogenic assertion of previously not reported BRCA2:c.8487G>T was reinforced based on its spliceogenic property and tumor LOH, while BRCA2:c.793G>A failed to present aberrant splicing in spite of suggestive predictions, which altered its original VUS evaluation into likely benign class. CONCLUSION: We presented molecular and clinical evidence for reclassification of four out of five BRCA1/2 variants. Both up- and down-classification harbour important clinical significance. Patients carrying re-classified pathogenic variants in the future will not be dropped out from medical surveillance, preventive measures, treatment and predictive family screening in relatives at risk.

Germline Structural Variations in Cancer Predisposition Genes.

In addition to single nucleotide variations and small-scale indels, structural variations (SVs) also contribute to the genetic diversity of the genome. SVs, such as deletions, duplications, amplifications, or inversions may also affect coding regions of cancer-predisposing genes. These rearrangements may abrogate the open reading frame of these genes or adversely affect their expression and may thus act as germline mutations in hereditary cancer syndromes. With the capacity of disrupting the function of tumor suppressors, structural variations confer an increased risk of cancer and account for a remarkable fraction of heritability. The development of sequencing techniques enables the discovery of a constantly growing number of SVs of various types in cancer predisposition genes (CPGs). Here, we provide a comprehensive review of the landscape of germline SV types, detection methods, pathomechanisms, and frequency in CPGs, focusing on the two most common cancer syndromes: hereditary breast- and ovarian cancer and gastrointestinal cancers. Current knowledge about the possible molecular mechanisms driving to SVs is also summarized.

Germline Genetic Variants of Viral Entry and Innate Immunity May Influence Susceptibility to SARS-CoV-2 Infection: Toward a Polygenic Risk Score for Risk Stratification.

The ongoing COVID-19 pandemic caused by the novel coronavirus, SARS-CoV-2 has affected all aspects of human society with a special focus on healthcare. Although older patients with preexisting chronic illnesses are more prone to develop severe complications, younger, healthy individuals might also exhibit serious manifestations. Previous studies directed to detect genetic susceptibility factors for earlier epidemics have provided evidence of certain protective variations. Following SARS-CoV-2 exposure, viral entry into cells followed by recognition and response by the innate immunity are key determinants of COVID-19 development. In the present review our aim was to conduct a thorough review of the literature on the role of single nucleotide polymorphisms (SNPs) as key agents affecting the viral entry of SARS-CoV-2 and innate immunity. Several SNPs within the scope of our approach were found to alter susceptibility to various bacterial and viral infections. Additionally, a multitude of studies confirmed genetic associations between the analyzed genes and autoimmune diseases, underlining the versatile immune consequences of these variants. Based on confirmed associations it is highly plausible that the SNPs affecting viral entry and innate immunity might confer altered susceptibility to SARS-CoV-2 infection and its complex clinical consequences. Anticipating several COVID-19 genomic susceptibility loci based on the ongoing genome wide association studies, our review also proposes that a well-established polygenic risk score would be able to clinically leverage the acquired knowledge.

Exploiting collateral sensitivity controls growth of mixed culture of sensitive and resistant cells and decreases selection for resistant cells in a cell line model.

BACKGROUND: CDK4/6 inhibitors such as ribociclib are becoming widely used targeted therapies in hormone-receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, cancers can advance due to drug resistance, a problem in which tumor heterogeneity and evolution are key features. METHODS: Ribociclib-resistant HR+/HER2- CAMA-1 breast cancer cells were generated through long-term ribociclib treatment. Characterization of sensitive and resistant cells were performed using RNA sequencing and whole exome sequencing. Lentiviral labeling with different fluorescent proteins enabled us to track the proliferation of sensitive and resistant cells under different treatments in a heterogeneous, 3D spheroid coculture system using imaging microscopy and flow cytometry. RESULTS: Transcriptional profiling of sensitive and resistant cells revealed the downregulation of the G2/M checkpoint in the resistant cells. Exploiting this acquired vulnerability; resistant cells exhibited collateral sensitivity for the Wee-1 inhibitor, adavosertib (AZD1775). The combination of ribociclib and adavosertib achieved additional antiproliferative effect exclusively in the cocultures compared to monocultures, while decreasing the selection for resistant cells. CONCLUSIONS: Our results suggest that optimal antiproliferative effects in heterogeneous cancers can be achieved via an integrative therapeutic approach targeting sensitive and resistant cancer cell populations within a tumor, respectively.

True MEN1 or phenocopy? Evidence for geno-phenotypic correlations in MEN1 syndrome.

PURPOSE: Multiple endocrine neoplasia type 1 is a rare tumor syndrome caused by germline mutations of MEN1 gene. Phenotype varies widely, and no definitive correlation with the genotype has been observed. Mutation-negative patients with MEN1-associated tumors represent phenocopies. By comparing mutation-positive and mutation-negative patients, we aimed to identify phenotype features predictive for a positive genetic test and to evaluate the role of MEN1 mutations in phenotype modulation. METHODS: Mutation screeening of MEN1 gene by Sanger sequencing and assessment of clinical data of 189 consecutively enrolled probands and relatives were performed at our national and European Reference Center. Multiple ligation probe amplification analysis of MEN1 gene and Sanger sequencing of CDKN1B were carried out in clinically suspicious but MEN1-negative cases. RESULTS: Twenty-seven probands and twenty family members carried MEN1 mutations. Five mutations have not been described earlier. Pronouncedly high number of phenocopies (>70%) was observed. Clinical suspicion of MEN1 syndrome emerged at significantly earlier age in MEN1-positive compared to MEN1-negative probands. Gastroenteropancreatic neuroendocrine tumors developed significantly earlier and more frequently in carriers compared to non-carriers. Probands with high-impact (frameshift, nonsense, large deletions) mutations, predicted to affect menin function significantly, developed GEP-NETs more frequently compared to low-impact (inframe and missense) mutation carriers. CONCLUSIONS: MEN1 phenocopy is common and represents a significant confounder for the genetic testing. GEP-NET under 30 years best predicted a MEN1 mutation. The present study thus confirmed a previous proposal and suggested that GEP-NET under 30 years should be considered as a part of the indication criteria for MEN1 mutational analysis.

Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms

Objective: Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas; however, their prognosis differs significantly upon their proliferative state, which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods: MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of five miRNAs on an independent validation cohort of 63 primary PanNEN samples. Cox proportional hazards survival regression models were fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results: Nineteen miRNAs displayed differential expression between tumor grades. The altered expression of three out of five chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were upregulated in more proliferative PanNENs compared to Grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b of primary PanNENs predicted worse progression-free and overall survival; however, multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions: The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.

[Evolution of molecular genetic methods in the clinical diagnosis of hereditary endocrine tumour syndromes]. / Molekuláris genetikai vizsgálatok az örökletes endokrinológiai tumor szindrómák klinikai diagnosztikájában.

The common features of hereditary endocrine tumour syndromes or multiple endocrine neoplasias (MEN) are the association of various tumours of different endocrine organs in one patient or within the same family. Different types can be distinguished from among which type 1 and type 2 are the most common. The mode of inheritance is autosomal dominant, meaning that there is a 50% chance to inherit the pathogenic alteration. The pathogenic variants of genes responsible for MEN syndromes have also been identified in sporadic endocrine tumours and many cases initially referred to as sporadic have been later categorized as familiar based on genetic analysis. The main role of the molecular genetic analysis in these syndromes is to identify the pathogenic variant, then, after appropriate genetic counseling, to perform the genetic screening of first-degree relatives. Following molecular genetic analysis, the state-of-the-art clinical follow-up of the clinically healthy mutation carriers may decrease or even prevent the morbidity and mortality. Due to technological developments in recent years, the molecular genetic analysis of hereditary tumour syndromes has also been changed. Using next generation based sequencing methods in routine clinical diagnostics, the number of pathogenic genes in endocrine tumours has also increased. The present review focuses on the genetic background of hereditary endocrine tumour syndromes and the recently used molecular biological methods will also be presented. Orv Hetil. 2018; 159(7): 285-292.

MEN1 mutations and potentially MEN1-targeting miRNAs are responsible for menin deficiency in sporadic and MEN1 syndrome-associated primary hyperparathyroidism.

Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.

Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer.

Adrenocortical cancer (ACC) is a rare, but agressive malignancy with poor prognosis. Histopathological diagnosis is challenging and pharmacological options for treatment are limited. By the comparative reanalysis of the transcriptional malignancy signature with the cell cycle dependent transcriptional program of ACC, we aimed to identify novel biomarkers which may be used in the histopathological diagnosis and for the prediction of therapeutical response of ACC. Comparative reanalysis of publicly available microarray datasets included three earlier studies comparing transcriptional differences between ACC and benign adrenocortical adenoma (ACA) and one study presenting the cell cycle dependent gene expressional program of human ACC cell line NCI-H295R. Immunohistochemical analysis was performed on ACC samples. In vitro effects of antineoplastic drugs including gemcitabine, mitotane and 9-cis-retinoic acid alone and in combination were tested in the NCI-H295R adrenocortical cell line. Upon the comparative reanalysis, ribonucleotide reductase subunit 2 (RRM2), responsible for the ribonucleotide dezoxyribonucleotide conversion during the S phase of the cell cycle has been validated as cell cycle dependently expressed. Moreover, its expression was associated with the malignancy signature, as well. Immunohistochemical analysis of RRM2 revealed a strong correlation with Ki67 index in ACC. Among the antiproliferative effects of the investigated compounds, gemcitabine showed a strong inhibition of proliferation and an increase of apoptotic events. Additionally, RRM2 has been upregulated upon gemcitabine treatment. Upon our results, RRM2 might be used as a proliferation marker in ACC. RRM2 upregulation upon gemcitabine treatment might contribute to an emerging chemoresistance against gemcitabine, which is in line with its limited therapeutical efficacy in ACC, and which should be overcome for successful clinical applications.

Fluorescence activated cell sorting followed by small RNA sequencing reveals stable microRNA expression during cell cycle progression.

BACKGROUND: Previously, drug-based synchronization procedures were used for characterizing the cell cycle dependent transcriptional program. However, these synchronization methods result in growth imbalance and alteration of the cell cycle machinery. DNA content-based fluorescence activated cell sorting (FACS) is able to sort the different cell cycle phases without perturbing the cell cycle. MiRNAs are key transcriptional regulators of the cell cycle, however, their expression dynamics during cell cycle has not been explored. METHODS: Following an optimized FACS, a complex initiative of high throughput platforms (microarray, Taqman Low Density Array, small RNA sequencing) were performed to study gene and miRNA expression profiles of cell cycle sorted human cells originating from different tissues. Validation of high throughput data was performed using quantitative real time PCR. Protein expression was detected by Western blot. Complex statistics and pathway analysis were also applied. RESULTS: Beyond confirming the previously described cell cycle transcriptional program, cell cycle dependently expressed genes showed a higher expression independently from the cell cycle phase and a lower amplitude of dynamic changes in cancer cells as compared to untransformed fibroblasts. Contrary to mRNA changes, miRNA expression was stable throughout the cell cycle. CONCLUSIONS: Cell cycle sorting is a synchronization-free method for the proper analysis of cell cycle dynamics. Altered dynamic expression of universal cell cycle genes in cancer cells reflects the transformed cell cycle machinery. Stable miRNA expression during cell cycle progression may suggest that dynamical miRNA-dependent regulation may be of less importance in short term regulations during the cell cycle.

Genetic variants of the HSD11B1 gene promoter may be protective against polycystic ovary syndrome.

The HSD11B1 gene encodes the type 1 isoform of the 11-ß-hydroxysteroid dehydrogenase that is responsible for the regeneration of glucocorticoids from hormonally-inactive metabolites into active forms in a tissue-specific manner. Altered activity of the enzyme, and certain genetic variants of the HSD11B1 gene, has been associated with various metabolic morbidities. In this study, our aim was to systematically test the potential role of the HSD11B1's single nucleotide polymorphisms (SNPs) in polycystic ovary syndrome (PCOS). Nine HSD11B1 SNPs were selected and genotyped using Taqman SNP assays on real-time PCR in a group of PCOS patients (n = 58) and in age-matched healthy controls (n = 64). Genotype-phenotype correlations were determined and haplotype analysis was performed. An in silico prediction for potential transcription factor binding sites was also performed. Of the 5 promoter SNPs, 3 (rs760951; rs4844880; rs3753519) were less frequent in the PCOS group compared to healthy controls. SNPs rs4844880 and rs3753519 were in a complete linkage and the mutant haplotype (AA) was less frequent in the PCOS group. No association between HSD11B1 variants and clinical, pathological findings was observed in patients, but in healthy women the rs4844880 and the AA haplotype were associated with higher levels of homeostasis model assessment of beta cell function. The polymorphic form of the rs4844880 was predicted to bind Pbx-1. Promoter SNPs of the HSD11B1 gene might exert a potential genetic protective role against the development of PCOS, possibly via their beneficial effect on carbohydrate homeostasis due to facilitation of insulin efflux from pancreatic beta-cells.

[Importance of the 11ß-hydroxysteroid dehydrogenase enzyme in clinical disorders]. / A 11-ß-hidroxi-szteroid-dehidrogenáz enzim jelentosége klinikai kórképekben.

Glucocorticoids play an important role in the regulation of carbohydrate and amino acid metabolism, they modulate the function of the immune system, and contribute to stress response. Increased and decreased production of glucocorticoids causes specific diseases. In addition to systemic hypo- or hypercortisolism, alteration of local synthesis and metabolism of cortisol may result in tissue-specific hypo- or hypercortisolism. One of the key enzymes participating in the local synthesis and metabolism of cortisol is the 11ß-hydroxysteroid dehydrogenase enzyme. Two isoforms, type 1 and type 2 enzymes are located in the endoplasmic reticulum and catalyze the interconversion of hormonally active cortisol and inactive cortisone. The type 1 enzyme mainly works as an activator, and it is responsible for the generation of cortisol from cortisone in liver, adipose tissue, brain and bone. The gene encoding this enzyme is located on chromosome 1. The authors review the physiological and pathophysiological processes related to the function of the type 1 11ß-hydroxysteroid dehydrogenase enzyme. They summarize the potential significance of polymorphic variants of the enzyme in clinical diseases as well as knowledge related to inhibitors of enzyme activity. Although further studies are still needed, inhibition of the enzyme activity may prove to be an effective tool for the treatment of several diseases such as obesity, osteoporosis and type 2 diabetes.