Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (4)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: PRSS1 (cancer-related)
Yi Q, Dong F, Lin L, et al.PRSS1 mutations and the proteinase/antiproteinase imbalance in the pathogenesis of pancreatic cancer.
Tumour Biol. 2016; 37(5):5805-10 [PubMed
] Related Publications
This study aimed to investigate the mutations in the serine protease 1 gene (PRSS1) and the imbalance between trypsin and α1-antitrypsin in patients with pancreatic cancer. Polymerase chain reaction (PCR) was performed to amplify the sequences of PRSS1 from 65 patients with pancreatic cancer and 260 healthy controls, direct sequencing was performed, and the clinical features were analyzed. In addition, enzyme-linked immunosorbent assay (ELISA) was employed to detect serum trypsin and α1-antitrypsin in pancreatic cancer patients and healthy controls in the same period. Mutations were found at the promoter and exon 3 of the PRSS1 in patients with pancreatic cancer. That is, five patients had c.410 C > T mutation causing p.Thr 137 Met, and three patients had c. -338 T > G mutation at the promoter of the PRSS1. In patients with PRSS1 mutations, serum trypsin was 34.5 ± 18.3 ng/mL, which was significantly higher than that in normal controls (10.65 ± 6.03 ng/mL) and other pancreatic cancer (28.61 ± 8.96 ng/mL). What is more, in pancreatic cancer patients, serum α1-antitrypsin was 1.69 ± 0.86 g/L, which was comparable to that in normal controls (1.55 ± 0.53 g/L), while the ratio of serum trypsin to α1-antitrypsin was 1.46-fold to normal controls. The results presented here have provided a greater insight into the PRSS1 mutations and proteinase-inhibitor interactions occurring in pancreatic cancer.
Proteases contribute to cancer in many ways, including tumor vascularization and metastasis, and their pharmacological inhibition is a potential anticancer strategy. We report that human endothelial cells (EC) express the trypsinogen 4 isoform of the serine protease 3 (PRSS3), and lack both PRSS2 and PRSS1. Trypsinogen 4 expression was upregulated by the combined action of VEGF-A, FGF-2 and EGF, angiogenic factors representative of the tumor microenvironment. Suppression of trypsinogen 4 expression by siRNA inhibited the angiogenic milieu-induced migration of EC from cancer specimens (tumor-EC), but did not affect EC from normal tissues. We identified tissue factor pathway inhibitor-2 (TFPI-2), a matrix associated inhibitor of cell motility, as the functional target of trypsinogen 4, which cleaved TFPI-2 and removed it from the matrix put down by tumor-EC. Silencing tumor-EC for trypsinogen 4 accumulated TFPI2 in the matrix. Showing that angiogenic factors stimulate trypsinogen 4 expression, which hydrolyses TFPI-2 favoring a pro-migratory situation, our study suggests a new pathway linking tumor microenvironment signals to endothelial cell migration, which is essential for angiogenesis and blood vessel remodeling. Abolishing trypsinogen 4 functions might be an exploitable strategy as anticancer, particularly anti-vascular, therapy.
Hansford S, Kaurah P, Li-Chang H, et al.Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.
JAMA Oncol. 2015; 1(1):23-32 [PubMed
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IMPORTANCE: E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options.
OBJECTIVES: To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC.
DESIGN, SETTING, AND PARTICIPANTS: Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes.
MAIN OUTCOMES AND MEASURES: Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers.
RESULTS: Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2.
CONCLUSIONS AND RELEVANCE: This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.
BACKGROUND & AIMS: We investigated the prevalence of germline mutations in APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, PRSS1, STK11, and TP53 in patients with pancreatic cancer.
METHODS: The Ontario Pancreas Cancer Study enrolls consenting participants with pancreatic cancer from a province-wide electronic pathology database; 708 probands were enrolled from April 2003 through August 2012. To improve the precision of BRCA2 prevalence estimates, 290 probands were selected from 3 strata, based on family history of breast and/or ovarian cancer, pancreatic cancer, or neither. Germline DNA was analyzed by next-generation sequencing using a custom multiple-gene panel. Mutation prevalence estimates were calculated from the sample for the entire cohort.
RESULTS: Eleven pathogenic mutations were identified: 3 in ATM, 1 in BRCA1, 2 in BRCA2, 1 in MLH1, 2 in MSH2, 1 in MSH6, and 1 in TP53. The prevalence of mutations in all 13 genes was 3.8% (95% confidence interval, 2.1%-5.6%). Carrier status was associated significantly with breast cancer in the proband or first-degree relative (P < .01), and with colorectal cancer in the proband or first-degree relative (P < .01), but not family history of pancreatic cancer, age at diagnosis, or stage at diagnosis. Of patients with a personal or family history of breast and colorectal cancer, 10.7% (95% confidence interval, 4.4%-17.0%) and 11.1% (95% confidence interval, 3.0%-19.1%) carried pathogenic mutations, respectively.
CONCLUSIONS: A small but clinically important proportion of pancreatic cancer is associated with mutations in known predisposition genes. The heterogeneity of mutations identified in this study shows the value of using a multiple-gene panel in pancreatic cancer.
Schubert S, Traub F, Brakensiek K, et al.CFTR, SPINK1, PRSS1, and CTRC mutations are not associated with pancreatic cancer in German patients.
Pancreas. 2014; 43(7):1078-82 [PubMed
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OBJECTIVE: Mutations in the cationic trypsinogen (PRSS1), cystic fibrosis transmembrane conductance regulator (CFTR), serine protease inhibitor Kazal type 1 (SPINK1), and chymotrypsin C (CTRC) genes are associated with an elevated risk for chronic pancreatitis, which is a known risk factor for pancreatic cancer (PC). Therefore, we analyzed whether PRSS1, CFTR, SPINK1, and/or CTRC mutations are associated with pancreatic adenocarcinoma.
METHODS: The study cohort was composed of 121 PC patients, of whom 74 were classified as having chronic pancreatitis, 102 patients with idiopathic chronic pancreatitis, and 130 as healthy controls. Mutation analyses for the CFTR, SPINK1, PRSS1, and CTRC genes were performed for the presence of the most common mutations.
RESULTS: The frequency of CFTR mutations in patients with PC was not significantly different in comparison with healthy controls and controls with pancreatitis. The SPINK1 mutation frequency was significantly decreased in patients with PC in comparison with patients with idiopathic pancreatitis but varied not significantly in comparison with healthy controls. None of the selected 121 PC samples showed a pancreatitis-predisposing mutation in the PRSS1 or CTRC gene.
CONCLUSIONS: Mutations in the genes CFTR, SPINK1, PRSS1, and CTRC do not seem to significantly increase the risk for pancreatic adenocarcinoma.
PURPOSE: Multiple-gene sequencing is entering practice, but its clinical value is unknown. We evaluated the performance of a customized germline-DNA sequencing panel for cancer-risk assessment in a representative clinical sample.
METHODS: Patients referred for clinical BRCA1/2 testing from 2002 to 2012 were invited to donate a research blood sample. Samples were frozen at -80° C, and DNA was extracted from them after 1 to 10 years. The entire coding region, exon-intron boundaries, and all known pathogenic variants in other regions were sequenced for 42 genes that had cancer risk associations. Potentially actionable results were disclosed to participants.
RESULTS: In total, 198 women participated in the study: 174 had breast cancer and 57 carried germline BRCA1/2 mutations. BRCA1/2 analysis was fully concordant with prior testing. Sixteen pathogenic variants were identified in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1, and SLX4 among 141 women without BRCA1/2 mutations. Fourteen participants carried 15 pathogenic variants, warranting a possible change in care; they were invited for targeted screening recommendations, enabling early detection and removal of a tubular adenoma by colonoscopy. Participants carried an average of 2.1 variants of uncertain significance among 42 genes.
CONCLUSION: Among women testing negative for BRCA1/2 mutations, multiple-gene sequencing identified 16 potentially pathogenic mutations in other genes (11.4%; 95% CI, 7.0% to 17.7%), of which 15 (10.6%; 95% CI, 6.5% to 16.9%) prompted consideration of a change in care, enabling early detection of a precancerous colon polyp. Additional studies are required to quantify the penetrance of identified mutations and determine clinical utility. However, these results suggest that multiple-gene sequencing may benefit appropriately selected patients.
Stress has been reported to induce alterations of skin pigmentary response. Acute stress is associated with increased turnover of serotonin (5-hydroxytryptamine; 5-HT) whereas chronic stress causes a decrease. 5-HT receptors have been detected in pigment cells, indicating their role in skin pigmentation. To ascertain the precise role of 5-HT in stress-induced pigmentary responses, C57BL/6 mice were subjected to chronic restraint stress and chronic unpredictable mild stress (CRS and CUMS, two models of chronic stress) for 21 days, finally resulting in abnormal pigmentary responses. Subsequently, stressed mice were characterized by the absence of a black pigment in dorsal coat. The down-regulation of tyrosinase (TYR) and tyrosinase-related proteins (TRP1 and TRP2) expression in stressed skin was accompanied by reduced levels of 5-HT and decreased expression of 5-HT receptor (5-HTR) system. In both murine B16F10 melanoma cells and normal human melanocytes (NHMCs), 5-HT had a stimulatory effect on melanin production, dendricity and migration. When treated with 5-HT in cultured hair follicles (HFs), the increased expression of melanogenesis-related genes and the activation of 5-HT1A, 1B and 7 receptors also occurred. The serum obtained from stressed mice showed significantly decreased tyrosinase activity in NHMCs compared to that from nonstressed mice. The decrease in tyrosinase activity was further augmented in the presence of 5-HTR1A, 1B and 7 antagonists, WAY100635, SB216641 and SB269970. In vivo, stressed mice received 5-HT precursor 5-hydroxy-l-tryptophan (5-HTP), a member of the class of selective serotonin reuptake inhibitors (fluoxetine; FX) and 5-HTR1A/1B agonists (8-OH-DPAT/CP94253), finally contributing to the normalization of pigmentary responses. Taken together, these data strongly suggest that the serotoninergic system plays an important role in the regulation of stress-induced depigmentation, which can be mediated by 5-HT1A/1B receptors. 5-HT and 5-HTR1A/1B may constitute novel targets for therapy of skin hypopigmentation disorders, especially those worsened with stress.
Beset by poor prognosis, pancreatic ductal adenocarcinoma is classified as familial or sporadic. This review elaborates on the known genetic syndromes that underlie familial pancreatic cancer, where there are opportunities for genetic counseling and testing as well as clinical monitoring of at-risk patients. Such subsets of familial pancreatic cancer involve germline cationic trypsinogen or PRSS1 mutations (hereditary pancreatitis), BRCA2 mutations (usually in association with hereditary breast-ovarian cancer syndrome), CDKN2 mutations (familial atypical mole and multiple melanoma), or DNA repair gene mutations (e.g., ATM and PALB2, apart from those in BRCA2). However, the vast majority of familial pancreatic cancer cases have yet to have their genetic underpinnings elucidated, waiting in part for the results of deep sequencing efforts.
Hamoir C, Pepermans X, Piessevaux H, et al.Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants.
Digestion. 2013; 87(4):229-39 [PubMed
] Related Publications
BACKGROUND/AIMS: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis.
METHODS: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68).
RESULTS: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers.
CONCLUSION: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking.
AIM: To describe protease serine 1 (PRSS1) gene mutations in patients with autoimmune pancreatitis (AIP) and the clinical features of AIP.
METHODS: Fourteen patients with AIP, 56 with other chronic pancreatitis, 254 with pancreatic cancer and 120 normal controls were studied. The mutations and polymorphisms of four genes involved with pancreatitis or pancreatic cancer, PRSS1, SPINK1, CFTR and MEN1, were sequenced. The pathogenic mechanism of AIP was investigated by comparing the wild-type expression system with the p.81Leu→Met mutant expression system.
RESULTS: Two novel mutations (p.81Leu→Met and p.91Ala→Ala) were found in PRSS1 gene from four patients with AIP. PRSS1_p.81Leu→Met mutation led to a trypsin display reduction (76.2%) combined with phenyl agarose (Ca(2+) induced failure). Moreover, the ratio of trypsin/amylase in patients with AIP was higher than in the patients with pancreatic cancer and other pancreatitis. A large number of lymphocytes and plasma cells were found in the bile ducts accompanied by hyperplasia of myofibroblasts.
CONCLUSION: Autoimmune pancreatitis may be related to PRSS1 gene mutations.
Watanuki Y, Takayasu S, Kageyama K, et al.Involvement of Nurr-1/Nur77 in corticotropin-releasing factor/urocortin1-induced tyrosinase-related protein 1 gene transcription in human melanoma HMV-II cells.
Mol Cell Endocrinol. 2013; 370(1-2):42-51 [PubMed
] Related Publications
Recent molecular and biochemical analyses have revealed the presence of corticotropin-releasing factor (CRF) and urocortin (Ucn), together with their corresponding receptors in mammalian skin. The melanosomal enzyme tyrosinase-related protein 1 (TRP1) is involved in modulation of pigment production in response to stressors. Although CRF and Ucn are thought to have potent effects on the skin system, their possible roles and regulation have yet to be fully determined. This study aimed to explore the effects of CRF and Ucn on TRP1 gene expression using human melanoma HMV-II cells. The mRNA of CRF, Ucn1, Ucn2, and CRF receptor type 1 (CRF1 receptor) was detected in HMV-II cells. CRF and Ucn1 stimulated TRP1 gene transcription via the CRF1 receptor, and increased both Nurr-1 and Nur77 mRNA expression levels. Both CRF- and Ucn1-induced Nurr-1/Nur77 acted via a NGFI-B response element on the TRP1 promoter. The combination of Nurr-1/Nur77 and microphthalmia-associated transcription factor, a melanocyte-specific transcription factor gene induced by α-melanocyte-stimulating hormone, had additive effects on activation of TRP1 gene transcription. The findings suggest that in human melanoma HMV-II cells both CRF and Ucn1 regulate TRP1 gene expression via Nurr-1/Nur77 production, independent of pro-opiomelanocortin or α-melanocyte-stimulating hormone stimulation.
Pancreatic cancer remains one of the most challenging of all cancers. Genetic risk factors are believed to play a major role, but other than genes coding for blood group, genetic risks for sporadic cases remain elusive. However, several germline mutations have been identified that lead to hereditary pancreatic cancer, familial pancreatic cancer, and increased risk for pancreatic cancer as part of a familial cancer syndrome. The most important genes with variants increasing risk for pancreatic cancer include BRCA1, BRCA2, PALB2, ATM, CDKN2A, APC, MLH1, MSH2, MSH6, PMS2, PRSS1, and STK11. Recognition of members of high-risk families is important for understanding pancreatic cancer biology, for recommending risk reduction strategies and, in some cases, initiating cancer surveillance programs. Because the best methods for surveillance have not been established, the recommendation to refer at-risk patients to centers with ongoing research programs in pancreatic cancer surveillance is supported.
Gou S, Yu J, Wang C, et al.Three female familial cases of solid pseudopapillary tumors with a protease serine 1 gene mutation.
Pancreas. 2013; 42(1):168-73 [PubMed
] Related Publications
Solid pseudopapillary tumors (SPTs) are a rare pancreatic neoplastic lesion. Familial aggregation has not been reported in this disease. The objectives of this study were to report the history, clinicopathological features, and gene mutations of 3 familial cases of SPT. Three female cases of SPT presented in 1 family. Eight family relatives, 5 healthy volunteers, and 8 patients with SPT acted as controls. Histological examination and immunohistochemistry were performed on the surgical tumor specimens. Polymerase chain reaction-single-strand conformation polymorphism and gene sequencing were performed on genomic DNA extracted from blood. All 3 patients underwent surgical treatment, 2 patients died (3 months and 5 months after surgery), whereas neither recurrence nor metastasis was observed in the other patient during 2-year follow-up. The tumors from the 3 cases had identical immunoreactivity to a series of molecular markers. A Leu104Val mutation of protease serine 1 (PRSS1) was observed in the familial patients and 2 healthy male family members; no β-catenin or adenomatous polyposis coli mutations were detected in the familial cases. This study indicates the possibility of genetic involvement in the pathogenesis of SPT. Family history may be a positive predictive factor for malignancy in SPT.
Gao F, Liu QC, Zhang S, et al.PRSS1 intron mutations in patients with pancreatic cancer and chronic pancreatitis.
Mol Med Rep. 2012; 5(2):449-51 [PubMed
] Related Publications
Genetic risk factors of chronic pancreatitis (CP) have been identified and a number of studies have found that CP can lead to pancreatic cancer. Therefore, the detection of pancreatitis-associated gene mutations can aid the pancreatic cancer diagnostic process. Mutations in three genes, the cationic trypsinogen (PRSS1) gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the pancreatic secretory trypsin inhibitor (SPINK1) gene, have been identified as risk factors for CP. The aim of this study was to describe specific novel mutations in the intron of the PRSS1 gene in patients with pancreatic cancer and CP. A total of 65 unrelated patients with pancreatic cancer and 29 with CP were reviewed. Mutations and polymorphisms of the PRSS1 gene were analyzed by direct sequencing. Information regarding clinical data and smoking exposure was collected by personal interviews using a structured questionnaire. IVS 3+36 A>G mutation in the PRSS1 gene was found in 2 cases with pancreatic cancer, and these 2 patients were classified as never-smokers. IVS 3+127 T>A and IVS 3+157 G>C double mutations were identified in one patient with CP. All patients were found to have serum trypsin levels lower than that of the normal controls. Therefore, the PRSS1 gene mutation may be a special common cause of pancreatic cancer and CP.
Zeng K, Liu QC, Lin JH, et al.Novel mutations of PRSS1 gene in patients with pancreatic cancer among Han population.
Chin Med J (Engl). 2011; 124(13):2065-7 [PubMed
] Related Publications
BACKGROUND: A high mortality rate of pancreatic cancer becomes a bottleneck for further treatment with long-term efficacy. It is urgent to find a new mean to predict the early onset of pancreatic cancer accurately. The authors hypothesized that genetic variants of cationic trypsinogen (PRSS1) gene could affect trypsin expression/function and result in abnormal activation of protease activated receptor-2 (PAR-2), then lead to pancreatic cancer. The aim of this study was to elaborate some novel mutations of PRSS1 gene in the patients with pancreatic cancer.
METHODS: Totally 156 patients with pancreatic cancer and 220 unrelated individuals as controls were enrolled in this study. The mutations of PRSS1 gene were analyzed by direct sequencing. K-ras Mutation Detection Kit was used to find the general k-ras gene disorder in the pancreatic cancer tissue. Then the clinical data were collected and analyzed simultaneously.
RESULTS: There were two patients who carried novel mutations which was IVS 3 + 157 G > C of PRSS1 gene in peripheral blood specimens and pancreatic cancer tissue. What's more, it was surprising to find a novel complicated mutation of exon 3 in PRSS1 gene (c.409 A > G and c.416 C > T) in another young patient. The complicated mutation made No. 135 and No. 137 amino acid transfer from Thr to Ala and Thr to Met respectively. No any mutation was found in the normal controls while no mutations of k-ras gene were detected in the three patients.
CONCLUSION: Mutations of PRSS1 gene may be an important factor of pancreatic cancer.
Liu Q, Lin X, Liu J, et al.The -409 C/T genotype of PRSS1 protects against pancreatic cancer in the Han Chinese population.
Dig Dis Sci. 2012; 57(2):573-9 [PubMed
] Related Publications
BACKGROUND AND AIMS: The high mortality rate of pancreatic cancer is a bottleneck for further treatment with long-term efficacy. Thus, it is urgent to identify new methods to accurately predict the early onset of pancreatic cancer. We hypothesized that the different genotypes of cationic trypsinogen (PRSS1) gene could confer susceptibility and/or resistance to pancreatic cancer in the Han Chinese population.
METHODS: The genotypes of PRSS1 were determined in 154 patients with pancreatic cancer and in a control group of 520 healthy individuals of Han Chinese descent. Clinical information was obtained, single-nucleotide polymorphisms (SNPs) of the PRSS1 gene were analyzed by direct sequencing, and the distribution of the genotypes were tested for Hardy-Weinberg equilibrium. Odds ratios and 95% confidence intervals were calculated by logistic regression analysis to estimate the associations between the different genotypes or haplotypes and the risk of pancreatic cancer.
RESULTS: Three SNPs (-409 C/T, -204 A/C, and c.486 C/T) were identified. A case-control analysis revealed a 0.118-fold (95% CI: 0.037-0.653), 0.842-fold (95% CI: 0.177-4.010), and 0.750-fold (95% CI: 0.519-1.085) change in risk of developing pancreatic cancer for individuals harboring these SNPs, respectively. The individuals with the -409 C/T genotype tended to have a reduced risk compared to those who carried the -409 T/T genotype. A protective effect was observed for the C(-409)-A(-204)-C(486) haplotype compared to the T(-409)-A(-204)-T(486) haplotype (OR = 0.115, 95% CI: 0.016-0.849) or compared to the T(-409)-A(-204)-C(486) haplotype (OR = 0.090, 95% CI: 0.012-0.667). Serum levels of trypsin in patients with the -409 C/T genotype were only one-fourth that of those with the -409 T/T genotype and only one-third that of the healthy controls.
CONCLUSIONS: The -409 C/T genotype of PRSS1 was revealed to be a protective factor against pancreatic cancer in the Han Chinese population.
Rebours V, Lévy P, Ruszniewski PAn overview of hereditary pancreatitis.
Dig Liver Dis. 2012; 44(1):8-15 [PubMed
] Related Publications
Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22-25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.
Lee YJ, Kim KM, Choi JH, et al.High incidence of PRSS1 and SPINK1 mutations in Korean children with acute recurrent and chronic pancreatitis.
J Pediatr Gastroenterol Nutr. 2011; 52(4):478-81 [PubMed
] Related Publications
OBJECTIVES: We evaluated the frequencies and clinical consequences of mutations in the genes encoding cationic trypsinogen, serine protease 1 (PRSS1), and serine protease inhibitor Kazal type 1 (SPINK1) in children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP).
PATIENTS AND METHODS: The study population consisted of 32 children with ARP or CP and 28 healthy controls. We analyzed clinical data and the sequences of the entire coding region and the intron-exon boundaries of the PRSS1 and SPINK1 genes from each patient.
RESULTS: Fifteen (46.9%) of the 32 patients had at least 1 PRSS1 or SPINK1 mutation. Four (12.5%) of the 32 patients carried the p.N29I, p.R122H, or p.N29T mutation or a p.G208A variant of the PRSS1 gene in a heterozygote state. Eleven (34.4%) of the 32 patients carried either the IVS3 + 2T>C or p.N34S mutation of the SPINK1 gene. No PRSS1 or SPINK1 mutations were identified in the control group. In particular, mutations were identified in 4 of our patients who experienced pancreas divisum with CP, whereas the remaining 2 patients with pancreas divisum and ARP did not have mutation.
CONCLUSIONS: The frequencies of the PRSS1 and SPINK1 mutations are relatively high in Korean children with ARP or CP. Mutations in the PRSS1 and SPINK1 genes are highly associated with the development of childhood ARP or CP. Our findings suggest that patients with genetic mutations combined with pancreas divisum tend to develop CP early.
Hasegawa K, Furuya R, Mizuno H, et al.Inhibitory effect of Elephantopus mollis H.B. and K. extract on melanogenesis in B16 murine melanoma cells by downregulating microphthalmia-associated transcription factor expression.
Biosci Biotechnol Biochem. 2010; 74(9):1908-12 [PubMed
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In this study, the inhibitory effect of Elephantopus mollis H.B. and K. extract on melanogenesis in B16 murine melanoma cells was examined and possible mechanisms were elucidated. The melanin content in B16 cells decreased when they were treated with E. mollis extract. Inhibition was accompanied by reduced expression of tyrosinase (TYR) and tyrosinase-related protein 1 (TRP1). Furthermore, the expression level of microphthalmia-associated transcription factor (MITF), a major transcriptional regulator of genes encoding melanogenic enzymes such as Tyr and Trp1, decreased as assessed by western blotting and quantitative reverse transcriptase polymerase chain reaction (RT-PCR). These results suggest that E. mollis extract reduces melanogenesis by downregulating Mitf expression, leading to reduced expression of Tyr and Trp1. In addition, melanocortin-1 receptor (MC1R) expression was downregulated by E. mollis extract, suggesting desensitization to α-melanocyte-stimulating hormone (α-MSH) of cells treated with the extract.
Wang L, Huang J, Jiang M, Zheng XAFP computational secreted network construction and analysis between human hepatocellular carcinoma (HCC) and no-tumor hepatitis/cirrhotic liver tissues.
Tumour Biol. 2010; 31(5):417-25 [PubMed
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Alpha-fetoprotein (AFP) computational secreted network construction and analysis of human hepatocellular carcinoma (HCC) is very useful to identify novel markers and potential targets for prognosis and therapy. By integration of gene regulatory network infer and the database for annotation, visualization, and integrated discovery, we identified and constructed significant molecule AFP secreted network from 25 no-tumor hepatitis/cirrhotic liver tissues and 25 HCC patients in the same GEO Dataset GSE10140-10141. Our result verified AFP secreted module in the upstream of no-tumor hepatitis/cirrhotic liver tissues (AMELY, LCN2, and REG3A activation; DKK1, SFRP4, and SPINK1 inhibition) and its downstream (PRSS1, REG3A, and TSHB activation; AMELY and DKK1 inhibition), and also in the upstream of HCC (LCN2, REG3A, and SFRP4 activation; AMELY and DKK1 inhibition) and its downstream (AMELY activation; DKK1, LCN2, PRSS1, SEMA3B, and SPINK1 inhibition). Importantly, we data-mined that AFP secreted cluster of HCC is involved in disease mutation (only in HCC terms) without cell surface receptor linked signal transduction, neuroactive ligand-receptor interaction, cell-cell signaling, and pancreas (only in no-tumor hepatitis/cirrhotic liver tissues terms), the condition which is vital to invasion of HCC. Our result demonstrated that common terms in both no-tumor hepatitis/cirrhotic liver tissues and HCC include secreted extracellular region, extracellular region part, extracellular space, signal peptide, signal, disulfide bond, glycosylation site N-linked (GlcNAc...), and glycoprotein, and these terms are less relative to invasion; therefore, we deduced the weaker AFP secreted network in HCC consistent with our number computation. We predicted AFP high expression localization within cells of HCC and without secretion to extracellular matrix. It would be necessary of AFP secreted function to decrease invasion of HCC.
Lu S, Slominski A, Yang SE, et al.The correlation of TRPM1 (Melastatin) mRNA expression with microphthalmia-associated transcription factor (MITF) and other melanogenesis-related proteins in normal and pathological skin, hair follicles and melanocytic nevi.
J Cutan Pathol. 2010; 37 Suppl 1:26-40 [PubMed
] Free Access to Full Article Related Publications
BACKGROUND: Melastatin (TRPM1), a.k.a. transient receptor potential cation channel, subfamily M, member 1 (TRPM-1) regulates melanocyte differentiation and proliferation. TRPM1 is transcriptionally regulated by the essential melanocyte transcription factor MITF (microphthalmia-associated transcription factor). For the most part, MITF expression is preserved during melanoma progression, while TRPM1 mRNA expression decreases or is completely lost. The loss of TRPM1 is associated with melanomas that are more aggressive.
OBJECTIVE: To assess the relationship between TRPM1 mRNA expression and the expression of MITF and nine other markers of melanocytes and melanin-related proteins by immunohistochemistry in normal skin, scars, hair follicles and ordinary melanocytic nevi.
METHODS: Samples of normal skin (n = 102; from tumor excisions and plastic procedures), scars (n = 5; from re-excision specimens) and compound melanocytic nevi (n = 4) were evaluated for the presence of TRPM1 mRNA transcripts as detected by chromogenic in situ hybridization (CISH). Immunohistochemical techniques were used to detect melanin-related proteins including: MITF, S100 protein, Mart-1, tyrosinase, Mel5, HMB45, tyrosinase-related protein-1 (TRP1), TRP2 and alpha-melanocyte stimulating hormone (alphaMSH). The labeling index (LI) was defined as the number of intraepidermal cells expressing mRNA or protein per one hundred basal keratinocytes.
RESULTS: A wide range of LI was found for all markers (0-33 positive cells/100 keratinocytes). When these LI were compared, no significant differences in the expression of MITF, S100, Mart1, tyrosinase proteins and TRPM1 mRNA were identified. The LI for TRPM1 mRNA expression ranged from 74% of that for MITF to 86% for tyrosinase. The LI for TRP-1, TRP-2 and Mel5 was similar to that of TRPM1, while HMB-45 had a significantly lower LI than all other markers. TRPM1 mRNA correlated most tightly with MITF and tyrosinase expression (r = 0.81 and 0.68, respectively, both p = 0.0001). Likewise, the strongest correlation among all the melanin-related proteins existed between tyrosinase and MITF (r = 0.79, p = 0.0001). There was variable expression of melanin-related proteins when LI were analyzed by anatomic site, patient age, extent of sun-damage and proximity to a melanocytic tumor. Anogenital skin showed the highest and acral skin the lowest LI for TRPM1, MITF, S100 protein, Tyrosinase, Mel5 and HMB45. Advanced age (> 60 years) was associated with decreased TRPM1 expression. Sun-damaged skin exhibited significantly increased LI as measured by MITF, S100 protein, Mart1, tyrosinase and HMB-45, but no differences for TRPM1. However, the MITF-TRPM1 differential (i.e. MITF LI-TRPM1 LI = MITF+TRPM1--melanocytes) was significantly increased in site-matched skin (4.6 +/- 4.4 vs. 1.5 +/- 2.5, p = 0.01). There was a suggestion of reduced LI in normal skin in the proximity of melanoma (from melanoma re-excision specimens) for S100, HMB45 and TRPM1 mRNA. TRPM1 LI was significantly decreased in scars compared to normal skin (5.6 +/- 1.4 vs. 9.7 +/- 4.3, p = 0.02), this was reflected in an increase in the MITF-TRPM1 differential (9.6 +/- 7.5 vs. 3.2 +/- 3.1, p = 0.0001). MITF LI were consistently higher than MSLN LI at all levels of the hair follicle; notably, MITF was expressed by isthmic-bulge cells. In ordinary melanocytic nevi, MITF and TRPM1 expression decreased with melanocyte descent: there was more signal for both markers in superficial epithelioid type A melanocytes than deeper type C melanocytes.
CONCLUSIONS: By CISH, TRPM1 mRNA expression is specific for melanocytes and strongly associated with MITF and tyrosinase expression, the latter implicating a mature melanocyte phenotype. However, in normal skin, TRPM1 mRNA expression appears to be dynamic, labeling most but not all melanocytes, with variable expression ostensibly related to local environmental factors.
Joergensen MT, Brusgaard K, Crüger DG, et al.Genetic, epidemiological, and clinical aspects of hereditary pancreatitis: a population-based cohort study in Denmark.
Am J Gastroenterol. 2010; 105(8):1876-83 [PubMed
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OBJECTIVES: In a population-based, well-defined group of patients first regarded as having pancreatitis of unknown origin (PUO), we identified, described, and compared the clinical and genetic aspects of patients with hereditary pancreatitis (HP) and with cystic fibrosis transmembrane conductance regulator gene (CFTR) and serine protease inhibitor Kazal type 1 gene (SPINK1) mutations with patients who retained the diagnosis of true idiopathic pancreatitis (tIP) after genetic testing for HP, SPINK1, and CFTR mutations.
METHODS: Patients with PUO were identified in the Danish National Registry of Patients or were referred by clinicians. DNA from blood was analyzed for cationic trypsinogen (PRSS1), SPINK1, and CFTR mutations. Considering the diagnosis of HP, a pedigree was drawn for each patient.
RESULTS: A genetic mutation was found in 40% of 122 patients with PUO. After testing first-degree relatives of the 18 initially identified HP patients, 38 HP patients in total were identified, and 28 patients had SPINK1-CFTR mutations. Among HP patients, no p.N29I mutations were found and the p.A16V mutation was more frequent than previously reported, 45 and 32% had exocrine and endocrine insufficiency, respectively, and among tIP patients 9 and 12%, respectively. Pancreatic cancer was diagnosed in 5% of the HP families.
CONCLUSIONS: The genotype of the Danish population with HP differs from that of previously described cohorts. The occurrence of exocrine and endocrine insufficiency is higher among patients with HP than in patients with SPINK1-CFTR mutations and tIP, and more HP families develop pancreatic cancer. Genetic testing thus helps to predict the prognosis of the pancreatitis.
Nakanuma S, Tajima H, Okamoto K, et al.Tumor-derived trypsin enhances proliferation of intrahepatic cholangiocarcinoma cells by activating protease-activated receptor-2.
Int J Oncol. 2010; 36(4):793-800 [PubMed
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In primary malignant liver tumors, trypsinogen-immunoreactivity was present in 70% of intrahepatic cholangiocarcinoma (ICC) specimens, but absent in hepatocellular carcinoma (HCC) specimens. We suggest the secretion of trypsinogen to be a key difference in biological behavior between ICC and HCC cells. The purpose of this study was to investigate the secretion of tumor-derived trypsin and the expression of its specific receptor, protease-activated receptor-2 (PAR-2), in ICC using cell lines and surgical specimens. The expression of trypsinogen-1 mRNA was observed in three of four ICC cell lines, but none of three HCC cell lines. Western blot analysis detected trypsinogen-1 in serum-free conditioned medium from one of the ICC cell lines positive for the mRNA. Gelatin zymography revealed a gelatinolytic activity for trypsin, the activated form of trypsinogen, in the same conditioned medium. PAR-2 mRNA and protein were observed in ICC cell lines. The proliferative activity of ICC cells was increased by concentrations of trypsin as low as 10 nM, and peaked at 100 nM. The effect of trypsin was suppressed by a serine protease inhibitor, gabexate mesilate. PAR-2 expression was detected in 64% of ICC surgical specimens immunohistochemically. In addition, stroma fibroblasts expressed PAR-2 in 52% of ICC specimens. These results suggest that trypsinogen-1 contributes to the growth of ICC cells and also tumor-associated fibroblasts.
Schmitt F, Le Henaff G, Piloquet H, et al.Hereditary pancreatitis in children: surgical implications with special regard to genetic background.
J Pediatr Surg. 2009; 44(11):2078-82 [PubMed
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PURPOSE: Hereditary pancreatitis (HP) is the primary etiology of chronic pancreatitis during childhood, progressing through recurrent episodes of acute pancreatitis and finally leading to pancreatic insufficiencies. Hereditary pancreatitis is because of mutations of the cationic trypsinogen (PRSS1) gene. Some other genes, such as SPINK1 or CFTR, have been associated with familial idiopathic chronic pancreatitis. The aim of our study was to clearly define diagnostic and therapeutic strategies for HP patients, through an analysis of our study group and a review of the literature.
METHODS: All children admitted from 1995 to 2007 with a final diagnosis of hereditary pancreatitis were restrospectively included in the study. We analyzed all medical records with special attention given to cases involving genetic screening (PRSS1, SPINK1, and CFTR genes).
RESULTS: Ten children were included. Eight had HP with PRSS1 mutation, 2 of them without a familial history of chronic pancreatitis. The 2 others patients had SPINK1 mutations. Three HP patients were operated on for acute complications of pancreatitis and are well with a mean follow-up of 5.5 years. No patient had pancreatic insufficiencies or weight loss.
CONCLUSIONS: Hereditary pancreatitis is associated with severe pancreatitis, with a greater risk of developing pancreatic cancer. It must therefore be diagnosed correctly and treated to prevent its considerable complications.
BACKGROUND: Inherited risk of pancreatic cancer has been associated with mutations in several genes, including BRCA2, CDKN2A (p16), PRSS1, and PALB2. We hypothesized that common variants in these genes, single nucleotide polymorphisms (SNP), may also influence risk for pancreatic cancer development.
METHODS: A clinic-based case-control study in non-Hispanic white persons compared 1,143 patients with pancreatic adenocarcinoma with 1,097 healthy controls. Twenty-eight genes directly and indirectly involved in the Fanconi/BRCA pathway (includes BRCA1, BRCA2, and PALB2) were identified and 248 tag SNPs were selected. In addition, 11 SNPs in CDKN2A, PRSS1, and PRSS2 were selected. Association studies were done at the gene level by principal components analysis, whereas recursive partitioning analysis was used to investigate pathway effects. At the individual SNP level, adjusted additive, dominant, and recessive models were investigated, and gene-environment interactions were also assessed.
RESULTS: Gene level analyses showed no significant association of any genes with altered pancreatic cancer risk. Multiple single SNP analyses showed associations, which will require replication. Exploratory pathway analyses by recursive partitioning showed no association between SNPs and risk for pancreatic cancer.
CONCLUSION: In a candidate gene and pathway SNP association study analysis, common variations in the Fanconi/BRCA pathway and other candidate familial pancreatic cancer genes are not associated with risk for pancreatic cancer.
Rebours V, Boutron-Ruault MC, Schnee M, et al.The natural history of hereditary pancreatitis: a national series.
Gut. 2009; 58(1):97-103 [PubMed
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BACKGROUND AND AIMS: The prevalence and natural history of hereditary pancreatitis (HP) remain poorly documented. The aims of this study were to assess genetic, epidemiological, clinical and morphological characteristics of HP in an extensive national survey.
METHODS: A cohort comprising all HP patients was constituted by contacting all gastroenterologists and paediatricians (response rate 84%) and genetics laboratories (response rate 100%) in France (60,200,000 inhabitants). Inclusion criteria were the presence of mutation in the cationic trypsingen gene (PRSS1 gene), or chronic pancreatitis in at least two first-degree relatives, or three second-degree relatives, in the absence of precipitating factors for pancreatitis.
RESULTS: 78 families and 200 patients were included (181 alive, 6673 person-years, males 53%, alcoholism 5%, smoking 34%). The prevalence was 0.3/100,000 inhabitants. PRSS1 mutations were detected in 68% (R122H 78%, N29I 12%, others 10%). Penetrance was 93%. Median age at first symptom, diagnosis and date of last news, were 10 (range 1-73), 19 (1-80) and 30 (1-84) years, respectively. HP was responsible for pancreatic pain (83%), acute pancreatitis (69%), pseudocysts (23%), cholestasis (3%), pancreatic calcifications (61%), exocrine pancreatic insufficiency (34%, median age of occurrence 29 years), diabetes mellitus (26%, median age of occurrence 38 years) and pancreatic adenocarcinoma (5%, median age 55 years). No differences in clinical and morphological data according to genetic status were observed. 19 patients died, including 10 directly from HP (8 from pancreatic adenocarcinoma).
CONCLUSION: The prevalence of HP in France is at least 0.3/100,000. PRSS1 gene mutations are found in 2/3 with a 93% penetrance. Mutation type is not correlated with clinical/morphological expression. Pancreatic adenocarcinoma is the cause of nearly half the deaths.
Teich N, Mössner JHereditary chronic pancreatitis.
Best Pract Res Clin Gastroenterol. 2008; 22(1):115-30 [PubMed
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Hereditary chronic pancreatitis (HCP) is a very rare form of early-onset chronic pancreatitis. Apart from young age at diagnosis and a slower progression, the clinical course, morphological features and laboratory findings of HCP do not differ from those of patients with alcoholic chronic pancreatitis. Diagnostic criteria and treatment of HCP also resemble those of chronic pancreatitis of other causes. The clinical presentation is highly variable and includes chronic abdominal pain, impairment of endocrine and exocrine pancreatic function, nausea and vomiting, maldigestion, diabetes, pseudocysts, bile-duct and duodenal obstruction, and rarely pancreatic cancer. Fortunately, the disease is mild in most patients. Mutations in the PRSS1 gene, encoding cationic trypsinogen, play a causative role in chronic pancreatitis. It has been shown that the PRSS1 mutations increase autocatalytic conversion of trypsinogen to active trypsin, and thus probably cause premature, intrapancreatic trypsinogen activation, disturbing the intrapancreatic balance of proteases and their inhibitors. Other genes--such as the anionic trypsinogen (PRSS2), the serine protease inhibitor Kazal type 1 (SPINK1), and the cystic fibrosis transmembrane conductance regulator (CFTR)--have also been found to be associated with chronic pancreatitis (idiopathic and hereditary). Genetic testing should only be performed in carefully selected patients by direct DNA sequencing, and antenatal diagnosis should not be encouraged. Treatment focuses on enzyme and nutritional supplementation, pain management, pancreatic diabetes, and local organ complications such as pseudocysts and bile-duct or duodenal obstruction. The disease course and prognosis of patients with HCP is unpredictable. The risk of pancreatic cancer is elevated. Therefore, HCP patients should strongly avoid environmental risk factors for pancreatic cancer.
Rebours V, Boutron-Ruault MC, Schnee M, et al.Risk of pancreatic adenocarcinoma in patients with hereditary pancreatitis: a national exhaustive series.
Am J Gastroenterol. 2008; 103(1):111-9 [PubMed
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BACKGROUND AND AIMS: An increased risk of pancreatic adenocarcinoma (PA) in patients with hereditary pancreatitis (HP) was previously demonstrated in two multinational studies. The PA frequency in this setting is however unknown due to lack of exhaustive case collection. The aims of this study were to evaluate the standardized incidence ratio (SIR) of PA in an exhaustive national series of patients with HP and to search for risk factors.
METHODS: All French genetic laboratories (response rate 100%), pediatricians, and gastroenterologists (response rate 84%) were contacted.
INCLUSION CRITERIA: mutation in the PRSS1 gene or recurrent, acute, or chronic pancreatitis, with no precipitating factors in two first-degree relatives or >or=3 second-degree relatives in >or=2 generations. Diagnosis of PA was based on histological records.
RESULTS: Seventy-eight families and 200 patients were included (181 alive, 6,673 person-years, median number of generations 3, men 53%, alcoholism 5%, and smoking 34%). PRSS1 mutations were searched for in 96% of the patients and were detected in 68% (maternal inheritance 54%, R122H 78%, N29I 12%, and others 10%). Ten PA were diagnosed (median age 55 yr). SIR of PA for the whole population, men, and women were 87 (95% CI 42-113), 69 (25-150), and 142 (38-225), respectively, with no influence of genetic mutation. At ages 50 and 75 yr, the cumulated risk of PA was 11% and 49% for men and 8% and 55% for women, respectively. Smoking and diabetes mellitus were the main associated risk factors.
CONCLUSION: Patients with HP have a marked relative and absolute increased risk of PA as compared to the general population, especially in smokers. There is no correlation with the type of PRSS1 mutation.
Fadlelmola FM, Zhou M, de Leeuw RJ, et al.Sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization profiling reveals novel gains and losses of chromosomal regions in Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma cell lines.
Mol Cancer. 2008; 7:2 [PubMed
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BACKGROUND: Hodgkin lymphoma (HL) and Anaplastic Large Cell Lymphoma (ALCL), are forms of malignant lymphoma defined by unique morphologic, immunophenotypic, genotypic, and clinical characteristics, but both overexpress CD30. We used sub-megabase resolution tiling (SMRT) array-based comparative genomic hybridization to screen HL-derived cell lines (KMH2 and L428) and ALCL cell lines (DEL and SR-786) in order to identify disease-associated gene copy number gains and losses.
RESULTS: Significant copy number gains and losses were observed on several chromosomes in all four cell lines. Assessment of copy number alterations with 26,819 DNA segments identified an average of 20 genetic alterations. Of the recurrent minimally altered regions identified, 11 (55%) were within previously published regions of chromosomal alterations in HL and ALCL cell lines while 9 (45%) were novel alterations not previously reported. HL cell lines L428 and KMH2 shared gains in chromosome cytobands 2q23.1-q24.2, 7q32.2-q36.3, 9p21.3-p13.3, 12q13.13-q14.1, and losses in 13q12.13-q12.3, and 18q21.32-q23. ALCL cell lines SR-786 and DEL, showed gains in cytobands 5p15.32-p14.3, 20p12.3-q13.11, and 20q13.2-q13.32. Both pairs of HL and ALCL cell lines showed losses in 18q21.32-18q23.
CONCLUSION: This study is considered to be the first one describing HL and ALCL cell line genomes at sub-megabase resolution. This high-resolution analysis allowed us to propose novel candidate target genes that could potentially contribute to the pathogenesis of HL and ALCL. FISH was used to confirm the amplification of all three isoforms of the trypsin gene (PRSS1/PRSS2/PRSS3) in KMH2 and L428 (HL) and DEL (ALCL) cell lines. These are novel findings that have not been previously reported in the lymphoma literature, and opens up an entirely new area of research that has not been previously associated with lymphoma biology. The findings raise interesting possibilities about the role of signaling pathways triggered by membrane associated serine proteases in HL and aggressive NHL, similar to those described in epithelial tumors.
Lu F, Yan D, Zhou X, et al.Expression of melanin-related genes in cultured adult human retinal pigment epithelium and uveal melanoma cells.
Mol Vis. 2007; 13:2066-72 [PubMed
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PURPOSE: Controversy exists over melanogenesis of adult human RPE cells in vitro. This study investigated melanin content and production and expression of tyrosinase (TYR), tyrosinase-related-protein-1 (TRP1), tyrosinase-related-protein-2 (TRP2), and P gene in cultured human RPE cells and uveal melanoma cells.
METHODS: RPE cells were isolated and cultured from three adult donor eyes. A continuous human uveal melanoma cell line was established from primary choroidal melanoma. Melanin content and production were measured, and the expression of TYR, TRP1, TRP2, and P gene at the mRNA and protein levels were detected by RT-PCR and western blot, respectively.
RESULTS: Melanin content per cell of cultured RPE decreased rapidly and in proportion to cell division. No melanin production could be demonstrated in any passages. In cultured RPE cells, mRNA expression of TYR, TRP1, TRP2, and P-gene and protein expression of TYR, TRP1, and TRP2 could not be detected. In uveal melanoma cells, melanin content per cell remained stable, and melanin production could be detected in each passage. Expression of mRNA of TYR, TRP1, TRP2, and P-gene and protein of TYR, TRP1, and TRP2 could be detected in melanoma cells.
CONCLUSIONS: Human RPE cells under standard culture circumstances do not produce melanin and do not express the four key genes required in melanin biosynthesis pathway. In contrast, human uveal melanoma cells produce melanin and express all of these melanogenic genes in vitro.