OLAH

Gene Summary

Gene:OLAH; oleoyl-ACP hydrolase
Aliases: SAST, AURA1, THEDC1
Location:10p13
Summary:-
Databases:VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:S-acyl fatty acid synthase thioesterase, medium chain
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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).

Latest Publications: OLAH (cancer-related)

Rebbeck TR, Mitra N, Wan F, et al.
Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
JAMA. 2015; 313(13):1347-61 [PubMed] Related Publications
IMPORTANCE: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.
OBJECTIVE: To identify mutation-specific cancer risks for carriers of BRCA1/2.
DESIGN, SETTING, AND PARTICIPANTS: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.
EXPOSURES: Mutations of BRCA1 or BRCA2.
MAIN OUTCOMES AND MEASURES: Breast and ovarian cancer risks.
RESULTS: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.
CONCLUSIONS AND RELEVANCE: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

Kuchenbaecker KB, Ramus SJ, Tyrer J, et al.
Identification of six new susceptibility loci for invasive epithelial ovarian cancer.
Nat Genet. 2015; 47(2):164-71 [PubMed] Free Access to Full Article Related Publications
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

Osorio A, Milne RL, Kuchenbaecker K, et al.
DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.
PLoS Genet. 2014; 10(4):e1004256 [PubMed] Free Access to Full Article Related Publications
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

Treszl A, Steiber Z, Schally AV, et al.
Substantial expression of luteinizing hormone-releasing hormone (LHRH) receptor type I in human uveal melanoma.
Oncotarget. 2013; 4(10):1721-8 [PubMed] Free Access to Full Article Related Publications
Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, theseanalogs could be considered for the LHRH receptor-based treatment of uveal melanoma.

Phillips KA, Milne RL, Rookus MA, et al.
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
J Clin Oncol. 2013; 31(25):3091-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers.
METHODS: Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up.
RESULTS: Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases).
CONCLUSION: This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.

Bojesen SE, Pooley KA, Johnatty SE, et al.
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
Nat Genet. 2013; 45(4):371-84, 384e1-2 [PubMed] Free Access to Full Article Related Publications
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ∼480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10(-8)) and BRCA1 mutation carrier (P = 1.1 × 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10(-12)) and BRCA1 mutation carrier (P = 1.6 × 10(-14)) breast and invasive ovarian (P = 1.3 × 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Balogh K, Széll M, Polyánka H, et al.
Detection of a rare CDKN2A intronic mutation in a Hungarian melanoma-prone family and its role in splicing regulation.
Br J Dermatol. 2012; 167(1):131-3 [PubMed] Related Publications
BACKGROUND: The major locus for melanoma predisposition is the cell cycle regulatory CDKN2A gene on chromosome 9p21. However, the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21.
OBJECTIVES: To investigate whether the rare IVS1+37 G/C intronic mutation of the CDKN2A gene, recently identified in a Hungarian melanoma-prone family, influences mRNA splicing regulation.
METHODS: CDKN2A minigenes containing the wild-type and the mutant intronic sequence were created and transfected into HeLa cells with the aim of studying the mRNA transcripts.
RESULTS: The results revealed the emergence of a differential splicing pattern from the wild-type and the mutant minigene, suggesting that this mutation may alter the splicing of CDKN2A primary mRNA and therefore might have a pathogenetic role in familial melanoma.
CONCLUSIONS: We believe that these results confirm the importance of the identification and characterization of CDKN2A intronic mutations with a view to improving our understanding of the pathogenesis, and explain why the frequency of germline coding mutations of the CDKN2A gene is lower than expected in melanoma-prone families linked to chromosome 9p21.

Csoma Z, Tóth-Molnár E, Balogh K, et al.
Neonatal blue light phototherapy and melanocytic nevi: a twin study.
Pediatrics. 2011; 128(4):e856-64 [PubMed] Related Publications
BACKGROUND: Neonatal blue light phototherapy (NBLP) has been widely and successfully used for the treatment of neonatal jaundice to reduce the plasma concentration of bilirubin and, hence, to prevent kernicterus. Only a few and controversial data are available in the literature as to how NBLP influences melanocytic nevus development.
OBJECTIVE: Our goal was to conduct a twin study with the aim of better understanding the role of NBLP in melanocytic nevus development. We also investigated the roles of other environmental and constitutional factors in nevus formation.
METHODS: Fifty-nine monozygotic and dizygotic twins were included in this cross-sectional study. One of the twin members received NBLP, and the other did not. A whole-body skin examination was performed to determine the density of melanocytic skin lesions. The prevalence of benign pigmented uveal lesions was evaluated during a detailed ophthalmologic examination. A standardized questionnaire was used to assess data relating to constitutional, sun-exposure, and other variables. To search for possible gene-environmental interactions involved in the appearance of pigmented lesions, the melanocortin 1 receptor variants and the I439V polymorphism of histidine ammonia-lyase genes were also determined in the enrolled twins.
RESULTS: NBLP was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions. No association was found between the examined gene polymorphisms and the number of pigmented alterations in the examined study group.
CONCLUSIONS: Our data suggest that NBLP could well be a risk factor for melanocytic nevus development. Phototherapy with blue-light lamps is a standard and essential therapeutic modality in neonatal care; therefore, additional in vivo and in vitro studies are necessary to establish its potential long-term adverse effects.

Antoniou AC, Kartsonaki C, Sinilnikova OM, et al.
Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers.
Hum Mol Genet. 2011; 20(16):3304-21 [PubMed] Free Access to Full Article Related Publications
Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Otvos L, Kovalszky I, Riolfi M, et al.
Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer.
Eur J Cancer. 2011; 47(10):1578-84 [PubMed] Related Publications
Triple-negative breast cancers, which represent 10-20% of all mammary tumours, are characterised by the aggressive phenotype, are often found in younger women and have been associated with poor prognosis. Obesity increases the risk for triple-negative breast cancer development. Because triple-negative breast cancer patients are unresponsive to current targeted therapies and other treatment options are only partially effective, new pharmacological modalities are urgently needed. Here we examined if the leptin (obesity hormone) receptor is a viable target for the treatment of this cancer subtype. In human triple-negative breast cancer tissues, the leptin receptor was expressed in 92% (64/69) and leptin in 86% (59/69) of cases. In a model triple-negative breast cancer cell line MDA-MB-231, the leptin receptor antagonist peptide Allo-aca inhibited leptin-induced proliferation at 50 pM concentration. In an MDA-MB-231 orthotopic mouse xenograft model, Allo-aca administered subcutaneously significantly extended the average survival time from 15.4 days (untreated controls) to 24 and 28.1 days at 0.1 and 1mg/kg/day doses, respectively. In parallel, conventional treatment with 1mg/kg/day intraperitoneal cisplatin prolonged the average survival time to 18.6 days, while administration of 20mg/kg/day oral Tamoxifen (negative control) had no significant survival effects relative to controls. In normal CD-1 mice, Allo-aca produced no systemic toxicity up to the highest studied subcutaneous bolus dose of 50mg/kg, while, as expected, it induced a modest 6-10% body weight increase. Our results indicate that leptin receptor antagonists could become attractive options for triple-negative breast cancer treatment, especially in the obese patient population.

Kempers MJ, Kuiper RP, Ockeloen CW, et al.
Risk of colorectal and endometrial cancers in EPCAM deletion-positive Lynch syndrome: a cohort study.
Lancet Oncol. 2011; 12(1):49-55 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lynch syndrome is caused by germline mutations in MSH2, MLH1, MSH6, and PMS2 mismatch-repair genes and leads to a high risk of colorectal and endometrial cancer. We previously showed that constitutional 3' end deletions of EPCAM can cause Lynch syndrome through epigenetic silencing of MSH2 in EPCAM-expressing tissues, resulting in tissue-specific MSH2 deficiency. We aim to establish the risk of cancer associated with such EPCAM deletions.
METHODS: We obtained clinical data for 194 carriers of a 3' end EPCAM deletion from 41 families known to us at the Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands and compared cancer risk with data from a previously described cohort of 473 carriers from 91 families with mutations in MLH1, MSH2, MSH6, or a combined EPCAM-MSH2 deletion.
FINDINGS: 93 of the 194 EPCAM deletion carriers were diagnosed with colorectal cancer; three of the 92 women with EPCAM deletions were diagnosed with endometrial cancer. Carriers of an EPCAM deletion had a 75% (95% CI 65-85) cumulative risk of colorectal cancer before the age of 70 years (mean age at diagnosis 43 years [SD 12]), which did not differ significantly from that of carriers of combined EPCAM-MSH2 deletion (69% [95% CI 47-91], p=0·8609) or mutations in MSH2 (77% [64-90], p=0·5892) or MLH1 (79% [68-90], p=0·5492), but was higher than noted for carriers of MSH6 mutation (50% [38-62], p<0·0001). By contrast, women with EPCAM deletions had a 12% [0-27] cumulative risk of endometrial cancer, which was lower than was that noted for carriers of a combined EPCAM-MSH2 deletion (55% [20-90], p<0·0001) or of a mutation in MSH2 (51% [33-69], p=0·0006) or MSH6 (34% [20-48], p=0·0309), but did not differ significantly from that noted for MLH1 (33% [15-51], p=0·1193) mutation carriers. This risk seems to be restricted to deletions that extend close to the MSH2 gene promoter. Of 194 carriers of an EPCAM deletion, three had duodenal cancer and four had pancreatic cancer.
INTERPRETATION: EPCAM deletion carriers have a high risk of colorectal cancer; only those with deletions extending close to the MSH2 promoter have an increased risk of endometrial cancer. These results underscore the effect of mosaic MSH2 deficiency, leading to variable cancer risks, and could form the basis of an optimised protocol for the recognition and targeted prevention of cancer in EPCAM deletion carriers.

Papp J, Kovacs ME, Solyom S, et al.
High prevalence of germline STK11 mutations in Hungarian Peutz-Jeghers Syndrome patients.
BMC Med Genet. 2010; 11:169 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominantly inherited disease characterized by gastrointestinal hamartomatous polyposis and mucocutaneous pigmentation. The genetic predisposition for PJS has been shown to be associated with germline mutations in the STK11/LKB1 tumor suppressor gene. The aim of the present study was to characterize Hungarian PJS patients with respect to germline mutation in STK11/LKB1 and their association to disease phenotype.
METHODS: Mutation screening of 21 patients from 13 PJS families were performed using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). Comparative semi-quantitative sequencing was applied to investigate the mRNA-level effects of nonsense and splice-affecting mutations.
RESULTS: Thirteen different pathogenic mutations in STK11, including a high frequency of large genomic deletions (38%, 5/13), were identified in the 13 unrelated families studied. One of these deletions also affects two neighboring genes (SBNO2 and GPX4), located upstream of STK11, with a possible modifier effect. The majority of the point mutations (88%, 7/8) can be considered novel. Quantification of the STK11 transcript at the mRNA-level revealed that the expression of alleles carrying a nonsense or frameshift mutation was reduced to 30-70% of that of the wild type allele. Mutations affecting splice-sites around exon 2 displayed an mRNA processing pattern indicative of co-regulated splicing of exons 2 and 3.
CONCLUSIONS: A combination of sensitive techniques may assure a high (100%) STK11 mutation detection frequency in PJS families. Characterization of mutations at mRNA level may give a deeper insight into the molecular consequences of the pathogenic mutations than predictions made solely at the genomic level.

Kökény S, Papp J, Weber G, et al.
Ribavirin acts via multiple pathways in inhibition of leukemic cell proliferation.
Anticancer Res. 2009; 29(6):1971-80 [PubMed] Related Publications
UNLABELLED: The aim of this study was to elucidate the anticancer activity of Ribavirin, an antiviral drug and a known inhibitor of inositide-5'-monophosphate dehydrogenase.
MATERIALS AND METHODS: Using human cancer cell lines, the potential of the drug to inhibit growth and induce the apoptotic and differentiation pathways was investigated by cytological methods. The effect exerted upon gene expression was studied in K562 cells by Q-PCR.
RESULTS: Treatment with Ribavirin resulted in a significant growth inhibition (IC(50)=15 microM) via activating apoptosis and the differentiation pathway in K562 cells. It also modulated the expression of about 60 out of 85 genes having roles in cell proliferation, purine biosynthesis, translation initiation, oncogenic signaling and cell survival (p<0.05).
CONCLUSION: Ribavirin is a potent anticancer agent, being a strong inducer of apoptosis and a moderate inducer of differentiation in K562 cells. These effects are mediated through the modulation of key molecular and metabolic pathways.

Kovacs ME, Papp J, Szentirmay Z, et al.
Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome.
Hum Mutat. 2009; 30(2):197-203 [PubMed] Related Publications
Several different genetic alterations in the etiology of Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30-50%) of clinicopathologically well-defined HNPCC families, suggesting the presence of other predisposing mechanisms. In a set of probands from 27 Lynch syndrome families who lacked evidence of a germline mutation in either the MSH2 or MLH1 gene, we performed genomic deletion screening with the use of multiplex ligation-dependent probe amplification (MLPA) and sequencing. We used immunohistochemistry (IHC) and microsatellite instability (MSI) analyses on samples of the probands of all families. Comparative analysis of mRNA transcripts was performed on blood leukocyte-derived samples from mutation carriers and noncarrier controls. We report that large germline deletions encompassing the last exons of the TACSTD1 gene, upstream of MSH2, cosegregate with the HNPCC phenotype in 19% (5/27) of families tested. The tumors of the carriers show high-level MSI and MSH2 protein loss. We show that these deletions, by removing the transcriptional termination sequences of the upstream gene, give rise to multiple TACSTD1/MSH2 fusion transcripts. Our results provide evidence that deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Thus, analysis of the 3' region of the TACSTD1 gene should be included in the routine mutation screening protocols for HNPCC.

Antoniou AC, Cunningham AP, Peto J, et al.
The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions.
Br J Cancer. 2008; 98(8):1457-66 [PubMed] Free Access to Full Article Related Publications
Multiple genetic loci confer susceptibility to breast and ovarian cancers. We have previously developed a model (BOADICEA) under which susceptibility to breast cancer is explained by mutations in BRCA1 and BRCA2, as well as by the joint multiplicative effects of many genes (polygenic component). We have now updated BOADICEA using additional family data from two UK population-based studies of breast cancer and family data from BRCA1 and BRCA2 carriers identified by 22 population-based studies of breast or ovarian cancer. The combined data set includes 2785 families (301 BRCA1 positive and 236 BRCA2 positive). Incidences were smoothed using locally weighted regression techniques to avoid large variations between adjacent intervals. A birth cohort effect on the cancer risks was implemented, whereby each individual was assumed to develop cancer according to calendar period-specific incidences. The fitted model predicts that the average breast cancer risks in carriers increase in more recent birth cohorts. For example, the average cumulative breast cancer risk to age 70 years among BRCA1 carriers is 50% for women born in 1920-1929 and 58% among women born after 1950. The model was further extended to take into account the risks of male breast, prostate and pancreatic cancer, and to allow for the risk of multiple cancers. BOADICEA can be used to predict carrier probabilities and cancer risks to individuals with any family history, and has been implemented in a user-friendly Web-based program (http://www.srl.cam.ac.uk/genepi/boadicea/boadicea_home.html).

Linger R, Dudakia D, Huddart R, et al.
Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors.
Genes Chromosomes Cancer. 2008; 47(3):247-52 [PubMed] Free Access to Full Article Related Publications
A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.

Papp J, Kovacs ME, Olah E
Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.
World J Gastroenterol. 2007; 13(19):2727-32 [PubMed] Free Access to Full Article Related Publications
AIM: To analyze the prevalence of germline MLH1 and MSH2 gene mutations and evaluate the clinical characteristics of Hungarian hereditary non-polyposis colorectal cancer (HNPCC) families.
METHODS: Thirty-six kindreds were tested for mutations using conformation sensitive gel electrophoreses, direct sequencing and also screening for genomic rearrangements applying multiplex ligation-dependent probe amplification (MLPA).
RESULTS: Eighteen germline mutations (50%) were identified, 9 in MLH1 and 9 in MSH2. Sixteen of these sequence alterations were considered pathogenic, the remaining two were non-conservative missense alterations occurring at highly conserved functional motifs. The majority of the definite pathogenic mutations (81%, 13/16) were found in families fulfilling the stringent Amsterdam I/II criteria, including three rearrangements revealed by MLPA (two in MSH2 and one in MLH1). However, in three out of sixteen HNPCC-suspected families (19%), a disease-causing alteration could be revealed. Furthermore, nine mutations described here are novel, and none of the sequence changes were found in more than one family.
CONCLUSION: Our study describes for the first time the prevalence and spectrum of germline mismatch repair gene mutations in Hungarian HNPCC and suspected-HNPCC families. The results presented here suggest that clinical selection criteria should be relaxed and detection of genomic rearrangements should be included in genetic screening in this population.

Andrieu N, Goldgar DE, Easton DF, et al.
Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS).
J Natl Cancer Inst. 2006; 98(8):535-44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Multiparity, young age at first childbirth, and breast-feeding are associated with a reduced risk of breast cancer in the general population. The breast cancer predisposition gene, BRCA1, regulates normal cell differentiation. Because mammary gland cells divide and differentiate during pregnancy, reproductive factors may influence breast cancer risk in BRCA1/2 mutation carriers differently than they do in noncarriers.
METHODS: We performed a retrospective cohort study of 1601 women in the International BRCA1/2 Carrier Cohort Study cohort, all of whom carried a mutation in BRCA1 or BRCA2. Information on reproductive factors was obtained from a questionnaire. At the time of interview 853 subjects were classified with breast cancer. Data were analyzed by using a weighted cohort approach. All statistical tests were two-sided.
RESULTS: There was no statistically significant difference in the risk of breast cancer between parous and nulliparous women. Among parous women, an increasing number of full-term pregnancies was associated with a statistically significant decrease in the risk of breast cancer (Ptrend = .008); risk was reduced by 14% (95% confidence interval [CI] = 6% to 22%) for each additional birth. This association was the same for carriers of mutations in either BRCA1 or BRCA2 and was restricted to women older than 40 years. In BRCA2 mutation carriers, first childbirth at later ages was associated with an increased risk of breast cancer compared with first childbirth before age 20 years (20-24 years, hazard ratio [HR] = 2.33 [95% CI = 0.93 to 5.83]; 25-29 years, HR = 2.68 [95% CI = 1.02 to 7.07]; > or = 30 years, HR = 1.97 [95% CI = 0.67 to 5.81]), whereas in BRCA1 mutation carriers, first childbirth at age 30 years or later was associated with a reduced risk of breast cancer compared with first childbirth before age 20 years (HR = 0.58 [95% CI = 0.36 to 0.94]). Neither history of interrupted pregnancies (induced abortions or miscarriage) nor history of breast-feeding was statistically significantly associated with the risk of breast cancer.
CONCLUSIONS: BRCA1 and BRCA2 mutation carriers older than 40 years show a similar reduction in breast cancer risk with increasing parity as non-carriers.

Crockford GP, Linger R, Hockley S, et al.
Genome-wide linkage screen for testicular germ cell tumour susceptibility loci.
Hum Mol Genet. 2006; 15(3):443-51 [PubMed] Related Publications
A family history of disease is a strong risk factor for testicular germ cell tumour (TGCT). In order to identify the location of putative TGCT susceptibility gene(s) we conducted a linkage search in 237 pedigrees with two or more cases of TGCT. One hundred and seventy-nine pedigrees were evaluated genome-wide with an average inter-marker distance of 10 cM. An additional 58 pedigrees were used to more intensively investigate several genomic regions of interest. Genetic linkage analysis was performed with the ALLEGRO software using two model-based parametric analyses and a non-parametric analysis. Six genomic regions on chromosomes 2p23, 3p12, 3q26, 12p13-q21, 18q21-q23 and Xq27 showed heterogeneity LOD (HLOD) scores of greater than 1, with a maximum HLOD of 1.94 at 3q26. Genome-wide simulation studies indicate that the observed number of HLOD peaks greater than one does not differ significantly from that expected by chance. A TGCT locus at Xq27 has been previously reported. Of the 237 pedigrees examined in this study, 66 were previously unstudied at Xq27, no evidence for linkage to this region was observed in this new pedigree set. Overall, the results indicate that no single major locus can account for the majority of the familial aggregation of TGCT, and suggests that multiple susceptibility loci with weak effects contribute to the disease.

Nathanson KL, Kanetsky PA, Hawes R, et al.
The Y deletion gr/gr and susceptibility to testicular germ cell tumor.
Am J Hum Genet. 2005; 77(6):1034-43 [PubMed] Free Access to Full Article Related Publications
Testicular germ cell tumor (TGCT) is the most common cancer in young men. Despite a considerable familial component to TGCT risk, no genetic change that confers increased risk has been substantiated to date. The human Y chromosome carries a number of genes specifically involved in male germ cell development, and deletion of the AZFc region at Yq11 is the most common known genetic cause of infertility. Recently, a 1.6-Mb deletion of the Y chromosome that removes part of the AZFc region--known as the "gr/gr" deletion--has been associated with infertility. In epidemiological studies, male infertility has shown an association with TGCT that is out of proportion with what can be explained by tumor effects. Thus, we hypothesized that the gr/gr deletion may be associated with TGCT. Using logistic modeling, we analyzed this deletion in a large series of TGCT cases with and without a family history of TGCT. The gr/gr deletion was present in 3.0% (13/431) of TGCT cases with a family history, 2% (28/1,376) of TGCT cases without a family history, and 1.3% (33/2,599) of unaffected males. Presence of the gr/gr deletion was associated with a twofold increased risk of TGCT (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.3-3.6; P = .005) and a threefold increased risk of TGCT among patients with a positive family history (aOR 3.2; 95% CI 1.5-6.7; P = .0027). The gr/gr deletion was more strongly associated with seminoma (aOR 3.0; 95% CI 1.6-5.4; P = .0004) than with nonseminoma TGCT (aOR 1.5; 95% CI 0.72-3.0; P = .29). These data indicate that the Y microdeletion gr/gr is a rare, low-penetrance allele that confers susceptibility to TGCT.

Lakhani SR, Reis-Filho JS, Fulford L, et al.
Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype.
Clin Cancer Res. 2005; 11(14):5175-80 [PubMed] Related Publications
PURPOSE: To investigate the proportion of breast cancers arising in patients with germ line BRCA1 and BRCA2 mutations expressing basal markers and developing predictive tests for identification of high-risk patients.
EXPERIMENTAL DESIGN: Histopathologic material from 182 tumors in BRCA1 mutation carriers, 63 BRCA2 carriers, and 109 controls, collected as part of the international Breast Cancer Linkage Consortium were immunohistochemically stained for CK14, CK5/6, CK17, epidermal growth factor receptor (EGFR), and osteonectin.
RESULTS: All five basal markers were commoner in BRCA1 tumors than in control tumors (CK14: 61% versus 12%; CK5/6: 58% versus 7%; CK17: 53% versus 10%; osteonectin: 43% versus 19%; EGFR: 67% versus 21%; P < 0.0001 in each case). In a multivariate analysis, CK14, CK5/6, and estrogen receptor (ER) remained significant predictors of BRCA1 carrier status. In contrast, the frequency of basal markers in BRCA2 tumors did not differ significant from controls.
CONCLUSION: The use of cytokeratin staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available, that may be useful in selecting patients for BRCA1 mutation testing. The high percentage of BRCA1 cases positive for EGFR suggests that specific anti-tyrosine kinase therapy may be of potential benefit in these patients.

Antoniou AC, Pharoah PD, Narod S, et al.
Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.
J Med Genet. 2005; 42(7):602-3 [PubMed] Free Access to Full Article Related Publications
A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Bárdi E, Oláh AV, Bartyik K, et al.
Late effects on renal glomerular and tubular function in childhood cancer survivors.
Pediatr Blood Cancer. 2004; 43(6):668-73 [PubMed] Related Publications
BACKGROUND: Late nephrotoxicity among childhood cancer survivors is poorly documented.
METHODS: We investigated 115 patients and 86 controls assessing serum cystatin C concentration (CysC), urinary N-acetyl-beta-D-glucosaminidase activity (NAG), and microalbuminuria. Proteinuria was quantified and electrophoresis performed. Polymorphism of the angiotensin convertase enzyme (ACE) gene was determined by genomic PCR.
RESULTS: CysC was elevated in Wilms tumor (WT) patients. Gross proteinuria was observed in 30 patients including three patients with progressive proteinuria who improved on ACE-inhibitor treatment. Neither patients with proteinuria nor the entire study population differed from controls with respect to ACE polymorphism. Pathologically elevated urinary NAG was noted in 38% of leukemia/lymphoma, 54% of solid tumor, 20% of WT survivors. A similar distribution of pathological microalbuminuria was found.
CONCLUSIONS: Mild-to-moderate subclinical glomerular and tubular damage can be identified in many childhood cancer survivors. However, most patients experience some spontaneous recovery from acute nephrotoxicity.

Rapley EA, Hockley S, Warren W, et al.
Somatic mutations of KIT in familial testicular germ cell tumours.
Br J Cancer. 2004; 90(12):2397-401 [PubMed] Free Access to Full Article Related Publications
Somatic mutations of the KIT gene have been reported in mast cell diseases and gastrointestinal stromal tumours. Recently, they have also been found in mediastinal and testicular germ cell tumours (TGCTs), particularly in cases with bilateral disease. We screened the KIT coding sequence (except exon 1) for germline mutations in 240 pedigrees with two or more cases of TGCT. No germline mutations were found. Exons 10, 11 and 17 of KIT were examined for somatic mutations in 123 TGCT from 93 multiple-case testicular cancer families. Five somatic mutations were identified; four were missense amino-acid substitutions in exon 17 and one was a 12 bp in-frame deletion in exon 11. Two of seven TGCT from cases with bilateral disease carried KIT mutations compared with three out of 116 unilateral cases (P=0.026). The results indicate that somatic KIT mutations are implicated in the development of a minority of familial as well as sporadic TGCT. They also lend support to the hypothesis that KIT mutations primarily take place during embryogenesis such that primordial germ cells with KIT mutations are distributed to both testes.

Looijenga LH, de Leeuw H, van Oorschot M, et al.
Stem cell factor receptor (c-KIT) codon 816 mutations predict development of bilateral testicular germ-cell tumors.
Cancer Res. 2003; 63(22):7674-8 [PubMed] Related Publications
Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function.

Nagy E, Beck Z, Kiss A, et al.
Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase.
Eur J Cancer. 2003; 39(16):2298-305 [PubMed] Related Publications
The frequency and mechanism of p16(INK4A) and p14(ARF) gene alterations were studied in cell samples from 30 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML), both at diagnosis and at the onset of the accelerated phase (AP) of the disease. No alterations in the p16(INK4A) or p14(ARF) genes were found in any of the chronic phase (CP) samples. DNA sequencing analyses detected p16(INK4A) or p14(ARF) mutations in 17 AP samples. All mutations were heterozygous without loss of the other allele. Aberrant methylation of the p16(INK4A) or p14(ARF) promoters was found in 14 of 30 AP samples. The most common situation was the simultaneous methylation of both promoters. Our data indicate that p16(INK4A) and p14(ARF) are primary targets for inactivation by promoter methylation in the acceleration of CML. Transcriptional silencing of the p16(INK4A) and p14(ARF) genes may be important in the conversion of CML from the CP to the AP.

Orban TI, Olah E
Emerging roles of BRCA1 alternative splicing.
Mol Pathol. 2003; 56(4):191-7 [PubMed] Free Access to Full Article Related Publications
Germline mutations of the BRCA1 gene predispose individuals mainly to the development of breast and/or ovarian cancer. However, the exact function of the gene is still unclear, although the encoded proteins are involved in various cellular processes, including transcriptional regulation and DNA repair pathways. Several BRCA1 splice variants are found in different tissues, but in spite of intense investigations, their regulation and possible functions are poorly understood at the moment. This review summarises current knowledge on the roles of these splice variants and the mechanisms responsible for their formation. Because alternative splicing is now widely accepted as an important source of genetic diversity, elucidating the functions of the BRCA1 splice variants would help in the understanding of the exact role(s) of this tumour suppressor. This should help to resolve the current paradox that, despite its seemingly vital cellular functions, mutations of this gene are associated with tissue specific tumour formation predominantly in the breast and the ovary.

Antoniou A, Pharoah PD, Narod S, et al.
Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.
Am J Hum Genet. 2003; 72(5):1117-30 [PubMed] Free Access to Full Article Related Publications
Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

Thompson D, Szabo CI, Mangion J, et al.
Evaluation of linkage of breast cancer to the putative BRCA3 locus on chromosome 13q21 in 128 multiple case families from the Breast Cancer Linkage Consortium.
Proc Natl Acad Sci U S A. 2002; 99(2):827-31 [PubMed] Free Access to Full Article Related Publications
The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate "BRCA3" locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (alpha) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603-9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (alpha = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at alpha = 0.65 was -11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.

Burghardt B, Wenger C, Barabás K, et al.
GRP-receptor-mediated signal transduction, gene expression and DNA synthesis in the human pancreatic adenocarcinoma cell line HPAF.
Peptides. 2001; 22(7):1119-28 [PubMed] Related Publications
Bombesin-like peptides have been implicated as growth factors in various human cancers. Human adenocarcinoma cell lines (Capan-1, Capan-2, MiaPaCa-2 and HPAF) were tested to determine whether they express the gastrin-releasing peptide-preferring bombesin receptor (GRPR) and neuromedin B-preferring bombesin receptor (NMBR). Using RT-PCR the highest level of GRP receptor mRNA was found in HPAF cells. NMB receptor mRNA expression moderate in all cell lines investigated. We therefore selected the HPAF cell line to investigate whether bombesin treatment affects intracellular Ca(2+) ([Ca(2+)](i)), cAMP level, DNA synthesis as a measure of cell proliferation, and expression of three transcription factors: c-fos, c-myc and high mobility group protein IY (HMG-I(Y)).Bombesin administration led to an immediate increase in free intracellular Ca(2+) concentration ([Ca(2+)](i)) but did not change cAMP levels. The peptide also enhanced [(3)H]thymidine incorporation in HPAF cells (but not in the other cell lines), an effect that was concentration dependent, reaching 36 +/- 5% stimulation over control values at 24 h with an EC(50) of 2.27 x 10(-12) M. Furthermore, bombesin stimulated c-fos, c-myc and HMG-I(Y) expression in a time-dependent manner: the c-fos mRNA level increased dramatically in the first 30 min of exposure, then returned to basal level within 2 h, while the c-myc and HMG-I(Y) mRNA levels peaked at 2 h and 4h, respectively. All actions of bombesin were blocked by BME (D-Phe(6)-bombesin-(6-13)-methylester), a selective GRP receptor antagonist, but not by the NMB receptor antagonist BIM-23127 (D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH(2)). We conclude that HPAF cells express mRNA for GRP receptors and that functional receptors are present in the cell membrane. The occupation of these receptors leads to a sequence of intracellular events involving rapid mobilization of intracellular Ca(2+), expression of c-fos, c-myc and HMG-I(Y) mRNA, and stimulation of cell proliferation. Conversely, although NMB receptor mRNA can be detected, its actual translation to functional receptors does not reach a detectable level.

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