Subtle variations in Pten dose determine cancer susceptibility.
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ABSTRACT:
SUBMITTER: Alimonti A
PROVIDER: S-EPMC3118559 | biostudies-literature | 2010 May
REPOSITORIES: biostudies-literature
Publications
Subtle variations in Pten dose determine cancer susceptibility.
Alimonti Andrea A Carracedo Arkaitz A Clohessy John G JG Trotman Lloyd C LC Nardella Caterina C Egia Ainara A Salmena Leonardo L Sampieri Katia K Haveman William J WJ Brogi Edi E Richardson Andrea L AL Zhang Jiangwen J Pandolfi Pier Paolo PP
Nature genetics 20100418 5
Cancer susceptibility has been attributed to at least one heterozygous genetic alteration in a tumor suppressor gene (TSG). It has been hypothesized that subtle variations in TSG expression can promote cancer development. However, this hypothesis has not yet been definitively supported in vivo. Pten is a TSG frequently lost in human cancer and mutated in inherited cancer-predisposition syndromes. Here we analyze Pten hypermorphic mice (Pten(hy/+)), expressing 80% normal levels of Pten. Pten(hy/+ ...[more]
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Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten ‘hypermorphic’ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs).
2010-02-15 | GSE20316 | GEO
Project description:Subtle variations in Pten dose determine cancer susceptibility: Gene expression profiling for MEF cells from a Ptenhy/+ mouse model. We have analyzed the survival and tumor spectrum in a population of Pten âhypermorphicâ mice (Ptenhy/+), which express approximately 80% of total Pten protein. Notably, the Ptenhy/+ developed a spectrum of tumors of variable latencies, with breast tumors occurring at the highest penetrance. Surprisingly, all breast tumors analyzed retain two intact copies of Pten, and maintain Pten protein levels above that observed in heterozygosity. Importantly, subtle down-regulation of Pten was found to alter the expression profile of genes involved in cell proliferation. Taken together, our findings support the notion that initiation of tumorigenesis can occur in the absence of genetic hits, thereby questioning the uniqueness of a saltatory model for cancer susceptibility. In order to understand whether subtle variations in Pten level may affect pathways involved in tumorigenesis, we analyzed the genome-wide expression profile of Ptenhy/+ mouse embryonic fibroblasts (MEFs). In the Ptenhy/+ mouse model, mice are born with approximately 80% of total Pten protein and are viable and normally fertile. To decrease the expression level of Pten below homozygosity, we targeted intron 3 of Pten with a neomycin (Neo) cassette, under the control of the strong CMV promoter, thereby taking advantage of transcriptional interference. Next, we intercrossed Pten hy/+ mice with Pten+/- mice to generate cohorts of hypomorphic littermate mice with decreasing levels of Pten expression as follows: Ptenwt > Ptenhy/+ > Pten+/- >Ptenhy/- mice littermates. To preserve a constant 129/C57BL/6 mixed genetic background, we have crossed Pten hy/+ mice with Pten +/- for more than seven generations prior to analysis. As expected, Ptenhy/+ mouse embryonic fibroblasts (MEFs) display a level of Pten protein below Ptenwt and above Pten+/- .
2010-02-21 | E-GEOD-20316 | biostudies-arrayexpress
Project description:We have previously identified large megabase-sized hypomethylated zones in the genome of the breast cancer cell line MCF-7 using the TspRI-ExoIII technique. In this report, we used a more convenient high throughput method for mapping the hypomethylated zones in a number of human tumor genomes simultaneously. The method was validated by the bisulfite sequencing of 39 randomly chosen sites in a demethylated domain and by bisulfite genome-wide sequencing of the MCF-7 genome. This showed that the genomes of the various tumor cell lines, as well as some primary tumors, exhibit common hypomethylated domains. Interestingly, these hypomethylated domains are correlated with low CpG density distribution genome-wide, together with the histone H3K27Me3 landscape. Furthermore, they are inversely correlated with the H3K9Ac landscape and gene expression as measured in MCF-7 cells. Treatment with drugs resulted in en-bloc changes to the methylation domains. A close examination of the methylation domains found differences between non-invasive and invasive tumors with respect to tumorigenesis related genes. Taken together these results suggest that the human genome is organized in epigenomic domains that contain various different types of genes and imply that there are cis- and trans-regulators that control these domain-wide epigenetic changes and hence gene expression in the human genome. The hypomethylated domains are located in gene deserts that contain mainly tissue-specific genes and therefore we hypothesize that tumor cells keep these regions demethylated and silenced in order to save energy and resources and allow higher levels of cell proliferation and better survival (a thrifty tumor genome hypothesis).
| S-EPMC3757401 | biostudies-literature
Project description:BackgroundCancer initiation and development are driven by key mutations in driver genes. Applying high-throughput sequencing technologies and bioinformatic analyses, The Cancer Genome Atlas (TCGA) project has identified panels of somatic mutations that contributed to the etiology of various cancers. However, there are few studies investigating the germline genetic variations in these significantly mutated genes (SMGs) and lung cancer susceptibility.Patients and methodsWe comprehensively evaluated 1655 tagged single nucleotide polymorphisms (SNPs) located in 127 SMGs identified by TCGA, and test their association with lung cancer risk in large-scale case-control study. Functional effect of the validated SNPs, gene mutation frequency and pathways were analyzed.ResultsWe found 11 SNPs in 8 genes showed consistent association (P < 0.1) and 8 SNPs significantly associated with lung cancer risk (P < 0.05) in both discovery and validation phases. The most significant association was rs10412613 in PPP2R1A, with the minor G allele associated with a decreased risk of lung cancer [odds ratio = 0.91, 95% confidence interval (CI): 0.87-0.96, P = 2.3 × 10-4]. Cumulative analysis of risk score built as a weight sum of the 11 SNPs showed consistently elevated risk with increasing risk score (P for trend = 9.5 × 10-9). In stratified analyses, the association of PPP2R1A:rs10412613 and lung cancer risk appeared stronger among population of younger age at diagnosis and never smokers. The expression quantitative trait loci analysis indicated that rs10412613, rs10804682, rs635469 and rs6742399 genotypes significantly correlated with the expression of PPP2R1A, ATR, SETBP1 and ERBB4, respectively. From TCGA data, expression of the identified genes was significantly different in lung tumors compared with normal tissues, and the genes' highest mutation frequency was found in lung cancers. Integrative pathway analysis indicated the identified genes were mainly involved in AKT/NF-κB regulatory pathway suggesting the underlying biological processes.ConclusionThis study revealed novel genetic variants in SMGs associated with lung cancer risk, which might contribute to elucidating the biological network involved in lung cancer development.
| S-EPMC5834153 | biostudies-literature
Project description:AimTo explore the association between mothers against decapentaplegic homolog 4 (SMAD4) gene polymorphisms and gastric cancer risk.MethodsFive tagging single nucleotide polymorphisms (tSNPs) in the SMAD4 gene were selected and genotyped in 322 gastric cancer cases and 351 cancer-free controls in a Chinese population by using the polymerase chain reaction restriction fragment length polymorphism method. Immunohistochemistry was used to examine SMAD4 protein expression in 10 normal gastric tissues adjacent to tumors.ResultsIn the single-locus analysis, two significantly decreased risk polymorphisms for gastric cancer were observed: the SNP3 rs17663887 TC genotype (adjusted odds ratio = 0.38, 95% confidence interval: 0.21-0.71), compared with the wild-type TT genotype and the SNP5 rs12456284 GG genotype (0.31, 0.16-0.60), and with the wild-type AA genotype. In the combined analyses of these two tSNPs, the combined genotypes with 2-3 protective alleles (SNP3 C and SNP5 G allele) had a significantly decreased risk of gastric cancer (0.28, 0.16-0.49) than those with 0-1 protective allele. Furthermore, individuals with 0-1 protective allele had significantly decreased SMAD4 protein expression levels in the normal tissues adjacent to tumors than those with 2-3 protective alleles (P = 0.025).ConclusionThese results suggest that genetic variants in the SMAD4 gene play a protective role in gastric cancer in a Chinese population.
| S-EPMC2992684 | biostudies-literature
Project description:PurposeCurrently, several active clinical trials of functional lung avoidance radiation therapy using different imaging modalities for ventilation or perfusion are underway. Patients with lung cancer often show ventilation-perfusion mismatch, whereas the significance of dose-function metric remains unclear. The aim of the present study was to compare dose-ventilation metrics with dose-perfusion metrics for radiation therapy plan evaluation.Methods and materialsPretreatment 4-dimensional computed tomography and 99mTc-macroaggregated albumin single-photon emission computed tomography perfusion images of 60 patients with lung cancer treated with radiation therapy were analyzed. Ventilation images were created using the deformable image registration of 4-dimensional computed tomography image sets and image analysis for regional volume changes as a surrogate for ventilation. Ventilation and perfusion images were converted into percentile distribution images. Analyses included Pearson's correlation coefficient and comparison of agreements between the following dose-ventilation and dose-perfusion metrics: functional mean lung dose and functional percent lung function receiving 5, 10, 20, 30, and 40 Gy (fV5, fV10, fV20, fV30, and fV40, respectively).ResultsOverall, the dose-ventilation metrics were greater than the dose-perfusion metrics (ie, fV20, 26.3% ± 9.9% vs 23.9% ± 9.8%). Correlations between the dose-ventilation and dose-perfusion metrics were strong (range, r = 0.94-0.97), whereas the agreements widely varied among patients, with differences as large as 6.6 Gy for functional mean lung dose and 11.1% for fV20. Paired t test indicated that the dose-ventilation and dose-perfusion metrics were significantly different.ConclusionsStrong correlations were present between the dose-ventilation and dose-perfusion metrics. However, the agreement between the dose-ventilation and dose-perfusion metrics widely varied among patients, suggesting that ventilation-based radiation therapy plan evaluation may not be comparable to that based on perfusion. Future studies should elucidate the correlation of dose-function metrics with clinical pulmonary toxicity metrics.
| S-EPMC7280081 | biostudies-literature
Project description:Background & aimsRisk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.MethodsBy using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States.ResultsWe identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women.ConclusionsBy incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.
| S-EPMC4446193 | biostudies-literature
Project description:Recently, the focus of Alzheimer's disease (AD) research has shifted from the clinical stage to the preclinical stage. We, therefore, aimed to develop a cognitive composite score that can detect the subtle cognitive differences between the amyloid positive (A?+) and negative (A?-) status in cognitively normal (CN) participants. A total of 423 CN participants with A? positron emission tomography images were recruited. The multiple-indicators multiple-causes model found the latent mean difference between the A?+?and A?- groups in the domains of verbal memory, visual memory, and executive functions. The multivariate analysis of covariance (MANCOVA) showed that the A?+?group performed worse in tests related to the verbal and visual delayed recall, semantic verbal fluency, and inhibition of cognitive inference within the three cognitive domains. The Preclinical Amyloid Sensitive Composite (PASC) model we developed using the result of MANCOVA and the MMSE presented a good fit with the data. The accuracy of the PASC score when applied with age, sex, education, and APOE ?4 for distinguishing between A?+?and A?- was adequate (AUC?=?0.764; 95% CI?=?0.667-0.860) in the external validation set (N?=?179). We conclude that the PASC can eventually contribute to facilitating more prevention trials in preclinical AD.
| S-EPMC7423599 | biostudies-literature
Project description:ObjectivesInherited genetic variability contributes to susceptibility to cervical cancer. We investigated the association of single nucleotide polymorphisms (SNPs) in the human epidermal growth factor receptor (ERBB) family with cervical cancer.MethodsWe used the transmission disequilibrium test (TDT) to look for excessive transmission of tag single nucleotide polymorphisms (tSNPs) in ERBB family members EGFR, ERBB2, ERBB3, and ERBB4 in a large sample of women with invasive and in situ cervical cancer and their biological parents (628 trios). The study used a discovery set of trios (244) analyzed by Illumina GoldenGate in which SNPs reaching a P<.05 were re-tested by TaqMan in the combined set of 628. We also explored collaborative effects of different ERBB alleles.ResultsBased on single SNP TDT tests we identified 16 significant SNPs in the discover stage and six of 14 SNPs that could be assayed by TaqMan were significantly overtransmitted in women with cervical cancer in the combined replication set. Four SNPs were located in intron 1 of EGFR and two SNPs in intron 24 of ERBB4. The EGFR variants are located near multiple enhancers, silencers, and the previously identified functional common polymorphisms in intron 1.ConclusionsOur data provide evidence for the involvement of intron 1 EGFR variants and intron 24 ERBB4 variants in modulating risk for the development of in situ and invasive cervical cancer. These variants should be examined in additional populations and functional studies would be needed to confirm this hypothesis.
| S-EPMC3831657 | biostudies-literature
Project description:Inhibition of WEE1 kinase by AZD1775 has shown promising results in clinical cancer trials, but markers predicting AZD1775 response are lacking. Here we analysed AZD1775 response in a panel of human breast cancer (BC) cell lines by global proteome/transcriptome profiling and identified two groups of basal-like BC (BLBCs): 'PTEN low' BLBCs were highly sensitive to AZD1775 and failed to recover following removal of AZD1775, while 'PTEN high' BLBCs recovered. AZD1775 induced phosphorylation of DNA-PK, protecting cells from replication-associated DNA damage and promoting cellular recovery. Deletion of DNA-PK or PTEN, or inhibition of DNA-PK sensitized recovering BLBCs to AZD1775 by abrogating replication arrest, allowing replication despite DNA damage. This was linked to reduced CHK1 activation, increased cyclin E levels and apoptosis. In conclusion, we identified PTEN and DNA-PK as essential regulators of replication checkpoint arrest in response to AZD1775 and defined PTEN as a promising biomarker for efficient WEE1 cancer therapy.
| S-EPMC7338058 | biostudies-literature