scholarly journals Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis

2015 ◽  
Vol 370 (1673) ◽  
pp. 20140222 ◽  
Author(s):  
Aleah F. Caulin ◽  
Trevor A. Graham ◽  
Li-San Wang ◽  
Carlo C. Maley
Keyword(s):  
Cancer Risk ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Size Analysis ◽  
Tumour Suppressor Genes ◽  
Division Rate ◽  
Somatic Evolution ◽  
Mammalian Genomes

Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans.

Use of Monozygotic Twins in Search for Breast Cancer Susceptibility Loci

Twin Research ◽  
2001 ◽  
Vol 4 (4) ◽  
pp. 251-259 ◽  
Author(s):  
Asta Försti ◽  
Qianren Jin ◽  
Lena Sundqvist ◽  
Magnus Söderberg ◽  
Kari Hemminki
Keyword(s):  
Breast Cancer ◽  
Cancer Susceptibility ◽  
Monozygotic Twins ◽  
Monozygotic Twin ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Twin Model

AbstractWe have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

p53 Tumour Suppressor Gene Mutations in Benign Prostatic Hyperplasia and Prostate Cancer

1998 ◽  
Vol 34 (5) ◽  
pp. 433-440 ◽  
Author(s):  
Horst Schlechte ◽  
Severin V. Lenk ◽  
Thomas Löning ◽  
Dietmar Schnorr ◽  
Birgit D. Rudolph ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Benign Prostatic Hyperplasia ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Prostatic Hyperplasia ◽  
Tumour Suppressor ◽  
P53 Tumour Suppressor Gene

scholarly journals Relationship between TP53 tumour suppressor gene mutations and smoking-related bulky DNA adducts in a lung cancer study population from Hungary

Mutagenesis ◽  
2009 ◽  
Vol 24 (6) ◽  
pp. 475-480 ◽  
Author(s):  
Lívia Anna ◽  
Reetta Holmila ◽  
Katalin Kovács ◽  
Erika Győrffy ◽  
Zoltán Győri ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Adducts ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Cancer Study ◽  
Study Population ◽  
Bulky Dna Adducts

Molecular profile of nasopharyngeal carcinoma: analysing tumour suppressor gene promoter hypermethylation by multiplex ligation-dependent probe amplification

2017 ◽  
Vol 71 (4) ◽  
pp. 351-359 ◽  
Author(s):  
Marc L Ooft ◽  
Jolique van Ipenburg ◽  
Rob van Loo ◽  
Rick de Jong ◽  
Cathy Moelans ◽  
...  
Keyword(s):  
Treatment Options ◽  
Disease Free Survival ◽  
Promoter Hypermethylation ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Molecular Profile ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Dependent Probe

AimsTo assess differences in methylation profiles, and thus pathogenesis, between Epstein-Barr virus (EBV)-positive and negative nasopharyngeal carcinomas (NPCs). Also, promoter hypermethylation is a common phenomenon in early carcinogenesis to inactivate tumour suppressor genes. Since epigenetic changes are reversible, the therapeutic application of methylation inhibitors could provide treatment options.MethodsWe evaluated promoter hypermethylation profiles of 22 common tumour suppressor genes in 108 NPCs using methylation-specific multiplex ligation-dependent probe amplification. Correlation between methylation, clinicopathological features (including EBV) and survival was examined. Cluster analysis was also performed.ResultsHypermethylation of RASSF1A and ESR1 was significantly more frequent in EBV-positive NPC, while hypermethylation of DAPK1 was more frequent in EBV-negative NPC. In logistic regression, age, with EBV-positive NPC occurring at earlier age, and RASSF1, with RASSF1 hypermethylation being more frequent in EBV-positive NPC, remained significant. In EBV-positive NPC, hypermethylation of RASSF1A predicted worse overall survival (OS) (HR 3.058,95% CI 1.027 to 9.107). In EBV-negative NPC, hypermethylated adenomatous polyposis coli (APC) was a predictor of poor disease-free survival (DFS) (HR 6.868, 95% CI 2.142 to 22.022).ConclusionThere are important epigenetic differences between EBV-negative and EBV-positive NPCs, with EBV-negative NPC having a more similar hypermethylation profile to other head and neck squamous cell carcinomas than EBV-positive NPC. Hypermethylation of RASSF1A might contribute to worse OS in EBV-positive NPC, and may be an important event in the pathogenesis of EBV-infected NPC. Hypermethylation of APC might contribute to worse DFS in EBV-negative NPC.

scholarly journals Preimplantation diagnosis for p53 tumour suppressor gene mutations

2001 ◽  
Vol 2 (2) ◽  
pp. 102-105 ◽  
Author(s):  
Yury Verlinsky ◽  
Svetlana Rechitsky ◽  
Oleg Verlinsky ◽  
Kangu Xu ◽  
Glenn Schattman ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Preimplantation Diagnosis ◽  
P53 Tumour Suppressor Gene

scholarly journals PTEN regulates glioblastoma oncogenesis through chromatin-associated complexes of DAXX and histone H3.3

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Jorge A. Benitez ◽  
Jianhui Ma ◽  
Matteo D’Antonio ◽  
Antonia Boyer ◽  
Maria Fernanda Camargo ◽  
...  
Keyword(s):  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Growth Defect ◽  
Tumour Suppressor Genes ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Pten Deletion ◽  
Therapeutic Opportunity ◽  
Associated Function

Abstract Glioblastoma (GBM) is the most lethal type of human brain cancer, where deletions and mutations in the tumour suppressor gene PTEN (phosphatase and tensin homolog) are frequent events and are associated with therapeutic resistance. Herein, we report a novel chromatin-associated function of PTEN in complex with the histone chaperone DAXX and the histone variant H3.3. We show that PTEN interacts with DAXX and, in turn PTEN directly regulates oncogene expression by modulating DAXX-H3.3 association on the chromatin, independently of PTEN enzymatic activity. Furthermore, DAXX inhibition specifically suppresses tumour growth and improves the survival of orthotopically engrafted mice implanted with human PTEN-deficient glioma samples, associated with global H3.3 genomic distribution changes leading to upregulation of tumour suppressor genes and downregulation of oncogenes. Moreover, DAXX expression anti-correlates with PTEN expression in GBM patient samples. Since loss of chromosome 10 and PTEN are common events in cancer, this synthetic growth defect mediated by DAXX suppression represents a therapeutic opportunity to inhibit tumorigenesis specifically in the context of PTEN deletion.

scholarly journals Non-accidental structural chromosome aberrations in established monkey B-lymphocyte cell lines

Biologija ◽  
2020 ◽  
Vol 65 (4) ◽  
Author(s):  
Daredzhan Araviashvili ◽  
Olga Chzhu ◽  
Igor Marinich ◽  
Irina Danilova
Keyword(s):  
Cell Lines ◽  
Chromosomal Aberrations ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor ◽  
Chromosome 8 ◽  
Tumour Suppressor Genes ◽  
Suppressor Genes ◽  
Cultivation In Vitro ◽  
Lymphocyte Cell

Established primate lymphocyte cell lines obtained from tumour samples and from EBV-positive monkeys served us as the model system for studying the role of genetic factors and chromosomal abnormalities in malignization. The investigation of chromosome regions and genes involved in chromosomal aberrations leading to malignization in these lines was the aim of our work. Cytogenetic analysis was performed at different stages of cultivation in vitro. To determine the oncogenes and tumour suppressor genes located on aberrant chromosomes, data on mapping rhesus macaque genes, and high similarity of human and monkey karyotypes were used. We found that, in the line obtained from lymphomatous baboon tissue, the inactivation of tumour suppressor gene RB1 on chromosome 17 after chromosomal rearrangement is one of the most probable causes of in vivo malignization. Chromosomal aberrations at the region of oncogene c-Ki-ras and tumour suppressor gene TP53 change the proliferative status and differentiation in established cell lines obtained from healthy but EBV-seropositive primates. The other cause of malignization in these lines is an increase in expression of the oncogene c-myc caused by trisomy of chromosome 8 where c-myc is located. Structural aberrations in established primate cell lines affecting several chromosomal loci were identified as: (1) causing the proto-oncogene activation – the central event in the tumour clone occurrence, and (2) deactivating tumour suppressor genes. The change in the chromosome number leads to increase in oncogenic products and to damage of regulatory functions associated with cell proliferation.

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