scholarly journals The Second Allele: A Key to Understanding the Timing of Sporadic and Hereditary Colorectal Tumorigenesis

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1515
Author(s):  
Mohammed Ali Abbass ◽  
Brandie Leach ◽  
James Michael Church
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Molecular Basis ◽  
Colorectal Neoplasia ◽  
Suppressor Gene ◽  
Suppressor Genes ◽  
Colorectal Tumorigenesis ◽  
Mendelian Genetics ◽  
Hereditary Syndromes

Our understanding of the molecular basis of colorectal neoplasia is derived from Mendelian genetics, with tumor suppressor genes contributing more to the deregulation of growth than oncogenes. In patients with hereditary syndromes, expression of one allele of a key tumor suppressor gene is absent at birth. The loss of the expression of the second allele precipitates tumorigenesis. However, there are multiple ways in which the expression of the second allele of a tumor suppressor gene is lost. Here, we review these ways and their possible effect on phenotype.

scholarly journals Familial Adenomatous Polyposis: Analysis of Genetic Instability of Microsatellites Loci and Genetic Alternations of Tumor Suppressor Genes

2008 ◽  
Vol 8 (2) ◽  
pp. 160-164 ◽  
Author(s):  
Vesna Hadžiavdić ◽  
Izet Eminović ◽  
Mensura Aščerić ◽  
Radovan Komel
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Tumor Suppressor ◽  
Microsatellite Instability ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Genetic Alteration ◽  
Adenomatous Polyposis ◽  
Suppressor Genes ◽  
Genetic Changes

Familial adenomatous polyposis (FAP) is an autosomal dominant illness with the highest risk for appearance of colorectal cancer’s disease. In our study, we have used Bethesda criteria that define colorectal cancers which can be tested on microsatellite instability. The aim of our study is make an analysis of microsatellite instability (MSI), appearance of RER+ phenotype, genetic alteration of tumor suppressor genes as like as one of responsible factor for genesis of adenomatous polyposis. The base for this study were shown families with clinical diagnosed FAP. In this study two families with clinical diagnosed adenomatous polyposis were involved. Our study of both families showed that three tumor tissues belonged to RER negative phenotype, but only one belonged to RER positive phenotype. Microsatellite analysis showed instability of mononucleotide marker Bat 40 at 4 samples and Bat 26 at 2 samples, but Bat 25 and in 1 sample. Dinucleotide marker TP 53 did no show any microsatellite alterations. Genetic alteration of tumor suppressor gene APC appeared at 4 samples, p53 at 3 samples, RB1 at 2 samples and NM23 only at 1 sample, but tumor suppressor genes DCC1 and DCC2 were homozygote. Our results are agree with results of earlier studies and also the got results confirm the fact that loss of heterozygosity of tumor suppressor gene APC and p53 are responsible for genesis of adenomatous polypose and it also represents the characteristic of genetic changes FAP’s patients in our region.

scholarly journals Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3086-3094 ◽  
Author(s):  
FA Asimakopoulos ◽  
NJ White ◽  
E Nacheva ◽  
AR Green
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Molecular Analysis ◽  
Myelodysplastic Syndromes ◽  
Tumor Suppressor Genes ◽  
Myeloproliferative Disorders ◽  
Suppressor Gene ◽  
Molecular Heterogeneity ◽  
Suppressor Genes ◽  
Physical Maps

Abstract Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16–21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.

scholarly journals The Evolution of Human Cancer Gene Duplications across Mammals

2020 ◽  
Author(s):  
Marc Tollis ◽  
Aika K. Schneider-Utaka ◽  
Carlo C. Maley
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Cancer Gene ◽  
Suppressor Genes ◽  
Copy Numbers

AbstractCancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species’ cancer gene copy number and it’s longevity, but not body size, contrary to predictions from Peto’s Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

scholarly journals Promoterless Transposon Mutagenesis Drives Solid Cancers via Tumor Suppressor Inactivation

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 225
Author(s):  
Aziz Aiderus ◽  
Ana M. Contreras-Sandoval ◽  
Amanda L. Meshey ◽  
Justin Y. Newberg ◽  
Jerrold M. Ward ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Sleeping Beauty ◽  
Transposon Mutagenesis ◽  
Gene Inactivation ◽  
Whole Body ◽  
Gene Effects ◽  
Suppressor Genes

A central challenge in cancer genomics is the systematic identification of single and cooperating tumor suppressor gene mutations driving cellular transformation and tumor progression in the absence of oncogenic driver mutation(s). Multiple in vitro and in vivo gene inactivation screens have enhanced our understanding of the tumor suppressor gene landscape in various cancers. However, these studies are limited to single or combination gene effects, specific organs, or require sensitizing mutations. In this study, we developed and utilized a Sleeping Beauty transposon mutagenesis system that functions only as a gene trap to exclusively inactivate tumor suppressor genes. Using whole body transposon mobilization in wild type mice, we observed that cumulative gene inactivation can drive tumorigenesis of solid cancers. We provide a quantitative landscape of the tumor suppressor genes inactivated in these cancers and show that, despite the absence of oncogenic drivers, these genes converge on key biological pathways and processes associated with cancer hallmarks.

scholarly journals The RB1 Story: Characterization and Cloning of the First Tumor Suppressor Gene

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 879 ◽  
Author(s):  
Jesse L. Berry ◽  
Ashley Polski ◽  
Webster K. Cavenee ◽  
Thaddeus P. Dryja ◽  
A. Linn Murphree ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Cancer Genetics ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Prognostic Information ◽  
Rb1 Gene ◽  
Suppressor Genes ◽  
Foundational Work

The RB1 gene is the first described human tumor suppressor gene and plays an integral role in the development of retinoblastoma, a pediatric malignancy of the eye. Since its discovery, the stepwise characterization and cloning of RB1 have laid the foundation for numerous advances in the understanding of tumor suppressor genes, retinoblastoma tumorigenesis, and inheritance. Knowledge of RB1 led to a paradigm shift in the field of cancer genetics, including widespread acceptance of the concept of tumor suppressor genes, and has provided crucial diagnostic and prognostic information through genetic testing for patients affected by retinoblastoma. This article reviews the long history of RB1 gene research, characterization, and cloning, and also discusses recent advances in retinoblastoma genetics that have grown out of this foundational work.

scholarly journals The Evolution of Human Cancer Gene Duplications across Mammals

2020 ◽  
Vol 37 (10) ◽  
pp. 2875-2886 ◽  
Author(s):  
Marc Tollis ◽  
Aika K Schneider-Utaka ◽  
Carlo C Maley
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Human Tumor ◽  
Suppressor Gene ◽  
Genetic Alterations ◽  
Gene Copy ◽  
Cancer Gene ◽  
Suppressor Genes ◽  
Copy Numbers

Abstract Cancer is caused by genetic alterations that affect cellular fitness, and multicellular organisms have evolved mechanisms to suppress cancer such as cell cycle checkpoints and apoptosis. These pathways may be enhanced by the addition of tumor suppressor gene paralogs or deletion of oncogenes. To provide insights to the evolution of cancer suppression across the mammalian radiation, we estimated copy numbers for 548 human tumor suppressor gene and oncogene homologs in 63 mammalian genome assemblies. The naked mole rat contained the most cancer gene copies, consistent with the extremely low rates of cancer found in this species. We found a positive correlation between a species’ cancer gene copy number and its longevity, but not body size, contrary to predictions from Peto’s Paradox. Extremely long-lived mammals also contained more copies of caretaker genes in their genomes, suggesting that the maintenance of genome integrity is an essential form of cancer prevention in long-lived species. We found the strongest association between longevity and copy numbers of genes that are both germline and somatic tumor suppressor genes, suggesting that selection has acted to suppress both hereditary and sporadic cancers. We also found a strong relationship between the number of tumor suppressor genes and the number of oncogenes in mammalian genomes, suggesting that complex regulatory networks mediate the balance between cell proliferation and checks on tumor progression. This study is the first to investigate cancer gene expansions across the mammalian radiation and provides a springboard for potential human therapies based on evolutionary medicine.

scholarly journals Genome-Wide Methylation Mapping Using Nanopore Sequencing Technology Identifies Novel Tumor Suppressor Genes in Hepatocellular Carcinoma

2021 ◽  
Vol 22 (8) ◽  
pp. 3937
Author(s):  
Colin F. Davenport ◽  
Tobias Scheithauer ◽  
Alessia Dunst ◽  
Frauke Sophie Bahr ◽  
Marie Dorda ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Suppressor Gene ◽  
Nanopore Sequencing ◽  
Sequencing Technology ◽  
Suppressor Genes ◽  
Genome Wide ◽  
A Genome

Downregulation of multiple tumor suppressor genes (TSGs) plays an important role in cancer formation. Recent evidence has accumulated that cancer progression involves genome-wide alteration of epigenetic modifications, which may cause downregulation of the tumor suppressor gene. Using hepatocellular carcinoma (HCC) as a system, we mapped 5-methylcytosine signal at a genome-wide scale using nanopore sequencing technology to identify novel TSGs. Integration of methylation data with gene transcription profile of regenerated liver and primary HCCs allowed us to identify 10 potential tumor suppressor gene candidates. Subsequent validation led us to focus on functionally characterizing one candidate—glucokinase (GCK). We show here that overexpression of GCK inhibits the proliferation of HCC cells via induction of intracellular lactate accumulation and subsequently causes energy crisis due to NAD+ depletion. This suggests GCK functions as a tumor suppressor gene and may be involved in HCC development. In conclusion, these data provide valuable clues for further investigations of the process of tumorigenesis in human cancer.

scholarly journals Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes

Blood ◽  
1994 ◽  
Vol 84 (9) ◽  
pp. 3086-3094 ◽  
Author(s):  
FA Asimakopoulos ◽  
NJ White ◽  
E Nacheva ◽  
AR Green
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Molecular Analysis ◽  
Myelodysplastic Syndromes ◽  
Tumor Suppressor Genes ◽  
Myeloproliferative Disorders ◽  
Suppressor Gene ◽  
Molecular Heterogeneity ◽  
Suppressor Genes ◽  
Physical Maps

Acquired deletions of the long arm of chromosome 20 are found in several hematologic conditions and particularly in the myeloproliferative disorders and myelodysplastic syndromes. The spectrum of diseases associated with 20q deletions suggests that such deletions may mark the site of a tumor suppressor gene that contributes to the regulation of normal multipotent hematopoietic progenitors. We present here the first detailed molecular analysis of 20q deletions associated with myeloid disorders. Thirty-four microsatellite primer pairs corresponding to loci on 20q have been used to study DNA samples from two cell lines and from highly purified peripheral blood granulocytes obtained from seven patients. In addition, Southern analysis of cell line DNA has been performed using 19 DNA probes that map to 20q. Three conclusions can be drawn from our results. Firstly, molecular heterogeneity of both centromeric and telomeric breakpoints was demonstrated, thus supporting the existence of a tumor suppressor gene on 20q. In addition many of the breakpoints have been mapped to small genetic intervals. Secondly, our results define a commonly deleted region of 16–21 cM which contains ADA, PLC1, TOP1, SEMG1, and PPGB. Several candidate tumor suppressor genes lie outside the common deleted region including SRC, HCK, p107, PTPN1, and CEBP beta. Thirdly, the data allow integration of genetic and physical maps and have refined the map positions of multiple genes. These results will facilitate attempts to identify candidate hematopoietic tumor suppressor genes on 20q.

scholarly journals Candidate tumor-suppressor genes MTS1 (p16INK4A) and MTS2 (p15INK4B) display frequent homozygous deletions in primary cells from T- but not from B-cell lineage acute lymphoblastic leukemias [see comments]

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4038-4044 ◽  
Author(s):  
J Hebert ◽  
JM Cayuela ◽  
J Berkeley ◽  
F Sigaux
Keyword(s):  
Tumor Suppressor ◽  
B Cell ◽  
Tumor Suppressor Gene ◽  
Tumor Suppressor Genes ◽  
Cell Lineage ◽  
Suppressor Gene ◽  
Suppressor Genes ◽  
Multiple Tumor ◽  
B Lineage ◽  
Homozygous Deletions

Using a Southern blot approach, deletions of MTS1 (multiple tumor- suppressor gene 1) and MTS2 (multiple tumor-suppressor gene 2) candidate tumor-suppressor genes have been studied in primary neoplastic cells from 55 acute lymphoblastic leukemia (ALL) patients. Homozygous MTS1 deletions were found in 20 of 24 T-ALL cases and in only 2 of 31 B-lineage cases (P < .001). The deletions involved MTS1 and MTS2 in most cases. Homozygous MTS2 deletions were observed in 16 of 24 T-ALL cases and in 1 of 31 B-lineage ALLs (P < .001), all of them displaying homozygous MTS1 deletions. In 5 cases (4 T and 1 B), deletions involved MTS1 but spared the MTS2 gene, showing that one deletion breakpoint was located between the two genes within a 25-kb region. In 1 T-ALL case, an MTS1 gene rearrangement has occurred downstream to exon 2. Possible hemizygous deletions were found in 6 cases, 4 of them of the B-cell lineage. In 7 ALL cases, cells obtained at presentation and at first relapse were studied and identical results were observed in 6 cases. In 1 B-lineage case, a germline pattern was found at presentation and a possible monoallelic MTS1/MTS2 deletion was observed at relapse. The high frequency of MTS1 and MTS2 homozygous deletions in T-ALLs supports the view that inactivation of these genes plays an important role in the pathogenesis of this type of human leukemia.

scholarly journals Novel Chromosomal Abnormalities Identified by Comparative Genomic Hybridization in Parathyroid Adenomas1

1998 ◽  
Vol 83 (5) ◽  
pp. 1766-1770 ◽  
Author(s):  
Nallasivam Palanisamy ◽  
Yasuo Imanishi ◽  
Pulivarthi H. Rao ◽  
Hideki Tahara ◽  
R. S. K. Chaganti ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Comparative Genomic Hybridization ◽  
Tumor Suppressor Genes ◽  
Chromosomal Abnormalities ◽  
Suppressor Gene ◽  
Comparative Genomic ◽  
Parathyroid Tumor ◽  
Genomic Hybridization ◽  
Suppressor Genes ◽  
Parathyroid Adenomas

The molecular basis of parathyroid adenomatosis includes defects in the cyclin D1/PRAD1 and MEN1 genes but is, in large part, unknown. To identify new locations of parathyroid oncogenes or tumor suppressor genes, and to further establish the importance of DNA losses described by molecular allelotyping, we performed comparative genomic hybridization (CGH) on a panel of 53 typical sporadic (nonfamilial) parathyroid adenomas. CGH is a new molecular cytogenetic technique in which the entire tumor genome is screened for chromosomal gains and/or losses. Two abnormalities, not previously described, were found recurrently: gain of chromosome 16p (6 of 53 tumors, or 11%) and gain of chromosome 19p (5 of 53, or 9%). Losses were found frequently on 11p (14 of 53, or 26%), as well as 11q (18 of 53, or 34%). Recurrent losses were also seen on chromosomes 1p, 1q, 6q, 9p, 9q, 13q, and 15q, with frequencies ranging from 8–19%. Twenty-four of the 53 adenomas were also extensively analyzed with polymorphic microsatellite markers for allelic losses, either in this study (11 cases) or previously (13 cases). Molecular allelotyping results were highly concordant with CGH results in these tumors (concordance level of 97.5% for all informative markers/chromosome arms examined). In conclusion, CGH has identified the first two known chromosomal gain defects in parathyroid adenomas, suggesting the existence of direct-acting parathyroid oncogenes on chromosomes 16 and 19. CGH has confirmed the locations of putative parathyroid tumor suppressor genes, also defined by molecular allelotyping, on chromosomes 1p, 6q, 9p, 11q, 13q, and 15q. Finally, CGH has provided new evidence favoring the possibility that distinct parathyroid tumor suppressors exist on 1p and 1q, and has raised the possibility of a parathyroid tumor suppressor gene on 11p, distinct from the MEN1 gene on 11q. CGH can identify recurrent genetic abnormalities in hyperparathyroidism, especially chromosomal gains, that other methods do not detect.

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