Cancer Genetics and Epigenetics
- Other groups
- Regulatory Genomics
- Chromatin and Cell Fate
- Disease Genomics
- Epigenetic Mechanisms of Cancer and Cell Differentiation
- Cancer Genetics and Epigenetics
- Cancer and Iron
- ICO-IMPPC Joint Program - Genetic Diagnostics
- Genetic Variation and Cancer
- Genomics and Bioinformatics
- ABO Histo-Blood Groups and Cancer
- Cancer Genome Biology
The Cancer Genetics and Epigenetics Group now forms part of the Program for Predictive and Personalized Medicine of Cancer at the Institute Germans Trias i Pujol (IGPT) on the Can Ruti Campus. Please see the IGTP website here.
In our group we study tumours from the intestinal tract (i.e. colon, and stomach) that sometimes develop when the cell machinery preserving the integrity of the genome, rather like computer spelling programs that detect errors and correct them, is not working properly. When these corrector genes (mutators) are inactivated, the mutations that occur in all normal cells accumulate in large numbers because they are not repaired. This originates a remarkable genomic instability and cancer eventually develops when mutations occur in some cancer genes, such as the oncogenes and tumour suppressor genes. Some of the mutator genes are not inactivated by mutations (mutator mutations) but by epigenetic silencing. This results as a consequence of the disintegration of the epigenetic code, an unexplored process that is strongly associated to aging. These studies have clinical applications. For instance, many hereditary colon tumours originate by mutations in mutator genes that are transmitted from generation to generation. Molecular diagnosis of the deficient mutator genes determines which members of these families will be affected in the future. Identification of tumours with this kind of genomic instability is also useful to detect familial cancer patients and to predict survival.
Molecular mechanisms for gastrointestinal cancer pathogenesis.
Our research aims to understand better the mechanisms of genomic instability as a “remote control”, and cancer epigenetics as an “ultraremote control” mechanisms underlying tumorigenesis.Using unbiased DNA fingerprinting aproaches we obtained panoramic views of the genetic and epigenetic disruption of the genome in cancer. A picture is emerging from these studies in which epigenetic alterations precede and determine the occurrence of genetic alterations in gastrointestinal tumorigenesis:
o In tumors with microsatellite instability (MSI), gradual and age-associated CpG island hypermethylation underlies the manifestation of the mutator phenotype when the DNA mismatch repair gene MLH1 becomes epigenetically silenced.
o In MSI negative tumors, a gradual increase in DNA hypomethylation during aging may underlie genome disruption accompanying tumor progression. This “wear & tear” model proposes that the loss of methylation relentlessly spreads throughout the chromosomes leading to mitotic errors when certain chromosomal regions are hit, followed by genomic damage and ultimately cancer development.
Epigenetic biomarkers for cancer susceptibility and metastatic spread.
We are currently analyzing the impact of the alterations in patterns of DNA methylation in genome disruption and studying the applications of these epigenetic somatic alterations for gastrointestinal cancer diagnosis and prognosis. Specifically we are studying the epigenomics of proteolysis and the applications of epigenetic alterations in several members of the metalloproteinase gene family as biomarkers for defining individuals at high risk for field cancerization. Also, these studies should yield tools predictive for metastatic homing tendency of primary colorectal cancers, and diagnostic for distinguishing primary ovarian cancers from metastatic gastrointestinal tumors.
DNA demethylation, predictive for the development of multiple colon cancers.
Some colon cancer patients present synchronous cancers (multiple simultaneous cancers) at diagnosis and others develop later additional primary (metachronous) cancers, but the risk factors are unknown for nonhereditary colon cancer. We have discovered that high levels of DNA demethylation in non-cancerous mucosa from patients who underwent primary colon cancer resection was predictive for metachronous neoplasms. The levels of demethylation would serve as a prognostic biomarker that would allow for improved identification of individuals at high risk for the development of metachronous colorectal cancer. This would consequently lead to increased efficiency of surveillance and prognosis.
Genomics and epigenomics of colorectal cancer prediction.
In addition, we are starting new projects to discover cancer susceptibilty and resistance genes by using genomic and epigenomic approaches. Genome Wide Association Study (GWAS) preliminary study with Spanish cases and controls confirmed some of the loci previously reported as colorectal cancer susceptibilty genes and identified novel single loci associated to increased risk.
Exome deep sequencing and methylation profiling together with array CGH approaches will integrate the genomic and epigenomic somatic alterations underlying gastrointestinal cancer, providing novel diagnostic and prognostic markers that could not be obtained by any of the individual approaches in isolation.
ADE10/00026 Set up Grant for the Genomics & Epigenomics of Cancer Prediction Program at the IMPPC
IP Funding Starts Ends Manuel Perucho MEC 01-01-2011 31-12-2016
PI15/01763_Alteraciones epigenéticas en cáncer colorrectal (CCR): papel de metaloproteinasas de matriz extracelular, remodeladores de cromatina, y asociación con el microbioma intestinal
IP Funding Starts Ends Manuel Perucho ISCIII 01-01-2016 31-12-2018
(+34) 93 554 3054 (extn 3164)
Leodolter A, Alonso S, Gonzalez B, Ebert MP, Vieth M, Röcken C, Wex T, Peitz U, Malfertheiner P, Perucho M. Somatic DNA Hypomethylation in H. pylori-Associated High-Risk Gastritis and Gastric Cancer: Enhanced Somatic Hypomethylation Associates with Advanced Stage Cancer. Clin Transl Gastroenterol 2015; 6: e85
Alonso S, Dai Y, Yamashita K, Horiuchi S, Dai T, Matsunaga A, Sánchez-Muñoz R, Bilbao-Sieyro C, Díaz-Chico JC, Chernov AV, Strongin AY, Perucho M. Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget 2015 Feb; 6(5): 3420-31
Real LM, Ruiz A, Gayán J, González-Pérez A, Sáez ME, Ramírez-Lorca R, Morón FJ, Velasco J, Marginet-Flinch R, Musulén E, Carrasco JM, Moreno-Rey C, Vázquez E, Chaves-Conde M, Moreno-Nogueira JA, Hidalgo-Pascual M, Ferrero-Herrero E, Castellví-Bel S, Castells A, Fernandez-Rozadilla C, Ruiz-Ponte C, Carracedo A, Gonzalez B, Alonso S, Perucho M. A colorectal cancer susceptibility new variant at 4q26 in the Spanish population identified by genome-wide association analysis. PLoS ONE 2014; 9(6): e101178
Kamiyama H, Suzuki K, Maeda T, Koizumi K, Miyaki Y, Okada S, Kawamura YJ, Samuelsson JK, Alonso S, Konishi F, Perucho M. DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene 2012 Nov; 31(48): 5029-37
Koizumi K, Alonso S, Miyaki Y, Okada S, Ogura H, Shiiya N, Konishi F, Taya T, Perucho M, Suzuki K. Array-based identification of common DNA methylation alterations in ulcerative colitis. Int. J. Oncol. 2012 Apr; 40(4): 983-94
Samuelsson JK, Alonso S, Yamamoto F, Perucho M. DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer. Mutat. Res. 2010 Nov; 693(1): 61-76
Baranovskaya S, Martin Y, Alonso S, Pisarchuk KL, Falchetti M, Dai Y, Khaldoyanidi S, Krajewski S, Novikova I, Sidorenko YS, Perucho M, Malkhosyan SR. Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability. Clin. Cancer Res. 2009 Jul; 15(14): 4531-7
Suzuki K, Suzuki I, Leodolter A, Alonso S, Horiuchi S, Yamashita K, Perucho M. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell 2006 Mar; 9(3): 199-207
Yamashita K, Dai T, Dai Y, Yamamoto F, Perucho M. Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 2003 Aug; 4(2): 121-31
Ionov Y, Yamamoto H, Krajewski S, Reed JC, Perucho M. Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc. Natl. Acad. Sci. U.S.A. 2000 Sep; 97(20): 10872-7
Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 1993 Jun; 363(6429): 558-61
Winter E, Yamamoto F, Almoguera C, Perucho M. A method to detect and characterize point mutations in transcribed genes: amplification and overexpression of the mutant c-Ki-ras allele in human tumor cells. Proc. Natl. Acad. Sci. U.S.A. 1985 Nov; 82(22): 7575-9