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Jean-Pierre Issa

Publications and source records attributed to Jean-Pierre Issa.

26 records · Page 2Linked to original sources
PubMed2003

Age-related epigenetic changes and the immune system.

The role of DNA methylation in immune function is discussed extensively in other papers in this issue. Many of these discussions assume that DNA methylation, a major mediator of epigenetic information, is fairly immutable and uniform in adult cells and tissues. There is, however, growing evidence that DNA methylation changes subtly with age. Normal aging cells and tissues show a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences, but also in potential gene regulatory areas. In parallel, selected genes show progressive age-related increases in promoter methylation, which, once a critical methylation density is reached, have the potential to permanently silence gene expression. These changes are highly mosaic within a given tissue and introduce a high degree of epigenetic variability in aging cells. Such epigenetic phenomena could impact immune response through masking/unmasking potential tissue antigens as well as by modulating the differentiation and response of immune effector cells. The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation.

Aging↗
PubMed2003

Decitabine.

PURPOSE OF REVIEW: Decitabine is a cytosine analogue synthesized in the 1960s that is currently enjoying a revival of interest prompted by the elucidation of DNA methylation inhibition as its major mechanism of action, along with increased understanding of the role of DNA methylation in epigenetic dysregulation in cancer. These advances have turned this agent from just another cytosine analogue into a targeted drug aimed at reversing epigenetic silencing in cancer cells. Here, recent clinical and translational studies with decitabine are reviewed. RECENT FINDINGS: Scientists are now taking a closer look at this drug as a targeted agent, with particular attention to schedules of administration and mechanisms of in vivo efficacy. Two phase II trials have reported substantial clinical activity of decitabine in the myelodysplastic syndrome and in chronic myelogenous leukemia. There is considerable interest in combining decitabine with histone deacetylase inhibitors and in using it to sensitize cells to chemotherapy or to biologic therapy. Finally, ongoing efforts are deciphering the in vivo mechanisms of responses seen after decitabine administration. SUMMARY: Decitabine, an old drug, has now made a comeback as a targeted agent and a prototype for epigenetic therapy in cancer. Doses, schedules of administration, and the development of rational combinations including this agent must all take this critical mechanism of action into account.

Antimetabolites, Antineoplastic↗
PubMed2003

Comparison of epigenetic and genetic alterations in mucinous cystic neoplasm and serous microcystic adenoma of pancreas.

Mucinous cystic neoplasms and serous microcystic adenomas account for the majority of cystic tumors of pancreas. Mucinous cystic neoplasms and serous microcystic adenomas have different frequencies of progression to malignancy. The genetic and epigenetic alterations of these tumors have not been studied in detail. In this study, we compared methylation status of p16, p14, VHL, and ppENK genes by methylation-specific PCR (MSP), and genetic alterations including K-ras and beta-catenin gene mutations, chromosome 3p loss, and microsatellite instability in 15 mucinous cystic neoplasms (10 benign and 5 borderline) and 16 serous microcystic adenomas. There were no significant differences between mucinous cystic neoplasms and serous microcystic adenomas in methylation of p16 (14%, 2/14 and 12%, 2/16), p14 (15%, 2/13 and 37%, 6/16), VHL (0/14 and 7%, 1/14), and ppENK (0/14 and 0/13), respectively. K-ras mutation was present only in mucinous cystic neoplasms but not in serous microcystic adenomas (33%, 5/15 versus 0/16; P =.004). In addition, LOH at 3p25, the chromosomal location of VHL gene, was present in 57% (8/14) of serous microcystic adenomas compared with in 17% (2/12) of mucinous cystic neoplasms (P =.03). No beta-catenin mutation, microsatellite instability, or mutation of transforming growth factor beta type II receptor was present in either type of tumors. In conclusion, K-ras mutations and allelic loss of VHL locus at 3p25, but not methylation, distinguished mucinous cystic neoplasms and serous microcystic adenomas. The differences in genetic alterations but not epigenetic alterations may explain the pathogenesis and progression to malignancy of these cystic tumors of pancreas.

Adenoma↗
PubMed2003

Epigenetic regulation of ARHI in breast and ovarian cancer cells.

ARHI (Ras homologue member I) encodes a 26-kDa GTPase with 50-60% amino acid homology to Ras and Rap. ARHI and Ras share similar GTP/GDP binding domains, but exert opposite functions. ARHI is one of the first reported tumor suppressors in the ras superfamily. ARHI is expressed consistently in normal breast and ovarian epithelial cells, but not in breast or ovarian cancers. The loss of ARHI can be related to tumor progression. Reexpression of ARHI induces apoptosis of breast and ovarian cancer cells by a caspase-independent, calpain-dependent pathway. ARHI is consistently expressed in normal breast and ovarian epithelial cells but is dramatically downregulated in more then 70% of breast and ovarian cancers. ARHI is maternally imprinted with methylation of the three CpG islands in the maternal allele of normal cells. ARHI is expressed only from the paternal allele whose three CpG islands are not methylated. Loss of ARHI expression can occur through a genetic event, with loss of heterozygosity observed in 40% of breast, ovarian, and pancreatic cancers; but it can also occur through epigenetic mechanisms, including DNA methylation, histone deacetylation, histone methylation, and transcriptional regulation. Our data suggest that acetylation and methylation of chromatin associated with the ARHI promoter leads to loss of both ARHI expression and the ability to suppress tumor growth. Changes in chromatin that silence ARHI may be driven by methylation-dependent and -independent pathways. Reactivation of both the silenced paternal and imprinted maternal alleles can be achieved by demethylation and inhibition of histone deacetylation.

Acetylation↗
PubMed2002

HLTF gene silencing in human colon cancer.

Chromatin remodeling enzymes are increasingly implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, have been shown to be disrupted in cancer. In this study we identified as a target for gene inactivation in colon cancer the gene for helicase-like transcription factor (HLTF), a SWI/SNF family protein. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in nine of 34 colon cancer cell lines. In these cell lines HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colony growth in each of three different HLTF-deficient cell lines, but showed no suppressive effect in any of three HLTF-proficient cell lines. These findings show that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggest HLTF is a candidate colon cancer suppressor gene.

Base Sequence↗
PubMed2002

Epigenetic variation and human disease.

Cytosine guanine dinucleotide (CpG) island methylation is a known mechanism of epigenetic inheritance in postmeiotic cells. Through associated chromatin changes and silencing, such epigenetic states can influence cellular physiology and affect disease risk and severity. Our studies of CpG island methylation in normal colorectal mucosa revealed progressive age-related increases at multiple gene loci, suggesting genome-wide molecular alterations with potential to silence gene expression. However, there was considerable variation in the degree of methylation among individuals of comparable ages. Such variation could be related to genetic factors, lifestyle, or environmental exposures. Studies in ulcerative colitis and hepatocellular cirrhosis and neoplasia revealed that chronic inflammatory states are accompanied by marked increases in CpG island methylation in normal-appearing tissues, confirming the hypothesis that proinflammatory exposures could account for part of the epigenetic variation in human populations. Preliminary data also suggest potential influences of lifestyle and exposure factors on CpG island methylation. It is suggested that epigenetic variation related to aging, lifestyle, exposures and possibly genetic factors, is one of the modulators of acquired, age-related human diseases, including neoplasia.

CpG Islands↗
PubMed2002

Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation.

PURPOSE: The PTEN gene at chromosome 10q23.3 is a tumor-suppressor genethat is inactivated in several types of human tumors. Althoughmutation and homozygous deletion are the most commonmechanisms of PTEN inactivation, promoter methylation and translational modification can also account for PTEN silencing. The aim of this study was to investigate the expression of PTEN protein in primary non-small cell lung cancer (NSCLC) samples and to investigate the promoter methylation status of the gene in a panel of NSCLC cell lines as well as primary tumors. EXPERIMENTAL DESIGN: We analyzed PTEN expression by immunohistochemistry in tissue samples from 125 patients with early-stage NSCLC. We also evaluated PTEN promoter methylation status by methylation-specific PCR in 20 microdissected PTEN-negative primary tumors from among the last specimens as well as in a panel of 16 NSCLC cell lines. Western and Northern blotting were performed in the same panel of NSCLC cell lines. RESULTS: Thirty (24%) of the 125 specimens showed a lack of staining for PTEN. PTEN methylation was detected in 7 (35%) of the 20 PTEN-negative NSCLC samples and in none of the 10 PTEN-positive NSCLC samples that were microdissected. Furthermore, PTEN methylation was observed in 11 (69%) of the 16 NSCLC cell lines tested. PTEN mRNA expression was increased in the NCI-H1299 cell line by in vitro treatment with the demethylating agent 5-aza-2'-deoxycytidine. PTEN methylation was well correlated with PTEN expression in NSCLC cell lines by Western and Northern blot (P = 0.025). CONCLUSIONS: Although genetic alterations of the PTEN gene are rare in NSCLC, loss of PTEN protein is not an uncommon event in early-stage NSCLC. Lack of PTEN expression may be partially explained by promoter methylation.

Adult↗