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B Iacopetta

Publications and source records attributed to B Iacopetta.

At least 19 recordsLinked to original sources
PubMed2006

Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study.

BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity. MATERIALS AND METHODS: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation. RESULTS: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability. CONCLUSIONS: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

Adenocarcinoma↗
PubMed2006

DNA hypermethylation in the normal colonic mucosa of patients with colorectal cancer.

The CpG-island methylator phenotype (CIMP+) in colorectal cancer (CRC) is characterised by frequent hypermethylation of promoter regions in tumour suppressor genes. Low level methylation of some CpG islands is also seen in the normal colonic mucosa and increases with age; however, it is still unclear what other factors regulate this phenomenon. The first aim of our study was to determine whether the level of promoter methylation is elevated in the normal colonic mucosa of patients with CIMP+ tumours. The second aim was to investigate whether common, functional polymorphisms in genes involved in methyl group metabolism are associated with the level of methylation in this tissue. CpG islands within the ERalpha, MYOD, P16(INK4A), MLH1, APC, P14(ARF), DAPK and TIMP3 genes were quantitatively evaluated for methylation in normal colonic mucosa from a large series of CRC patients using the MethyLight assay. Genotyping was carried out for polymorphisms in the MTHFR, TS, MS, MTHFD1 and DNMT3b genes. Methylation of ERalpha and MYOD in normal colonic mucosa increased with age and was higher in female subjects. Methylation of P16(INK4A), MLH1, TIMP3 and DAPK in normal mucosa occurred at a lower level than ERalpha and MYOD but also increased with age and was significantly higher in patients with CIMP+ tumours. The DNMT3b C46359T polymorphism was associated with significantly less methylation of MYOD and MLH1 and with trends for lower methylation in each of the other CpG islands examined. Our results demonstrate that age, gender and genetic factors can influence the methylation level of CpG islands in gene promoter regions of normal colonic mucosa. Further work is required to determine whether such methylation is associated with the development of CIMP+ CRC.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Population-based study of prognostic factors in stage II colonic cancer.

BACKGROUND: Adjuvant chemotherapy in stage II colorectal cancer may be considered for patients whose tumours have poor prognostic features. The aim of this study was to evaluate the prognostic significance of commonly reported clinical and pathological features of stage II colonic cancer. METHODS: A population-based observational study of all patients with stage II colonic cancer diagnosed in the state of Western Australia from 1993 to 2003 was performed. A total of 1306 patients treated by surgery alone were identified, with a median follow-up of 59 (range 0-145) months. RESULTS: Multivariable analysis revealed that the only independent prognostic factors for disease-specific survival were stage T4 (hazard ratio (HR) 1.75 (95 per cent confidence interval (c.i.) 1.32 to 2.32); P < 0.001) and vascular invasion (HR 1.63 (95 per cent c.i. 1.15 to 2.30); P < 0.001). In younger patients (aged 75 years or less), who are more likely to be considered for chemotherapy, these two features showed independent prognostic significance but with higher HR values (1.96 for stage T4 and 2.73 for vascular invasion). Stage T4 and/or the presence of vascular invasion identified a 'poor' prognostic group, comprising 26.6 per cent of younger patients and with a 5-year survival rate of 71.2 per cent. The remaining 'good' prognostic group had a survival rate of 84.3 per cent at 5 years' follow-up. CONCLUSION: This study highlights the importance of accurate pathological assessment of tumour stage and vascular invasion for the prognostic stratification of patients with stage II colonic cancer. The results provide clarification of guidelines for the management of stage II disease in relation to recommendations for chemotherapy.

Adolescent↗
PubMed2006

p53 and disease: when the guardian angel fails.

The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.

Animals↗
PubMed2004

The -174 G/C gene polymorphism in interleukin-6 is associated with an aggressive breast cancer phenotype.

Serum and tissue levels of interleukin-6 (IL-6) have been implicated in the biological phenotype of breast carcinoma. A common G/C polymorphism at position -174 of the IL-6 promoter can influence the expression level of this gene. We therefore investigated for associations between this polymorphism and various phenotypic features in a series of 256 breast cancers. Individuals who were homozygous for the C allele (n=55) were more likely to have higher-grade tumours (P=0.039) with ductal histology (P=0.030) compared to those harbouring at least one wild-type G allele (n=201). Homozygosity for the C allele was also associated with significantly worse overall survival (P=0.031). We conclude that the -174 C allele of IL-6 is associated with a more aggressive breast cancer phenotype.

Adolescent↗
PubMed2002

A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability.

BACKGROUND: The enzyme methylenetetrahydrofolate reductase (MTHFR) catalyses the formation of folate intermediates that are vital to methylation reactions. A polymorphic variant (TT) has been linked to reduced levels of plasma folate, aberrant DNA methylation in leucocytes, and increased risk of colorectal cancer (CRC) under conditions of low folate intake. The cystathionine beta-synthase (CBS) enzyme reduces homocysteine levels and thus may protect against CRC. The CBS gene has a variant, 844ins68, that has been linked with increased activity. These variants may be involved in the development of the subgroup of CRC displaying aberrant DNA methylation and frequently associated with microsatellite instability (MSI). AIM: To investigate the frequencies of the TT and 844ins68 genotypes in CRC patients with MSI+ tumours compared with those with MSI- tumours and a control population. SUBJECTS: Patients with CRC (n=501) and healthy control subjects (n=1207) were studied. CRC cases were classified as MSI+ (n=75) or MSI- (n=426) based on deletions within the BAT-26 mononucleotide repeat. METHODS: Subjects were genotyped for MTHFR using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and PCR-restriction fragment length polymorphism (PCR-RFLP) techniques, and for CBS using PCR. RESULTS: The MTHFR TT genotype was more frequent in older CRC patients (>or=70 y) compared with equivalent aged controls (p=0.03), was associated with a significantly later age of diagnosis in patients with proximal colon tumours (p=0.02), and was almost twice as frequent in MSI+ than in MSI- tumours (p=0.05). Compared with normal controls, the 844ins68 variant of CBS was less frequent in patients with proximal tumours (p=0.02). CONCLUSIONS: The TT genotype of MTHFR is associated with an increased risk of CRC in older populations, possibly due to age related disturbances in folate metabolism. The TT genotype appears to predispose to CRC that is MSI+. This may reflect the involvement of aberrant DNA methylation frequently associated with MSI+. The 844ins68 CBS polymorphism may protect against proximal tumours.

Adult↗
PubMed2002

Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands.

BACKGROUND AND AIMS: A subgroup of colorectal cancers (CRC) referred to as the CpG island methylator phenotype (CIMP+) shows simultaneous methylation of multiple CpG islands. The clinicopathological and molecular characteristics of this phenotype remain uncertain however. METHODS: We analysed methylation of CpG islands in the p16 and MDR1 genes and MINT-2 clone in 275 stage II/III CRCs. RESULTS: Concurrent methylation of two or more CpG islands was observed in 32% of cases and was considered to represent CIMP+. These were often poorly differentiated, had less TP53 mutations, and originated frequently in the proximal or higher stage CRC compared with CIMP- tumours (p<0.05 for each). CIMP+ had no prognostic significance in stage II or stage III CRC treated by surgery alone. hMLH1 methylated tumours comprised the majority (81%) of cases with microsatellite instability, were frequently observed in older female patients, were often poorly differentiated or CIMP+, and contained wild-type K-ras (p<0.05 for each). Females who were heterozygous or homozygous for the C677T MTHFR polymorphism were at increased risk of developing CIMP+ CRC (odds ratio 2.17, 95% confidence interval 1.03-4.57; p=0.037). CONCLUSIONS: These observations made in a relatively large unselected series of CRC support the notion that CIMP+ characterises a subgroup of tumours with distinctive phenotypic features.

Aged↗
PubMed2001

Conservation of mononucleotide repeats within 3' and 5' untranslated regions and their instability in MSI-H colorectal cancer.

Messenger RNA contains untranslated 3' and 5' regions (3' and 5' UTRs) with sequence elements that are essential for the regulation of gene expression. A systematic search of GenBank revealed a large number of mononucleotide repeats within these UTRs. We selected 35 such mononucleotide repeats ranging in length from 15 bp to 32 bp and analysed their size in a series of 60 normal individuals. The conservation of repeats correlated inversely to their length, with longer repeats generally being more polymorphic than shorter repeats, irrespective of 3' or 5' location. Several long repeats were identified however to be monomorphic and we postulate that their conservation may be due to selective pressures relating to a possible functional role. We analysed 19 conserved UTR repeats in 117 colorectal cancers (CRC), 43 of which had defective mismatch repair characterized by widespread microsatellite instability (MSI-H). The UTR repeats were very often deleted in MSI-H tumors, with the length of deletion being proportional to the size of the repeat. Because of the high frequency of deletion observed in the conserved UTR repeats of MSI-H tumors, these could serve as a useful model for the study of possible changes in gene expression resulting from such mutations.

3' Untranslated Regions↗
PubMed2001

A polymorphism in the enhancer region of the thymidylate synthase promoter influences the survival of colorectal cancer patients treated with 5-fluorouracil.

High levels of thymidylate synthase (TS) expression have been associated with poor survival of colorectal cancer (CRC) patients to 5-fluorouracil (5-FU)-based chemotherapy. Recent evidence suggests that a polymorphism within the enhancer region of the TS gene promoter can influence TS expression, with the triple repeat homozygote (3R/3R) being associated with significantly higher tumour TS levels than either the double repeat homozygote (2R/2R) or heterozygotes (2R/3R). In the present study we investigated whether TS genotype was associated with the degree of survival benefit from chemotherapy in 221 Dukes' C stage CRC patients. Patients with the 3R/3R polymorphism (n = 58, 26%) showed no significant long-term survival benefit from chemotherapy (RR = 0.62, 95% CI: 0.30-1.25, P = 0.18), whereas those with the 2R/2R or 2R/3R genotype (n = 163, 74%) showed significant gains in survival from this treatment (RR = 0.52, 95% CI: 0.52-0.82, P = 0.005). These results demonstrate that a polymorphism within the TS gene, probably through its effect on TS expression levels, can influence the survival benefit obtained by CRC patients from 5-FU-based chemotherapy.

Antimetabolites, Antineoplastic↗
PubMed2001

Evolution of instability at coding and non-coding repeat sequences in human MSI-H colorectal cancers.

A number of human genes containing coding mononucleotide repeat sequences are particularly prone to mutations in tumors with defects in mismatch repair (MMR) genes (MSI-H cancers). In a large series of MSI-H colorectal tumors, we looked for mutations in 25 coding repeats contained in eight genes already known to be mutated in these cancers or in 17 other genes with an expected role in carcinogenesis. Mutations were found in 19 of the 25 candidate genes. Using a maximum likelihood statistical method, they were separated into two different groups that differed significantly in their mutation frequencies, and were likely to represent mutations that do or do not provide selective pressures during MSI-H tumoral progression, respectively. Three new target genes were found (GRB-14, RHAMM, RAD50). Our results provide evidence that MSI-H tumoral progression involves the cumulative mutations of a large number of genes. For each MSI-H tumor we calculated indexes representing the number of mutations found in genes of these groups. We also evaluated a shortening index at both the Bat-25 and Bat-26 non-coding mononucleotide tracts that are known to be almost always unstable in MSI-H cancers. A significant correlation was observed between instability at both coding and non-coding repeats, suggesting that Bat-25 and Bat-26 could be used as simple phenotypical markers of the tumoral evolution. A preferential order of mutations was deduced. During this process, hMSH3 alterations, a target gene encoding for a MMR protein, was found to play an important role by increasing the instability phenomenon characterizing these cancers.

Base Pair Mismatch↗
PubMed2001

Ki-ras mutation type and the survival benefit from adjuvant chemotherapy in Dukes' C colorectal cancer.

Ki-ras mutations are associated with an increased risk of relapse and death in colorectal cancer (CRC) patients, with some mutations being more aggressive than others. The present study examined the predictive value of different Ki-ras mutation types in a retrospective series of 430 Dukes' C stage CRC patients, of whom 208 (48%) had received adjuvant chemotherapy with 5-fluorouracil/levamisole or 5-fluorouracil/leucovorin. A total of 140 mutations were detected, the majority (58%, 81/140) being glycine to aspartate mutations in codons 12 and 13. Glycine to valine mutations in codon 12 (14%, 20/140) and other less frequent, non-specified mutation types (28%, 39/140) accounted for the remaining mutations. Kaplan-Meier survival analysis revealed that both Ki-ras wild-type and mutant patient groups derived significant survival benefit from chemotherapy. However, when patients were stratified according to the type of mutation, those with non-aspartate mutations appeared to gain more benefit from this treatment than those with aspartate mutations. Multivariate analysis that included other possible predictive factors in Dukes' C CRC (tumour site, patient sex, TP53 mutation) demonstrated that non-aspartate mutations in particular were associated with a significant survival benefit from chemotherapy (HR=0.11, 95% CI: 0.04-0.30, p<0.001). These results suggest that the type of Ki-ras mutation could be a clinically useful molecular marker for the identification of CRC subgroups that are likely to benefit from 5-fluorouracil-based adjuvant chemotherapy.

Adult↗
PubMed2001

Prognostic value of TP53 gene mutation in adjuvant treated breast cancer patients.

We investigated the prognostic significance of mutation to the TP53 tumor suppressor gene in a series of 908 breast cancer patients treated with or without adjuvant therapies. The frequency of TP53 mutation detected by single strand conformation polymorphism (SSCP) was 19.4% (176/908) in the overall tumor series. In multivariate analysis, TP53 mutation was independently associated with worse survival in the overall (HR = 2.1, 95% CI [1.5-3.1], P<0.0001), non-adjuvant treated (HR=2.2, 95% CI [1.2-4.2], P=0.017) and adjuvant treated (HR= 2.0, 95% CI [1.3-3.1], P = 0.0009) patients.

Adult↗