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Barry Iacopetta

Publications and source records attributed to Barry Iacopetta.

29 records · Page 2Linked to original sources
PubMed2003

TP53 mutation in colorectal cancer.

Approximately half of all colorectal cancers show p53 (TP53) gene mutations, with higher frequencies observed in distal colon and rectal tumors and lower frequencies in proximal tumors and those with the microsatellite instability or methylator phenotypes. Alterations to this gene appear to have little or no prognostic value for colorectal cancer patients treated by surgery alone, but are associated with worse survival for patients treated with chemotherapy. There is some evidence that different p53 mutations are associated with different clinical features including prognosis and response to therapy, although further large studies are required to confirm this. Several in vitro, animal and clinical studies have shown that normal p53 is required for the response of colorectal cancers to 5-fluorouracil-based chemotherapy. This should be confirmed by additional retrospective cohort studies and by the incorporation of P53 status in ongoing and future clinical trials. The evaluation of p53 overexpression, using a standardized immunohistochemical (IHC) procedure, could be a clinically useful marker for the identification of colorectal cancer patients likely to benefit from the standard chemotherapy regime currently used for this disease.

Biomarkers, Tumor↗
PubMed2003

Prognostic significance of microsatellite instability and Ki-ras mutation type in stage II colorectal cancer.

OBJECTIVES: The survival of stage II colorectal cancer (CRC) patients is approximately 70% at 5 years. Identification of the patient subgroup at high risk for tumour recurrence and death would allow more informed use of chemotherapy for this stage of disease. Several clinical and pathological factors have been reported to associate with worse survival. In the present study we investigated the prognostic significance of two major genetic alterations in CRC: microsatellite instability (MSI+) and the type of Ki-RAS mutation. METHODS: PCR-based molecular techniques were used to screen for MSI+ and Ki-RAS mutation in 396 stage II CRC patients with an average follow-up time of 75 months. Clinicopathological information was obtained by retrospective review of pathology reports. RESULTS: Prominent vascular invasion was identified in 19% of cases and was found to be an independent prognostic factor for poor outcome (relative risk = 2.08, 95% confidence interval: 1.22-3.57, p = 0.008). The MSI+ phenotype was found in 23% of proximal tumours and Ki-RAS mutations in 38% of the overall series. Neither MSI+ nor the type of Ki-RAS mutation showed prognostic significance in this cohort of stage II CRC. CONCLUSIONS: MSI+ and Ki-RAS mutation type are not useful markers for the identification of high-risk stage II CRC patients. Further prospective and/or cohort studies are required to determine whether these molecular changes have predictive value for survival benefit from 5-fluorouracil-based adjuvant chemotherapy.

Adult↗
PubMed2002

Are there two sides to colorectal cancer?

Colorectal carcinomas (CRC) that arise proximal (right) or distal (left) to the splenic flexure exhibit differences in incidence according to geographic region, age and gender. Together with observations that tumours in the hereditary cancer syndromes HNPCC and FAP occur predominantly in the right and left colon, respectively, the existence of 2 categories of CRC based on site of origin in the large bowel was proposed more than a decade ago. Differences between normal right and left colonic segments that could favour progression through different tumourigenic pathways are summarized in this review. Accumulating evidence suggests that the risk of CRC conferred by various environmental and genetic factors is different for proximal and distal tumours. Right- and left-sided tumours also exhibit different sensitivities to fluorouracil-based chemotherapy. Such differences are probably related to the molecular characteristics of the tumours, with the microsatellite instability and CpG island methylator phenotypes being associated with right-sided tumours and chromosomal instability with left-sided tumours. Future molecular-based classification systems for CRC that rely upon distinctive gene expression patterns may allow a clearer discrimination of subgroups than that provided by tumour site alone. Until then however, the existence of 2 broadly different groups of cancer defined by site of origin in the colon should be considered in the design of future epidemiologic studies as well as in the design of new clinical trials aimed at testing novel adjuvant therapies.

Colonic Neoplasms↗
PubMed2002

Target gene mutation profile differs between gastrointestinal and endometrial tumors with mismatch repair deficiency.

Mutation frequencies at 25 genes containing coding repeats were compared in colorectal, gastric, and endometrial mismatch repair-deficient (MSI-H) tumors. The overall number of mutations was significantly lower in endometrial than in gastrointestinal MSI-H cancers. Using a likelihood statistical method, target genes were divided in each tumor location into two groups likely to represent gene mutations that do or do not provide selective pressures during tumoral progression. Mutation profiles were quite similar in gastric and colorectal MSI-H cancers but were different in endometrial MSI-H tumors. Deletions in Bat-25 and Bat-26 noncoding repeats were also significantly less important in endometrial as compared with gastrointestinal MSI-H tumors. Our results show that the profile of target gene mutations in MSI-H tumors is tissue specific, with both qualitative and quantitative differences between gastrointestinal and endometrial MSI-H cancers.

Base Pair Mismatch↗
PubMed2002

Extent of nodal involvement in Stage III colorectal carcinoma: relationship to clinicopathologic variables and genetic alterations.

PURPOSE: Recent evidence from our laboratory suggests that the factors of tumor site, patient gender, microsatellite instability, and mutations are important determinants in the survival benefit associated with adjuvant chemotherapy in Stage III colorectal carcinoma. In the present study we investigated whether these factors, as well as Ki- mutations, were also associated with the extent of nodal involvement in Stage III cancers. METHODS: Nodal involvement was retrospectively evaluated in a series of 645 patients with Stage III colorectal cancer from Sir Charles Gairdner Hospital. The number of involved nodes was correlated with the clinicopathologic features of gender, age, tumor site, and histologic grade, as well as to the genetic alterations of mutation, Ki- mutation, and microsatellite instability. RESULTS: The median number of nodes examined per tumor was 11 (range, 1-53). Forty-nine percent of cases had one or two involved nodes and 51 percent had three or more involved nodes, the latter feature being associated with significantly reduced patient survival. No differences in the extent of nodal involvement were apparent with respect to tumor site, patient gender, or or Ki- mutation status. Tumors from younger patients (P = 0.025) or with poorly differentiated histology (P = 0.007), were associated with significantly higher nodal burden, whereas the microsatellite instability phenotype was associated with less extensive nodal involvement (P = 0.020). Survival benefits from the use of chemotherapy were apparent for both the low and high nodal involvement groups, although the latter seemed to obtain relatively more benefit. Multivariate analysis of patients treated with chemotherapy found that gender, grade, and microsatellite instability, but not nodal involvement, were independently prognostic for survival. CONCLUSION: The extent of nodal involvement in Stage III colorectal cancer is related to patient age, tumor grade, and microsatellite instability status, but not to tumor site, patient gender, or Ki- mutation. These results indicate that differences in metastatic nodal burden cannot explain previously observed site, gender, and mutation differences in the response to chemotherapy.

Adult↗
PubMed2002

Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR.

BACKGROUND & AIMS: The microsatellite instability (MSI) phenotype is a characteristic of the hereditary nonpolyposis colorectal cancer syndrome as well as approximately 15% of sporadic colon and gastric tumors. It is a valuable diagnostic marker for the identification of hereditary nonpolyposis colorectal cancer cases and may be a molecular predictive marker for the identification of colon cancer patients who benefit from chemotherapy. To evaluate MSI, a reference panel was proposed at an international consensus meeting, comprised of 2 mononucleotide (BAT-25, BAT-26) and 3 dinucleotide repeats. Analysis of BAT-26 is sufficient for detecting the MSI phenotype in most, but not all, cases. Additional results with dinucleotide markers can sometimes lead to incorrect classification of MSI tumors. METHODS: We describe here a single fluorescent multiplex system comprising 5 quasimonomorphic mononucleotide repeats for the detection of MSI tumors. RESULTS: None of 184 germline DNA samples, including 56 from African subjects, was found to contain allelic size variations in more than 2 of these markers. In contrast, all MSI tumors showed allelic size variations in 3 or more of the microsatellites. Using this assay, we confirmed (or reclassified in 6 cases) the MSI status of 124 colon and 50 gastric primary tumors and 16 colon cell lines. CONCLUSIONS: We propose that using a pentaplex polymerase chain reaction system allows accurate evaluation of tumor MSI status of DNA with 100% sensitivity and specificity without the need to match normal DNA. This assay is simpler to use than those involving dinucleotides and is more specific than using BAT-26 alone.

Africa↗
PubMed2002

Associations between common polymorphisms in TP53 and p21WAF1/Cip1 and phenotypic features of breast cancer.

The tumour suppressor gene TP53 and its downstream effector p21 are thought to play major roles in the development of breast cancer. We investigated three common sequence variants in TP53 and p21 for possible associations with the risk of breast cancer and with various phenotypic features of this disease. A total of 351 cases were available for study. Germline DNA obtained from female subjects of similar age but without cancer was used to estimate the TP53 and p21 genotype frequencies in a control population. A single nucleotide polymorphism in intron 2 of p21 was associated with slightly increased breast cancer risk (RR = 1.4, P = 0.011) and with well/moderately differentiated tumour histology (P = 0.029). The 16 bp insertion polymorphism in intron 3 of TP53 was associated with poor histological grade (OR = 2.3, P = 0.013) independently of other pathological features. The codon 31 polymorphism in p21 was strongly linked to negative progesterone receptor status (OR = 3.4, P = 0.0001), suggesting this variant may have functional significance for the progesterone signalling pathway in breast cancer. These results add to the growing body of evidence that genetic variants can influence not only the risk of breast cancer but also the disease phenotype.

Adult↗
PubMedDate not supplied

Lack of association between CCND1 G870A polymorphism and the risk of breast and colorectal cancers.

BACKGROUND: The aim of this case-control study was to investigate whether the common G870A polymorphism in the Cyclin D1 gene (CCND1) is a risk factor for breast and colorectal cancers in an Australian population. PATIENTS AND METHODS: A total of 339 breast and 569 colorectal cancer cases were studied, together with 327 age-matched controls. Genotyping for the G870A polymorphism in CCND1 was carried out using single strand conformation polymorphism and Pyrosequencing methods. RESULTS: Comparison of the CCND1 G870A genotype frequencies revealed no significant associations between presence of the A allele and the risk of either breast or colorectal cancer. No associations were noted between presence of the A allele and pathological features of these tumours or patient survival. CONCLUSION: Although the CCND1 G870A polymorphism has been reported as a genetic risk factor for some tumour types, it does not appear to be linked to the risk of breast and colorectal cancers.

Alleles↗
PubMedDate not supplied

Methylenetetrahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype.

BACKGROUND: Aberrations in folate metabolism contribute to the risk of cancer via effects on the synthesis, methylation and repair of DNA. Functional genetic variants in the methylene tetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) genes may be risk factors for breast cancer because of their central roles in cellular folate metabolism. PATIENTS AND METHODS: The MTHFR C677T and TS tandem repeat polymorphisms were investigated in a case-control study of 339 women with breast cancer for possible associations with the risk of this disease, tumor phenotype and patient survival. RESULTS: The MTHFR and TS polymorphisms were not associated with a significantly increased risk of breast cancer. No associations were observed with any pathological or molecular feature and neither polymorphism was associated with survival from this disease. CONCLUSION: The common MTHFR C677T and TS enhancer region polymorphisms were not risk factors for breast cancer in this patient cohort nor were they associated with phenotypic features or with prognosis.

Adolescent↗