Biomedical subjects

Fabienne Grieu

Publications and source records attributed to Fabienne Grieu.

10 recordsLinked to original sources

PubMed2006

APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer.

The notion of a CpG island methylator phenotype (CIMP) was proposed to describe a subset of colorectal cancers (CRC) displaying frequent and concordant methylation of CpG islands located within gene promoter regions. Some workers have failed to observe associations between CIMP and specific clinicopathological features of CRC, possibly because of the choice of genes used to define this phenotype. The aim of the current study was to determine whether the aberrant methylation of 6 genes implicated in CRC development was associated with the same phenotypic features of this tumour type. The MethyLight assay was used to provide quantitative estimates of MLH1, P16, TIMP3, P14, DAPK and APC methylation levels in 199 unselected colorectal tumours. The methylation of MLH1, P16, TIMP3 and P14 was highly concordant (p < 0.0001 for each pair) but that of DAPK and APC was not. An inverse association was observed between the methylation of APC and TIMP3 (p = 0.004). Methylation of the MLH1, P16, TIMP3 and P14 genes was associated with tumour infiltrating lymphocytes (p < 0.05), microsatellite instability (p < 0.001), BRAF mutation (p < 0.0001) and elevated concentrations of the methyl group carriers tetrahydrofolate (THF) and 5,10-methylene THF (p < 0.05). In contrast, APC methylation was associated with wildtype BRAF (p = 0.003) and with lower concentrations of methyl group carriers (p < 0.05). These findings highlight the importance of gene selection in studies that aim to characterize the biological features and clinical behaviour of CIMP+ tumours.

Adaptor Proteins, Signal Transducing↗

PubMed2005

PIK3CA mutations in breast cancer are associated with poor outcome.

The phosphatidylinositol-3-kinase (PI3K)-AKT signaling pathway is considered to play an important role in tumorigenesis. Frequent somatic mutations in the PI3K subunit p110alpha (PIK3CA) occur in a variety of cancer types. We screened 250 primary human breast tumors for mutations in PIK3CA in order to determine associations with pathological features and with patient outcome. The frequency of PIK3CA mutations in the C2, helical and kinase domains was 35% (88/250). Mutations were associated with larger tumor size (p = 0.004) and positive estrogen receptor status (p = 0.008). Patients with PIK3CA mutations showed significantly worse survival (p = 0.004), particularly those with positive estrogen receptor expression or non-amplified erbB2 (both p = 0.002). PIK3CA mutation was an independent factor for worse survival in breast cancer patients with non-amplified erbB2 (RR = 2.6, 95%CI [1.2-5.5], p = 0.016).

Adolescent↗

PubMed2005

Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases.

AIMS: Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome. METHODS: Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenotypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116), alpha-smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR-SSCP) analysis were used to screen for mutations in exons 11 and 9 of c-kit. RESULTS: There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c-kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size > or = 10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity > or = 5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c-kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome. CONCLUSION: In this study, size > or = 10cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c-kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR-SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c-kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.

Adult↗

PubMed2004

Genetic polymorphisms in the MMP-2 and MMP-9 genes and breast cancer phenotype.

The matrix metalloproteinases (MMPs) have been shown to play important roles in cancer progression. In this study we examined whether common genetic variants in two key MMPs are associated with phenotypic features of breast cancers and patient outcome. A single nucleotide polymorphism in the promoter region of MMP-2 (-1306 C-->T) abolishes Sp1 binding and is associated with lower transcriptional activity, while another in the promoter region of MMP-9 (-1562 C-->T) increases the transcription of this gene. MMP-2 TT homozygous patients had smaller tumors (p=0.006) and contained lower concentrations of estrogen receptor (ER; p=0.002) compared to patients with the MMP-2 CC or CT genotype. Homozygosity for the MMP-2 -1306 T allele was associated with markedly different patient survival depending upon tumor ER status. For patients with ER negative tumors, the MMP-2 TT genotype was associated with poor survival (2/8 patients alive at end of study, 25%) compared to the CC or CT genotypes (59/70, 84%; p < 0.001). For patients with ER positive tumors, the MMP-2 TT genotype was associated with a trend for very good survival (10/10, 100%) compared to the CC or CT genotypes (130/157, 83%; p=0.16). The MMP-9 -1562 T allele was associated with features of good prognosis including non-ductal type histology, positive ER status and the absence of TP53 mutation. Patients with MMP-9 -1562 CT or TT genotypes showed marginally better prognosis compared to CC homozygotes (p=0.06). These findings suggest that breast cancer phenotype and outcome can be influenced by common functional polymorphisms in MMP genes.

Adolescent↗

PubMed2004

Screening for defective DNA mismatch repair in stage II and III colorectal cancer patients.

BACKGROUND & AIMS: Colorectal cancers associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome usually present in younger patients, show loss of mismatch repair (MMR) gene expression, and exhibit microsatellite instability (MSI). About 12% of sporadic colorectal cancers also show MMR loss and MSI. The aims of this study were to evaluate MMR loss and MSI in relation to patient age, sex, tumor stage, and site in the large bowel. METHODS: Tissue microarrays were created from 1020 stage II and III colorectal cancer cases and immunohistochemical staining performed to detect expression of the 2 major MMR proteins, hMLH1 and hMSH2. MSI was determined using the BAT-26 mononucleotide repeat. RESULTS: Ten percent of tumors showed loss of hMLH1 expression and 1.2% showed loss of hMSH2 expression. hMLH1 loss was more frequent in women (P < .001), older patients (P = .004), earlier stage tumors (P = .0001), and proximal colon tumors ( P < .0001). In contrast, tumors showing hMSH2 loss were more frequent in younger (P < .001), male (P = .05) patients and were distributed evenly between the proximal colon and distal colon/rectum. Eleven percent of tumors were MSI+ and these showed similar age, sex, stage, and site characteristics as tumors with hMLH1 loss. Discordance between MMR loss and MSI+ was found in 24 of 983 (2.4%) tumors. Of the 231 patients aged <60 years at diagnosis, 12 (5.2%) showed loss of hMLH1 and 8 (3.5%) showed loss of hMSH2. CONCLUSIONS: Routine immunohistochemical screening for MMR loss in younger colorectal cancer patients may provide a useful, first-step screening tool for the population-based detection of HNPCC.

Adaptor Proteins, Signal Transducing↗

PubMed2004

Development of a rapid genotyping method for single nucleotide polymorphisms and its application in cancer studies.

Single nucleotide polymorphisms (SNPs) in cancer-related genes can act as low risk genetic factors for the development of this disease. SNPs have also been shown to influence the efficacy and toxicity of various cytotoxic agents used in the treatment of cancer. Progress in these important areas of cancer research relies upon rapid, inexpensive and accurate means of SNP genotyping. In the present study we describe a fluorescent PCR-based method that utilizes single strand conformation polymorphism (SSCP) analysis to distinguish between different alleles. A real-time DNA fragment analysis platform and ultra-thin, re-useable gels allow short run times and hence a relatively high throughput to be achieved. A standardised procedure for the identification of optimal running conditions for each SNP is presented. We used this fluorescent-SSCP method to genotype SNPs in the MTHFR, p21, cyclin D1, MMP-2, vitamin D receptor, TNF-alpha and IL-6 genes. Multiplex PCR of two SNPs allows up to 500 genotypes per day to be evaluated with 100% accuracy. The low start-up and running costs make this method particularly well suited for SNP genotyping studies that involve up to 1,000 DNA samples.

Base Sequence↗

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

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↗