Browsing by Author "Chin, Suet-Feung"
Now showing 1 - 4 of 4
Results Per Page
Sort Options
- Allelic expression imbalance of PIK3CA mutations is frequent in breast cancer and prognostically significantPublication . Correia, Lizelle; Magno, Ramiro; Xavier, JM; Almeida, Bernardo; Duarte, Isabel; Esteves, Filipa; Ghezzo, Marinella; Eldridge, Matthew; Sun, Chong; Bosma, Astrid; Mittempergher, Lorenza; Marreiros, Ana; Bernards, Rene; Caldas, Carlos; Chin, Suet-Feung; Maia, Ana-TeresaPIK3CA mutations are the most common in breast cancer, particularly in the estrogen receptor-positive cohort, but the benefit of PI3K inhibitors has had limited success compared with approaches targeting other less common mutations. We found a frequent allelic expression imbalance between the missense mutant and wild-type PIK3CA alleles in breast tumors from the METABRIC (70.2%) and the TCGA (60.1%) projects. When considering the mechanisms controlling allelic expression, 27.7% and 11.8% of tumors showed imbalance due to regulatory variants in cis, in the two studies respectively. Furthermore, preferential expression of the mutant allele due to cis-regulatory variation is associated with poor prognosis in the METABRIC tumors (P = 0.031). Interestingly, ER-, PR-, and HER2+ tumors showed significant preferential expression of the mutated allele in both datasets. Our work provides compelling evidence to support the clinical utility of PIK3CA allelic expression in breast cancer in identifying patients of poorer prognosis, and those with low expression of the mutated allele, who will unlikely benefit from PI3K inhibitors. Furthermore, our work proposes a model of differential regulation of a critical cancer-promoting gene in breast cancer.
- Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriersPublication . Maia, Ana-Teresa; Antoniou, Antonis C.; O'Reilly, Martin; Samarajiwa, Shamith; Dunning, Mark; Kartsonaki, Christiana; Chin, Suet-Feung; Curtis, Christina; McGuffog, Lesley; Domchek, Susan M.; Easton, Douglas F.; Peock, Susan; Frost, Debra; Evans, D. Gareth; Eeles, Ros; Izatt, Louise; Adlard, Julian; Eccles, Diana; Sinilnikova, Olga M.; Mazoyer, Sylvie; Stoppa-Lyonnet, Dominique; Gauthier-Villars, Marion; Faivre, Laurence; Venat-Bouvet, Laurence; Delnatte, Capucine; Nevanlinna, Heli; Couch, Fergus J.; Godwin, Andrew K.; Caligo, Maria Adelaide; Barkardottir, Rosa B.; Chen, Xiaoqing; Beesley, Jonathan; Healey, Sue; Caldas, Carlos; Chenevix-Trench, Georgia; Ponder, Bruce A. J.Introduction: Cis-acting regulatory single nucleotide polymorphisms (SNPs) at specific loci may modulate penetrance of germline mutations at the same loci by introducing different levels of expression of the wild-type allele. We have previously reported that BRCA2 shows differential allelic expression and we hypothesize that the known variable penetrance of BRCA2 mutations might be associated with this mechanism. Methods: We combined haplotype analysis and differential allelic expression of BRCA2 in breast tissue to identify expression haplotypes and candidate cis-regulatory variants. These candidate variants underwent selection based on in silico predictions for regulatory potential and disruption of transcription factor binding, and were functionally analyzed in vitro and in vivo in normal and breast cancer cell lines. SNPs tagging the expression haplotypes were correlated with the total expression of several genes in breast tissue measured by Taqman and microarray technologies. The effect of the expression haplotypes on breast cancer risk in BRCA2 mutation carriers was investigated in 2,754 carriers. Results: We identified common haplotypes associated with differences in the levels of BRCA2 expression in human breast cells. We characterized three cis-regulatory SNPs located at the promoter and two intronic regulatory elements which affect the binding of the transcription factors C/EBP alpha, HMGA1, D-binding protein (DBP) and ZF5. We showed that the expression haplotypes also correlated with changes in the expression of other genes in normal breast. Furthermore, there was suggestive evidence that the minor allele of SNP rs4942440, which is associated with higher BRCA2 expression, is also associated with a reduced risk of breast cancer (per-allele hazard ratio (HR) = 0.85, 95% confidence interval (CI) = 0.72 to 1.00, P-trend = 0.048). Conclusions: Our work provides further insights into the role of cis-regulatory variation in the penetrance of disease-causing mutations. We identified small-effect genetic variants associated with allelic expression differences in BRCA2 which could possibly affect the risk in mutation carriers through altering expression levels of the wild-type allele.
- Germline allelic expression of genes at 17q22 locus associates with risk of breast cancerPublication . Esteves, Filipa; M Xavier, Joana; Ford, Anthony M.; Rocha, Cátia; Pharoah, Paul D. P.; Caldas, Carlos; Chin, Suet-Feung; Maia, Ana-TeresaIntroduction: Translation of genome-wide association study (GWAS) findings into preventive approaches is challenged by the identification of the causal risk variants and the understanding of the biological mechanisms by which they act. We present using allelic expression (AE) ratios to perform quantitative caseecontrol analysis as a novel approach to identify risk associations, causal regulatory variants, and target genes. Methods: Using the breast cancer (BC) risk locus 17q22 to validate this approach, we measured AE ratios in normal breast tissue samples from controls and cases, as well as from unmatched blood samples. Then we used in-silico and in-vitro analysis to map and functionally characterised candidate causal variants. Results: We found a significant shift in the AE patterns of STXBP4 (rs2628315) and COX11 (rs17817901) in the normal breast tissue of cases and healthy controls. Preferential expression of the G-rs2628315 and A-rs17817901 alleles, more often observed in cases, was associated with an increased risk for BC. Analysis of blood samples from cases and controls found a similar association. Furthermore, we identified two putative cis-regulatory variants - rs17817901 and rs8066588 - that affect a miRNA and a transcription factor binding site, respectively. Conclusion: We propose causal variants and target genes for the 17q22 BC risk locus and show that using AE ratios in caseecontrol association studies is helpful in identifying risk and mapping causal variants.
- TOX3 mutations in breast cancerPublication . Jones, James Owain; Chin, Suet-Feung; Wong-Taylor, Li-An; Leaford, Donna; Ponder, Bruce A. J.; Caldas, Carlos; Maia, Ana TeresaTOX3 maps to 16q12, a region commonly lost in breast cancers and recently implicated in the risk of developing breast cancer. However, not much is known of the role of TOX3 itself in breast cancer biology. This is the first study to determine the importance of TOX3 mutations in breast cancers. We screened TOX3 for mutations in 133 breast tumours and identified four mutations (three missense, one in-frame deletion of 30 base pairs) in six primary tumours, corresponding to an overall mutation frequency of 4.5%. One potentially deleterious missense mutation in exon 3 (Leu129Phe) was identified in one tumour (genomic DNA and cDNA). Whilst copy number changes of 16q12 are common in breast cancer, our data show that mutations of TOX3 are present at low frequency in tumours. Our results support that TOX3 should be further investigated to elucidate its role in breast cancer biology.