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Tesi etd-12072011-112544


Thesis type
Tesi di dottorato di ricerca
Author
IOFRIDA, CATERINA
URN
etd-12072011-112544
Title
Effects on human transcriptome of two BRCA1-BRCT mutations: M1775R and A1789T
Settore scientifico disciplinare
BIO/11
Corso di studi
ESPLORAZIONE MOLECOLARE, METABOLICA E FUNZIONALE DEL SISTEMA NERVOSO E DEGLI ORGANI DI SENSO
Commissione
tutor Dott.ssa Pellegrini, Silvia
commissario Sartucci, Ferdinando
commissario Bonuccelli, Ubaldo
Parole chiave
  • gene expression
  • microarray analysis
  • breast neoplasms
  • missense mutations
  • BRCA1 gene
Data inizio appello
16/12/2011;
Consultabilità
completa
Riassunto analitico
BRCA1 (breast cancer 1, early onset) mutations confer a high risk of breast and ovarian cancer. Most of BRCA1 cancer-predisposing mutations originate truncated proteins, but missense mutations have been also detected in familial breast and ovarian cancer patients. These variants are rare and their role in cancer predisposition is often difficult to ascertain. In the present work I studied the molecular mechanisms affected in human cells by two BRCA1 missense variants, M1775R and A1789T, both located in the second BRCT domain. These variants have been isolated from familial breast cancer patients and their effect on cell transcriptome has been previously investigated in yeast cells. Here I compared the expression profiles of HeLa cells transfected with one or the other variant and HeLa cells transfected with BRCA1 wild-type.<br>Microarray data analysis was performed by three comparisons: M1775R versus wild-type (M1775RvsWT-contrast), A1789T versus wild-type (A1789TvsWT-contrast) and the mutated BRCT domain versus wild-type (MutvsWT-contrast), obtained by considering the two variants as a whole. I found 201 differentially expressed genes in M1775RvsWT-contrast, 313 in A1789TvsWT-contrast and 173 in MutvsWT-contrast. Most of these genes participate in cell processes that are often deregulated in cancer, such as cell cycle progression and DNA damage response and repair. These results represent the first molecular evidence of the pathogenetic role of M1775R, already known by functional studies, and give support to a similar role for A1789T, first hypothesized based on yeast cell experiments.<br>
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