ABSTRACT
BACKGROUND: PALB2 1592delT mutation is associated with increased breast cancer and suggestive prostate cancer (PRCA) risk in Finland. In this study we wanted to assess if any other PALB2 variants associate to increased PRCA risk and clinically describe patients with formerly found PALB2 1592delT mutation. METHODS: Finnish families with two or more PRCA cases (n = 178) and unselected cases (n = 285) with complete clinical data were initially screened for variants in the coding region and splice sites of PALB2. Potentially interesting variants were verified in additional set of unselected cases (n = 463). RESULTS: From our clinically defined sample set we identified total of six variants in PALB2. No novel variants among Finnish PRCA cases were found. Clinical characteristics of the variant carriers, including the previously described family carrying PALB2 1592delT, revealed a trend towards aggressive disease, which also applied to a few non-familial cases. Hypersensitivity to mitomycin C (MMC) of lymphoblasts from individuals from the family with 1592delT revealed haploinsufficiency among carriers with altered genotype. CONCLUSIONS: Though any of the detected PALB2 variants do not associate to PRCA in population level in Finland it cannot be ruled out that some of these variants contribute to cancer susceptibility at individual level.
Subject(s)
Inheritance Patterns/genetics , Mutation/genetics , Nuclear Proteins/genetics , Prostatic Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Aged , Cell Line, Tumor , Cell Proliferation/drug effects , DNA Damage , DNA Mutational Analysis , Family , Fanconi Anemia Complementation Group N Protein , Female , Finland , Humans , Inheritance Patterns/drug effects , Male , Middle Aged , Mitomycin/pharmacology , Nuclear Proteins/deficiency , Pedigree , Tumor Suppressor Proteins/deficiencyABSTRACT
OBJECTIVE: In coeliac disease, small-bowel mucosal permeability is increased in response to gluten consumption. However, the signalling routes leading to such a barrier defect remain obscure. As the epidermal growth factor receptor (EGFR) pathway is up-regulated in untreated coeliac disease, and since this cascade has been related to epithelial hyperpermeability, the aim of this study was to establish whether blocking the EGFR route would restore the barrier after gliadin insult in vitro. MATERIAL AND METHODS: Epithelial barrier function was assessed by measuring transepithelial electrical resistance (TER) in Caco-2 epithelial monolayers treated with pepsin trypsin (PT)-digested gliadin with or without monoclonal antibodies against EGFR family members or by inhibitors of the EGFR pathway signalling molecules. Furthermore, tight-junctional integrity was determined by Western blotting and immunofluorescence staining of the tight-junctional protein occludin. RESULTS: PT-gliadin significantly reduced TER and the expression of occludin protein. Blocking of the EGFR signalling pathway could not prevent gliadin-triggered damage. In fact, a function-blocking monoclonal antibody against EGFR (ErbB1) actually potentiated the harmful effects of gliadin on TER. CONCLUSIONS: The epithelial barrier-disrupting properties of gliadin are independent of the EGFR signalling cascade. However, our results suggest that activation of the EGFR pathway might actually be protective against gliadin-triggered hyperpermeability. Further studies are needed to elucidate the specific gliadin-triggered signalling cascades which lead to increased epithelial permeability in coeliac disease.
