Principal Investigators related to gastric cancer research:
Carla Oliveira (HDGC molecular genetics),
Fátima Carneiro (Molecular Pathology),
Gianpaolo Suriano and Jose Carlos Machado (Gastric cancer related signalling pathways)
Céu Figueiredo (Helicobacter pylori related research)
Principal Investigators related to breast cancer research:
Joana Paredes (Signalling pathways related to breast cancer invasion),
Fernando Schmitt (Molecular pathology)
Location of the Group (Host-Institution):
IPATIMUP, Porto, Portugal
General Objectives of the Group
The research of our group focuses on the genetics of three common types of epithelial cancer: gastric, breast, and colorectal carcinoma. We focus at identifying 1) germline genetic alterations (high and low penetrance genes) associated with increased risk of these tumours; 2) pathological features and somatic molecular markers occurring in the setting of hereditary and sporadic carcinomas; 3) signalling pathways mediated by genetic and gene-environmental factors in tumour development in order to find molecular targets for therapeutic intervention.
The specific objectives of the group concerning HDGC related research are:
- To determine the prevalence and type of CDH1 germline mutations in Portuguese families with HDGC and in patients with early-onset cancer;
- To unravel the pathogenic role of HDGC-associated CDH1 missense mutations;
- To identify new regulatory mechanisms of CDH1 gene and the role of nonsense-mediated mRNA decay in the regulation of CDH1 gene expression
- To identify the morphological steps underlying the development of HDGC
- To identify the molecular mechanisms responsible for the downregulation of CDH1 gene in HDGC tumours.
We also aim to clarify the signaling pathways associated with alterations of adhesion molecules in cancer in order to identify effectors of E-cadherin in cell motility and invasion.
We identified germline mutations in HDGC Portuguese families and early-onset DGC. We defined a new syndrome with HDGC and midline malformations with CHD1 germline mutations.
We showed that NMD mRNA surveillance pathway downregulates aberrant CDH1 transcripts in mutation carriers.
We verified that E-cadherin is regulated by mechanisms of Endoplasmic Reticulum Quality Control and loss of protein expression can be the result of ER-associated degradation.
We proposed a pathological model of the early development of DGC in CDH1 mutation carriers and showed its implication for clinical screening.
We determined the second-hit inactivating mechanism in sporadic diffuse gastric cancer and HDGC tumours and found that CDH1 promoter hypermethylation is the most frequent alteration in both sporadic and hereditary primary tumours but not in HDGC metastatic tumours, suggesting that demethylation agents have limited therapeutic efficacy in the latter setting.
We established an in vitro model to assess the pathogenic role of CDH1 missense mutations and showed its added value in genetic counselling. The same model was used to demonstrate the existence of a genotype- phenotype association between CDH1 mutations and cell motility and to identify its underlying E-cadherin-dependent signalling pathways (i.e. EGFR- RhoA).
We showed that loss of E-cadherin render cells more resistant to pro-apoptotic agent currently used in conventional chemotherapy, questioning their effectiveness in the treatment of CDH1 mutation carriers.
Future Research Objectives
As a long term goal, Cancer Genetics group aims at identifying epigenetic and genetic risk factors, pathological features, somatic molecular markers and associated signaling pathways occurring in the setting of HDGC and sporadic gastric carcinoma.
As a short-term goal, the group aims:
- To identify new regulatory genomic regions at CDH1 locus and new regulatory partners of E-cadherin expression. The rationale is the following: in 60-70% of the HDGC families and in 90% of families with aggregation of diffuse gastric cancer not fulfilling clinical criteria for HDGC, CDH1 germline inactivation failed to be identified; despite being negative for CDH1 mutations, these tumours display similar morphological features and display aberrant E-cadherin expression.
- To develop new screening tools in HDGC since many HDGC cancers occur as metastasizing neoplasias mainly due to the lack of effective early diagnostic tools; to achieve this objective, we aim to identify molecular markers aberrantly expressed in CDH1 mutation carriers.
We expect to provide a significant contribution to the understanding of the mechanisms mediating E-cadherin down-regulation in cancer development and progression, which may have important implications for the development of specific therapeutics for HDGC and other types of invasive cancer.