Molecular determinants of gastric cancer: genotypes, phenotypes and impact in progression and treatment
Schedule
10.03.2017
02:00pm to 04:00pm
Location
ISPUP
Description

 

Gastric cancer is the third leading cause of cancer-related deaths worldwide, affecting close to one million people per year. Over 90% of all gastric cancers appear in a sporadic setting, less than 10% show familial clustering, and of these, only 1% to 3% constitute hereditary forms.

The majority of gastric cancer patients present with advanced disease at diagnosis, rendering the prognosis extremely poor, with a 5-year overall survival rate of less than 25%. Treatment of GC patients is often not efficient, as all patients are treated similarly regardless of the disease subtype. Next-generation sequencing data is increasing the knowledge of the molecular basis of gastric cancer and the comprehensive study of genomic and epigenomic alterations associated with this disease. Additionally, the integrative analyses of molecular profiling of gastric cancers allowed the identification of different subtypes and associated molecular pathways and initiated the discovery of relevant molecular classifiers in gastric cancer. Nonetheless, the clinical usefulness of these discoveries is still limited due to the lack of systematic genetic-clinical correlations for personalized use.

We have studied large series of sporadic gastric cancers using single gene approaches, miRNA microarrays, arrayCGH, whole genome sequencing, and bissulphite sequencing and have identified relevant molecular stratifiers, particularly mechanisms impairing the expression and function of E-cadherin, and involved in oncogene activation, with impact in gastric cancer prognosis and treatment. We have also worked towards identification of mediators of drug resistance in gastric cancer and demonstrated that anti-HER2 based therapy can be improved with photodynamic therapy.

In the hereditary setting of GC, and particularly in Hereditary diffuse gastric cancer (HDGC), we identified novel germline defects likely explaining 6% of the families. Of particular relevance, we proved that monoallelic CDH1 downregulation is present in the germline of most HDGC-families that remain mutation negative. To identify the genetic mechanism leading to this phenotype, we screened the complete CDH1 locus, including introns and UTRs in >150 HDGC probands lacking CDH1 coding mutations, by next generation sequencing. We filtered-out 11 intronic regions particularly rich in rare variants in HDGC probands. We used bioinformatics to characterize these regions and performed in vivo and in vitro enhancer-based assays to demonstrate the relevance of these intronic sequences in CDH1 expression regulation.

Details on these and other experiments will be presented in this seminar.

Speakers
Carla Oliveira
Affiliation
Group Leader, Expression Regulation in Cancer Group, i3S & Ipatimup

Carla Oliveira

Group Leader, Expression Regulation in Cancer Group, i3S & Ipatimup

Affiliated Professor, Dept. Pathology and Oncology, Fac. Medicina, Univ. Porto

Consultant for gastric-cancer related syndromes, IPATIMUP Diagnostics

Co-founder, Bioinf2Bio Company (http://www.frombioinformatics2biology.com/home.html)

Invited researcher, Max Planck Institute, Tuebingen, Germany, 2011/2012

Post-doc Researcher, Ipatimup, Porto, Portugal, 2002/2003

Post-doc Researcher, Univ. British Columbia, Vancouver, Canada, 2004/2005

PhD in Human Biology /GABBA Fac. Medicina, Univ. Porto (IPATIMUP & Univ. Cambridge), 2002

Biochemistry Degree, Fac. Science and Technology, Univ. Coimbra, 1996

Número de citações em August 2016=4768 por 3183 documentos (Scopus)

h-index = 38 (Scopus)

 

Carla Oliveira Carla Oliveira is co-author of more than 100 articles published in peer-reviewed Journals, (ResearcherID F-8188-2011; Scopus Author ID 7102223149; http://orcid.org/0000-0001-8340-2264 ou Oliveira C – Pubmed)

Carla Oliveira heads the Expression Regulation in Cancer group at i3S & Ipatimup. Ipatimup is a founding member of the Institute for Research and Innovation in Health Sciences (i3S), classified as exceptional (25/25) by a panel of ESF-FCT in 2014. She teaches mainly in Post-graduate programs at the Medical Faculty, Ipatimup, and i3S, but ids often invited to teach in other National and International PhD and Masters programs. She is responsible, at the IPATIMUP Diagnostics Unit, for genetic testing of gastric cancer associated syndromes since 2006, and launched the Bioinformatics company Bioinf2Bio in August 2013, that is a start-up from Ipatimup.

Carla undertook her post-graduate studies in the frame of the GABBA PhD program and got a PhD from the Medical Faculty of Porto, through a collaboration between IPATIMUP & University of Cambridge, and supervision by Raquel Seruca and Carlos Caldas. She carried out two Post-docs, one at Ipatimup and a 2nd at Univ. British Columbia, Vancouver, Canada. She became a Junior PI in 2005 at Ipatimup, and a Tenure Track Independent Group Leader in 2011 in the same institute.

Carla Oliveira is an International Expert and has an excellent track record in E-cadherin-related diseases namely hereditary diffuse gastric cancer (HDGC). She disclosed molecular and clinical aspects of worldwide series of families and sporadic gastric cancer cases, found novel germline CDH1 gene defects, defined somatic events with impact for patient management and therapy, and reported an association between germline CDH1 gene mutations and developmental malformations. Carla Oliveira’s group has also deeply characterized primary gastric cancers and metastases to disclose causes of E- cadherin impairment and their impact of patient’s prognosis and therapy.

Her current interests enclose the characterization of intronic regulatory mechanisms within the CDH1 intron 2, and development of in vivo models for their study. In parallel she’s interested in identifying circulating gastric cancer biomarkers (genotypic and phenotypic) that may help detecting gastric cancer and evaluating treatment response; and identifying gastric cancer specific resistant genotypes and phenotypes. Her team has expertise in human genetics, molecular and cell biology, Next Generation Sequencing and bioinformatics; and a strong link with hospitals that provide patients biological material, and the Industry that co-funds the research.

She has published >100 peer review publications and has h-index of 38 at the age of 43. She has been a PI of projects funded with nearly 2 million €, and funded with nearly the same for human resources. As a team member she participated in projects funded with more than 3 million €. She was an invited speaker in more than 60 National and International conferences/seminars, including in 2 of the most important conferences on her area of research, in USA (DDW 2013) and Europe (UEG 2014). Carla was/is a member of the Scientific Committees of the European and Portuguese Societies of Human Genetics, is an active members of a COST action on Exosomes in disease, and of the International Gastric Cancer Linkage Consortium (IGCLC). She has participated in numerous National and International fellowship and grant application Evaluation Committees. She has successfully supervised 7 students to PhD completion, the same number of post-docs and recently recruited 2 junior project leaders for her team, who are skilled in Bioinformatics and Drug Resistance.