Speakers SESSION 1 Clinical status and perspectives for hereditary - - PDF document

Speakers

Text to be added Professor Eccles is the Head of the Cancer Sciences Academic Unit which incorporates the Southampton Cancer Research UK Centre, the Southampton Clinical Trials Unit and links closely through our clinical academics to Cancer Care at UHS . She continues to work as an NHS consultant in clinical cancer genetics which encompasses diagnosis and management of many difgerent genetic conditions that predispose to tumour development in families.

• Fam. Breast and Ovarian Cancer

Tie Linn lab focuses on the development of prognostic and predic- tive markers for breast and ovarian cancer to guide systemic therapy decisions.

Fergus Couch Mayo Clinic Cancer Center and the Center for Individual- ized Medicine, USA Diana Eccles University of Southampton, Southampton, UK Rita Schmutzler University Hospital Cologne, Germany Sabine Linn The Netherlands Cancer Institute, The Netherlands SESSION 1 — Clinical status and perspectives for hereditary breast and ovarian cancer (HBOC) risk prediction.

I am fascinated by genetics, and how small genetic difgerences leads to phenotypic diversity that shapes our lives. Fueled by curiosity, I have spent my research career on developing statistical methods for under- standing the genetic architecture of traits and diseases. Tiis includes methods for detecting genetic associations in genome-wide association studies, and more recently, polygenic trait prediction and genetic disease risk assessment. Modeling of breast cancer using nongermline mouse model approaches. My team is investigating genome maintenance pathways including their close links with cell proliferation control. We are particularly interested in familial breast and ovarian cancer where we focus on factors and mechanisms that limit tumorigenesis.

Claus Storgaard Sørensen Biotech Research & Inno- vation Center, University of Copenhagen, Denmark Bjarni Jóhann Vilhjálmsson Center for Bioinformatics (BiRC), University of Aarhus, Denmark Stefano Annunziato The Netherlands Cancer Institute, The Netherlands SESSION 2 — Identifjcation of novel HBOC genes and variants

Our laboratory has developed and/or established powerful assay systems for the quantitative and qualitative analysis of DSB repair, recombination and replication stress response mechanisms in immor- talized and primary cells from difgerent organs. Identifjcation of response biomarkers to targeted therapy using PDX models of breast cancer. Tie main focus of my research is establishing new platforms for study- ing ovarian cancer. We are developing 3D culture systems that will support long-term expansion of ovarian cancer organoids, which would recapitulate both the diversity and heterogeneity of the disease. Fallopian tube (FT) and

• vary surface epithelium (OSE) are believed to be the origin of high

grade serous ovarian cancer (HGSOC), the most common type of

• varian cancer (~70%). Recently, we have established normal FT and

OSE organoid systems. Using crispr-Cas9 technology we genetically manipulate these organoids in order to investigate the role of difgerent genes and pathways in the development of HGSOC.

Lisa Wiesmüller University Hospital Ulm, Germany Violeta Serra Vall d’Hebron Institute of Oncology, Spain Oded Kopper Hubrecht Institute, The Netherlands SESSION 3 — Analysis of the efgects of HBOC gene variants on treatment response.

At Bio-Prodict we design and build information systems for protein (super)families, tailored towards fundamental and applied research in Protein Engineering and DNA Diagnostics. Tiese systems contain large amounts of very heterogeneous but highly integegrated data, e.g. alignment-derived data, structure data and information extracted from the literature. I am currently exploring novel ways of applying machine learning technology to predict the efgect of nsSNPs on protein function. Tie development of tools and solutions to facilitate Genome Editing. Tiis includes development of efgectors (Cas9 variants & Cas9 alterna- tives, and RNA triggers), controls, detection and visualization systems (fmuorescence, PCR, NGS). Developing in vivo and in vitro crispr-Cas9 approaches.

Joey Riepsaame Sir William Dunn School

• f Pathology, University
• f Oxford, UK.

Bas Vroling Bio-Prodict, The Netherlands Michel Cannieux Integrated DNA Technologies, USA SESSION 4 — Model systems and assays for the functional classifjcation of HBOC gene variants.

We are interested in the role of germline and somatic genetic factors in- volved in cancer predisposition, initiation, progression, and response to

• therapy. Our focus has been on four cancer sites: lung, brain, breast, and
• vary. Tie overarching theme across these cancer sites is the systems bi-
• logy approaches and genetics to perform in-depth studies with a view

to develop translational solutions to cancer therapy and prevention.

Alvaro NA Monteiro Moffjtt Cancer Center, USA

SESSION 5 — Novel insights in HBOC suppression and consequences for functional assays.

Tie focus of my research is on hereditary breast cancer, with special emphasis on the suppressor gene BRCA1. Together with my co-work- ers in the group of Jos Jonkers, I have generated several novel mouse models for BRCA1 associated tumorigenesis and used these to get more insight in the function of BRCA1 in tumor suppression and treat- ment response. Currently, I am focusing on the functional classifjcation

• f BRCA1 sequence variants of unknown clinical signifjcance.

Over the past decade, the overarching goal of our laboratory has been to understand the functional signifjcance of human BRCA1 and BRCA2 variants of unknown clinical signifjcance (VUS). We have used a mouse embryonic stem (ES) cells-based assay developed in

• ur laboratory. Desired variants are generated in the human BRCA1
• r BRCA2 gene in bacterial artifjcial chromosomes (BAC) using

recombineering technology. Tiese are then introduced into ES cells engineered to express a conditional-selectable allele of BRCA1 or

• BRCA2. Tie extent to which specifjc variants complement the lethality
• f ES cells with BRCA1 or BRCA2 defjciency and the known functions
• f these proteins in DNA repair cell and cycle regulation is used as a

surrogate readout to decipher their association with risk of developing the disease.To assess the physiological signifjcance of our fjndings, we are also engaged in generation of new mouse models. Tiese models serve as power powerful tools that have improved our understanding of the efgect of these variants on growth and development, hematopoiesis, fertility and tumorigenesis. Text to be added Using mouse models and a combination of single molecule, cell biological and biochemical approaches, we investigate the mechanisms underlying stability of the DNA replication process and its contribution to genome integrity. We are particularly focused on understanding how mutations in certain factors result in chemo-resistance in Breast and Ovarian cancers by mediating replication fork stability.

Peter Bouwman The Netherlands Cancer Institute, The Netherlands Shyam Sharan Center for Advanced Pre- clinical Research, National Cancer Institute, USA Ralph Scully Beth Israel Deaconess Medical Center, Harvard University, USA Arnab Ray Chaudhuri National Cancer Institute, USA

Our research is focused on the DNA damage response and the trans- lation towards clinical applications. We have developed tools for the reliable assessment of the clinical signifjcance of Variants of Uncertain Signifjcance in breast and ovarian cancer susceptibility genes.

Maaike Vreeswijk Dept.of Human Genetics, University Medical Center, The Netherlands

We study how cells repair DNA damage in the context of chromatin and use our expertise to development assays for the functional analysis

• f sequence variants in cancer.

Haico van Attikum

• Dept. of Human Genetics,

Leiden University, The Netherlands

Text to be added

Sean Tavtigian Huntsman Cancer Institute, University of Utah, USA

We study how cells repair DNA damage in the context of chromatin and use our expertise to development assays for the functional analysis

• f sequence variants in cancer.

Haico van Attikum

Our work focuses on the efgects of genetic variants on risk of breast cancer subtypes, prognosis and long-term outcome of breast cancer. We investigate the interactions between germline variants and life style on the incidence of specifjc breast cancer subtypes, and the interactions between germline variants, tumor genetic and molecular characteristics, breast cancer treatment, and lifestyle factors on breast cancer prognosis, incidence of second tumors, and mortality. A second research line focuses on patient information and consent procedures, and return of results from research using human materials. Tiis directly relates to the fjrst research line as increasingly studies generate genetic information about hereditary variants.

Marjanka Schmidt

I work as a postdoc in the lab of Jos Jonkers. My research projects include developing mouse models to functionally investigate BRIP1 as a tumour suppressor for breast cancer, and test treatment strategies for BRIP1 defjcient tumours using these mouse models. Moreover, I am working on setuing up crispr-Cas9 based in-vitro assays to identify pathogenic BRIP1 germline variants. Tiese variants have been identi- fjed in high-risk breast cancer families by large scale sequencing efgorts. Tie focus of my research is on the genetic dissection of human breast cancer through the use of genetically engineered mouse models (GEMMs) and patient-derived xenografu (PDX) models. My group has generated several mouse models for BRCA1/2-associated hereditary breast cancer and E cadherin-mutated invasive lobular breast cancer. Tiese models are used for both basic and translational studies focusing

• n genotype-phenotype correlations; discovery and validation of can-

cer genes and drug targets; tumor-host interactions; and mechanisms of therapy response and resistance.

Arne N. Kousholt Jos Jonkers

Organisers

Tie focus of my research is on hereditary breast cancer, with special emphasis on the suppressor gene BRCA1. Together with my co-work- ers in the group of Jos Jonkers, I have generated several novel mouse models for BRCA1 associated tumorigenesis and used these to get more insight in the function of BRCA1 in tumor suppression and treat- ment response. Currently, I am focusing on the functional classifjcation

• f BRCA1 sequence variants of unknown clinical signifjcance.

Peter Bouwman

Our research is focused on the DNA damage response and the trans- lation towards clinical applications. We have developed tools for the reliable assessment of the clinical signifjcance of Variants of Uncertain Signifjcance in breast and ovarian cancer susceptibility genes.

Maaike Vreeswijk Sabine Linn

Tie Linn lab focuses on the development of prognostic and predic- tive markers for breast and ovarian cancer to guide systemic therapy decisions.