Clinical and Molecular Investigations of Familial Breast-Ovarian Cancer

Lead Research Organisation: Institute of Cancer Research
Department Name: Division of Genetics and Epidemiology

Abstract

Breast and ovarian cancer can occur together in some families. Faults in two genes, BRCA1 and BRCA2, are known to increase the risks of breast and ovarian cancer resulting in families with both cancers (known as breast-ovarian cancer families). Individuals from families with BRCA1 or BRCA2 faults can undergo gene testing to see if they are at-risk of cancer. Individuals without the fault are reassured and those with the fault can have surveillance and/or preventative surgery to reduce their risk of cancer. However, the majority of breast-ovarian cancer families are not due to faults in BRCA1 or BRCA2 and there is currently little information available on how to best manage them. We have recruited 705 families with breast-ovarian cancer and I shall increase this to 1300 families. I shall investigate the contribution of BRCA1 and BRCA2 faults to these families and will look to see if newer breast cancer susceptibility genes, ATM, CHEK2, BRIP1 and PALB2 have a role in familial breast-ovarian cancer. By analysing the patterns of cancer clustering and gene faults in the families we will be able to clarify the cancer risks to unaffected relatives in breast-ovarian cancer families, which will allow us to better manage them in clinic.

Technical Summary

AIMS
1. To investigate the contribution of breast cancer susceptibility genes to familial breast-ovarian cancer.
2. To improve risk estimation and management of breast-ovarian cancer families.

BACKGROUND
Mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer but only account for a minority of breast cancer families. Further high penetrance predisposition genes have not been discovered and the residual susceptibility to breast cancer is believed to reside in multiple genes with smaller effects. The Breast Cancer Genetics Team at the ICR has led the way in identifying such genes and in recent years has demonstrated that inactivating mutations in CHEK2, ATM, BRIP1 and PALB2 double the risk of breast cancer. Families that include individuals with breast cancer and individuals with ovarian cancer (‘breast-ovarian cancer families‘) have been largely attributed to BRCA1 and BRCA2. However, BRCA1/2 mutations are not found in the majority of the smaller (<5 cases) breast-ovarian cancer clusters that are typically seen in the clinic. Robust cancer risks and optimal management for such families remain unclear. Given the close functional interaction between the recently identified lower penetrance genes and BRCA1/BRCA2, it is plausible that they are likewise contributing to familial breast-ovarian cancer and we have preliminary data to support this. To clarify genetic susceptibility underlying familial breast-ovarian cancer I have the following objectives:

OBJECTIVES
1: To construct a comprehensive resource of data and biological samples on 1300 breast-ovarian cancer families
2: To investigate the frequency of mutations in breast cancer susceptibility genes in 1300 breast-ovarian families
3: To investigate the phenotypes and risks associated with mutations in CHEK2, ATM, BRIP1 and PALB2
4: To improve clinical management of familial breast-ovarian cancer

METHODS
Using 705 existing breast-ovarian cancer families and 600 additional familthat I shall recruit, I shall generate a series of ~300 breast-ovarian cancer families with BRCA1/2 mutations and ~1000 families in which mutations have been excluded. I shall screen CHEK2, ATM, BRIP1 and PALB2 in index cases from all BRCA1/2 negative families using a combination of techniques.
In families with mutations I shall screen additional family members, review the clinical and pathological phenotype and estimate the cancer risks. I shall also undertake analyses of the full series to examine the contribution of known genes and to model the likely underlying susceptibility of the residual families. I shall use these combined data to inform clinical management of breast-ovarian cancer families.

Publications

10 25 50

 
Description Project Grant
Amount £764,646 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2010 
End 11/2011
 
Title CaVaDa Cancer Variant database 
Description Based on these principles, we have built an initial prototype of this system, which we entitled CaVaDa (Cancer Variant Datasystem: http://CaVaDa.dynalias.org/CaVaDa/.) This prototype is, in brief, a mySequel database of 74 tables accessed via a Shiny web interface (code available in a wiki at http://CaVaDa.dynalias.org/mediawiki/index.php/Main_Page). The database contains >1.2 million variants (ie all possible base substitutions in 106 cancer susceptibility genes) for all of which there are generic (ie non-gene specific) variant-level inputs such as in-silico predictions (eg AlignGVGD, SIFT, MAPP, Polyphen, CaDD, SusPECT, MaxEnt) and population data (1000GP, EVS). For BRCA1, BRCA2, MLH1, MSH2, MSH6 and PMS2, we have also integrated multiple expert-selected gene-level gene-specific inputs (eg LOVDs and selected large scale functional and genetic epidemiologic analyses). In consultation with experts in the field, Turnbull has developed gene-specific classification rules and had programmed computational gene-specific decision trees, applied to data inputs to produce systematic and 'automated classifications' for all variants in these genes (see Appendix 1). The CaVaDa web interface offers an 'Explore' function (for looking up a single variant) and a 'batch' function (for import of .txt or .csv file of vars; flexible to varying nomenclature). CaVaDa' s data and classifications can be outputted either via a PDF (for a single variant; see Appendix 2) or an annotated .xls (for a set of variants). The system also allows for input of notes and 'curated classifications' which a number of current users have submitted. Any PMIDs included in text are automatically hyper-linked out. This system is was developed in an heuristic, iterative fashion as a proof of concept over 7 months by Turnbull (clinical academic; 0.1 WTE) and Sultana (software engineer, 0.8 WTE). It is currently informally hosted on a domestic server but is in use by a number of research laboratories (Gonzalez de Castro laboratory (CMP ICR/RMH), Swanton laboratory (Crick), Eeles laboratory (ICR), Sternburg laboratory (Imperial)) as well as numerous clinicians and clinical genetics departments. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Supporting molecular cancer research from a number of notable PIs 
URL http://cavada.dynalias.org/cavada/
 
Description TP53 binding 
Organisation Ludwig Institute for Cancer Research
Department Oxford Branch
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Analysis of genetic associations for testicular cancer
Collaborator Contribution Functional analyses of TP53 binding sites
Impact ongoing analyses
Start Year 2013
 
Description TeCAC 
Organisation University of Pennsylvania
Department Perelman School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Collaborative analysis of GWAS data for testicular cancer
Collaborator Contribution Collaborative analysis of GWAS data for testicular cancer
Impact 2 publications
Start Year 2012
 
Description TeCAC 
Organisation University of Southern California
Department Department of Preventive Medicine
Country United States 
Sector Academic/University 
PI Contribution Collaborative analysis of GWAS data for testicular cancer
Collaborator Contribution Collaborative analysis of GWAS data for testicular cancer
Impact 2 publications
Start Year 2012
 
Description Doctors net interview 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact 5 minute interview at NCRI conference featured on Doctors.net.uk website, aimed at broad medical audience, Topic: a more mainstreamed approach to genetic testing

Site accessed by >200,000 doctors
Year(s) Of Engagement Activity 2013
URL http://www.doctors.net.uk/
 
Description Film for The Science Museum 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Film on Big Data to be screened at the Science Museum in mid 2016
Year(s) Of Engagement Activity 2016
 
Description Lab Tour 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Supporters
Results and Impact Lab tour and science afternoon for 10 Movember fundraisers to engage them in the science behind the fundraising

Additional requests for me to talk to lay audiences
Year(s) Of Engagement Activity 2013
URL http://instituteofcancerresearch.wordpress.com/tag/movember/
 
Description MCG press conference 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Press briefing as one of panel of 4 expert speakers via Wellcome Trust Media Center regarding extension of genetic testing for breast cancer predisposition

Widespread coverage eg BBC 6 o'clock News
Year(s) Of Engagement Activity 2013
 
Description Magazine interview Men's Health 2015 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact INterview about testicular cancer and mens health
Year(s) Of Engagement Activity 2015
URL http://www.menshealth.co.uk/healthy/beat-testicular-cancer
 
Description Movember Film 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Workshop Facilitator
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Worked with Movember to develop 2 minute film to go go onto their website and designed to go viral. Film about testicular cancer and research into the disease. Final film featured Ray Winstone and Jimmy White

>20,000 hits in its first week
Year(s) Of Engagement Activity 2013
URL http://www.youtube.com/watch?v=Yvc2UjkSddA
 
Description Movember launch 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Publicizing public health message about testicular cancer and research into testicular cancer to audience of 900 men.

Additional requests to talk to audiences. Article in the Metro
Year(s) Of Engagement Activity 2013
 
Description Podcast recording 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact 15 minute podcase recording for Movember radio on Men's Health and testicular cancer
Year(s) Of Engagement Activity 2015
URL http://www.podcastchart.com/podcasts/movember-radio/episodes/ep-12-clare-turnbull
 
Description TED-style talk at Adobe Technology Summit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact o TED-style talk for Adobe.Technology Summit at Excel 2015: "Mother Nature's Big Data"
Year(s) Of Engagement Activity 2015
URL http://2015.summit.adobe.com/emea/speakers/
 
Description Talk at House of Commons 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Talk on Precision Medicine at the House of Commons
Year(s) Of Engagement Activity 2016