BRCA2 What we know so far Dr Helen Hanson and Dr Katie Snape Joint Lead Consultants for Cancer Genetics Southwest Thames Regional Genetics Service St Georges Hospital London What are the ID: 912314
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Slide1
Overview of BRCA1 and BRCA2What we know so far
Dr Helen Hanson and Dr Katie SnapeJoint Lead Consultants for Cancer GeneticsSouthwest Thames Regional Genetics Service, St George’s Hospital, London
Slide2What are the BRCA1 and BRCA2 genes?
Slide3Genes are short pieces of our genetic codeWe all have about 20,000 genes packaged into 23 pairs of chromosomesEverybody has two copies of the BRCA1 gene and two copies of the
BRCA2 geneWe inherit one copy of each gene from our mother and one copy of each gene from father
Slide4What is a gene mutation?
Slide5A mutation (or pathogenic variant) is a permanent change in the genetic code of a gene e.g. in BRCA1
A mutation means that the gene can not work correctly in our bodies
Slide6How were BRCA1 and BRCA2 mutations discovered to be associated with cancer predisposition?
Slide71990 : Mary-Claire King of the University of California at Berkeley discovers the location of BRCA1 gene.
1994 : The complete sequence of BRCA1 gene is identified, including specific mutations related to hereditary breast and ovarian cancer, by the University of Utah Medical Center.1995 :The location of the BRCA2 gene is discovered in a collaborative effort led by a team from Institute of Cancer Research, UK.
Late 1990s: Genetic testing of BRCA1 and BRCA2 genes offered in NHSMid 2000’s: Complete test of BRCA1 and BRCA2 possible2013: Angelina Jolie reveals that she had a double mastectomy after learning that she had a hereditary mutation in the BRCA1 gene.
Slide8Why do mutations in BRCA1 and BRCA2 cause an increased risk of cancer?
Slide9DNA damage
External – UV light, ionising radiation
External – Cigarette smoke, chemical consumption
Internal – reactive oxygen species
Internal – ineffective DNA repair mechanisms
mechanism by which
BRCA
genes
increase cancer risk
Slide10DNA repair pathways
BRCA1 and BRCA2 repair a specific type of damaged DNAHelp “put a brake” on cancer cells developing
Slide11Knudson’s two-hit hypothesis
Sporadic cancer
BRCA carrier
Slide12How common is it to have a BRCA1 or BRCA2 mutation?
Slide13BRCA mutation carriers in the general population estimated at between 1/800 and 1/1000 (0.1%)
Prevalence may be increased in certain populations1 in 40 risk (2-3%) in Ashkenazi Jewish population due to founder mutations
Slide14Are there any other hereditary causes of breast and ovarian cancer susceptibility?
Slide15Inherited mutations in high risk genes are rareLarger proportion of familial breast cancer is caused by “polygenic inheritance”- inheriting multiple lower risk genetic variants that collectively increase cancer risk
Slide16The genetic architecture of disease
Slide17Genetic predisposition to breast cancer
BRCA1BRCA2
TP53STK11
PTEN
ATM
CHEK2
PALB2
>100 common
variants
CDH1
Slide18Genetic predisposition to ovarian cancer
BRCA1BRCA2
MLH1MSH2
MSH6
RAD51C
RAD51D
BRIP1
> 20 common
variants
Slide19Familial breast cancer
Slide20Familial ovarian cancer
Slide21What cancers are BRCA1 and BRCA2 carriers at risk of?
Slide22BRCA1
-associated Cancers
Slightly increased risk of other cancers (eg:
prostate, male breast, pancreatic)
Breast
cancer
Second primary breast
cancer
Ovarian/fallopian tube/
primary peritoneal
cancer
Slide23BRCA2
-Associated Cancers
Prostate cancer
B
reast
cancer
Ovarian/fallopian tube/
primary peritoneal
cancer
M
ale
breast cancer
Second primary breast
M
elanoma
P
ancreatic
cancer
Slide24Breast Cancer Linkage Consortium
Breast cancer risk in
BRCA1/BRCA2
BRCA1
BRCA2
General pop.
Slide25Breast Cancer Linkage Consortium
Ovarian cancer risk in
BRCA1/BRCA2
General pop.
BRCA2
BRCA1
Slide26What are the current recommendations for surveillance and management?https://
d1ijoxngr27nfi.cloudfront.net/research-divisions/protocol-3-brca-mutation-carrier-20150209-v4.pdf?sfvrsn=5e7f6f69_2
Slide27Screening for BRCA carriers
Breast Screening
annual MRI screening age 30-50annual mammogram from age 40>50 usually annual mammogram only
Slide28Screening for BRCA carriers
Ovarian ScreeningUnproven efficacyNot currently recommended
Research continuing
Slide29Ovarian screening research
ALDO study: 4-monthly CA-125, ROCANow closed to recruitment
ROCA = Risk of Ovarian CancerDetects personal changes in ca-125 levels
Slide30Surgical options: breast
Risk-reducing mastectomiesMost effective way of reducing Risk reduced to <5% over lifetime Choices: timing, breast reconstruction, skin-sparing, nipple-sparing
Slide31Surgical options: ovaries & tubes
Risk-reducing bilateral salpingo-oophorectomyOffered ~ age 40 (BRCA1) or 45 (BRCA2), or after completed family if applicableHRT recommended to age 50-52(unless ER+ breast cancer)
Only reliable way to reduce ovarian & tubal cancer riskPROTECTOR study: bilateral salpingectomy with delayed oophorectomy
Slide32ChemopreventionUse of medication to reduce risk of developing breast cancer
Tamoxifen (pre and post-menopausal) or Selective Oestrogen Receptor Modulators (SERMS) e.g. raloxifene or Aromatase Inhibitors e.g. anastrazole (post menopausal)No clear data in BRCA carriers currentlyNot recommended for BRCA1 currently (more likely to have ER-ve breast cancer)
Slide33What developments have there been in the management of cancers in BRCA carriers?
Slide34Slide35Cancer Genomics100,000 Genomes ProjectLooked at all of the genetic changes that are present in the cancer cell“Cancer Genome”
The cancers show changes which can tell us they are caused by faulty BRCA genes
Slide36DNA repair pathways
BRCA1 and BRCA2 repair a specific type of damaged DNAHelp “put a brake” on cancer cells developing
BRCA cancers show faulty DNA repair pathway – HOMOLOGOUS RECOMBINATION REPAIR DEFECT = HRD
Slide37Cancer mutational signatures
Cancer with HRD signatureCancer with normal HR
Slide38Why does this matter?If we know the underlying problem which is causing the cancer, this can help us treat the cancerNew drugs = PARP Inhibitors e.g. olaparib
Target cells which have lost BRCA (the cancer cells) and do not affect normal cells
Slide39Targeted therapy
Specific tumor cell killing
HR repair
Few normal tissue effects
BRCA1/BRCA2 carrier
normal tissue cells
DNA
repair
DNA
repair
Base excision
DNA repair
Homologous
recombination
(HR) repair
BRCA1/BRCA2 carrier
Tumor cells
HR repair
PARP inhibitor
Base excision
DNA repair
PARP inhibitor
Base excision
DNA repair
HR repair
Courtesy of Alan Ashworth / Andrew Tutt
Slide40PARP InhibitorsHave been shown to improve response to treatment in ovarian cancerIn trials in Triple Negative Breast cancer in BRCA carriersIn trials in pancreatic cancer
Slide41How might we be able to offer testing to more women in the future to identify if they are BRCA carriers?
Slide42National Genomic Medicine ServiceMoving towards testing ALL cancers for BRCAIf a BRCA mutation is found in the cancer – offer testing to see if person is a BRCA carrier
A desire to increase access to BRCA testing both for people with cancer and people in the populationStill currently limited by resourceMoney People
Slide43SummaryBRCA1 and BRCA2 are important cancer predisposition genes
Management of BRCA carriers, tailored to personal wishes, can reduce cancer risk or pick up cancers early at a curable stageLots of research on-going to improve screening, prevention and early detection for BRCA carriersNew treatments are becoming available to treat cancers in BRCA carriersWe are moving towards offering more testing and finding more carriers
Slide44Lunchtime focus group1235 -1305Grab some lunch and bring it back
to the Hyde Park RoomBring your smartphone/tabletTest the new online digital cancer FHQSGive verbal feedback and online evaluation