Mutation of BRCA 1 and BRCA 2 genes

Mutation of BRCA 1 and BRCA 2 genes in cancer Dr Dawn Smallwood dawn. smallwood@dmu. ac. uk

Learning objectives • Describe: • Mutation of BRCA 1/2 tumour suppressor genes • The genetic predisposition to cancer of BRCA 1/2 mutation carriers • Apply Knudson two hit hypothesis to BRCA 1/2 tumour suppressor genes • Suggest appropriate genetic counselling for individual members of a family in which the BRAC 1/2 mutation had been detected

Breast cancer is the most common cancer in women. Prostate cancer is the most common in men. (UK new diagnoses in 2015. ) Breast cancer

Breast cancer • In the UK, 1 in 8 women is likely to develop breast cancer at some time in their life • Most cases are sporadic (caused by genetic mutations that are not inherited)

Hereditary breast cancer 5 -10% of breast cancers are hereditary Characteristics: • Clusters in families ‒ Families with both breast and ovarian cancer ‒ Families with male breast cancer ‒ Lower age of onset ‒ Bilateral cancer

Mutation of BRCA 1 and BRCA 2 genes • The most common known cause of hereditary breast cancer is mutation of BRCA 1 or BRCA 2 • These two genes account for approximately 20% of familial breast cancers. Research to identify new genes that also contribute to a high risk of breast cancer is ongoing.

Facts and figures • BRCA 1 gene • • 17 q 21. 31 24 exons 100 kb genomic DNA 100 s mutations identified • BRCA 1– tumour suppressor gene • DNA repair • BRCA 2 - gene • 13 q 13. 1 • 28 exons • 70 kb genomic • BRCA 2 – tumour suppressor gene • DNA repair

BRCA 1 and BRCA 2 facts and figures https: //www. youtube. com/watch? v=-Gwd. ZIq. Jf 8 g

BRCA 1 and BRCA 2 mutation increase the risk of developing certain types of cancer Early age onset breast cancer Second primary breast cancer Male breast cancer Ovarian cancer Prostate cancer

BRCA 1/2 inheritance is autosomal dominant One mutated allele (copy of the gene) confers increased risk Gene can be inherited from either parent Autosomes 50% chance of inheriting the gene if a patent is positive https: //en. wikipedia. org/wiki/File: Ideogram_human_chromosome_13. svg

Tumour suppressor genes • BRCA 1/2 inheritance is dominant because one mutated allele (copy of the gene) confers increased risk • Loss of tumour suppressor protein is recessive because both genes must be mutated to prevent production of the tumour suppressor protein • Tumour suppressor gene mutations are deactivating mutations called ‘loss of function’ (e. g. the mutation stops the encoded protein being produced) • Tumour suppressor gene mutations are recessive: mutation of both copies is needed to prevent production of the tumour suppressor protein Single mutation inactivates gene on one allele Second mutation inactivates gene on second allele Enough tumour suppressor protein is produced from one allele Figure 23 -24 Alberts

Tumour suppressor genes Tumour suppressor gene + function of both alleles lost = protein that supresses proliferation is not produced Tumour suppressor gene inactivation is analogous to having no brakes (unable to stop cell division)

BRCA 1 and BRCA 2: Genetic predisposition to cancer • Breast cancer is more common in women than in men, but the mutated gene can be inherited from the mother or father • One copy of the altered gene increases the chance of developing cancer • People inherit an increased likelihood of developing cancer • Not everyone who inherits the mutation of BRCA 1 or BRCA 2 will ultimately develop cancer

Knudson’s two-hit hypothesis Cancer

BRCA 1 and BRCA 2 and cancer risk https: //www. nytimes. com/2013/05/14 /opinion/my-medical-choice. html Royal Marsden NHS Foundation Trust 2014

Average cancer risk with BRCA 1 or BRCA 2 mutation compared to no BRCA mutation

Ashkenazi Jewish population

Ashkenazi Jewish population • Study of specific mutations in Ashkenazi Jews • Combined prevalence of BRCA 1/2 mutation is 2. 6% as opposed to 0. 2% in the general USA population • Three founder mutations (due to common ancestral origins and endogamy) have been identified at a higher frequency than the other BRCA 1 or BRCA 2 gene mutations • BRCA 1: 187 del. AG • BRCA 1: 5385 ins. C • BRCA 2: 6174 del. T • About 78 to 96% of Ashkenazi Jews with BRCA 1/2 mutations carry one of the founder mutations • Founder mutations provide a highly efficient means of determining carrier status (geneticists know which mutations to look for)

Genetic Counselling https: //www. youtube. com/watch? v=_ISYOx. Bqw. Ak

Case study: the Wilson family • Wendy Wilson saw a television program about familial breast cancer • Became concerned about her own family • Her mother had breast cancer and died aged 42 • 3 other relatives had breast cancer including her aunt (aged 40) and cousin (age 36) and a male second cousin • Wendy was referred by her GP for genetic testing

The Wilson pedigree Not related as all breast cancer is on Wendy’s mother’s side of the family Breast cancer gene carried but disease not developed

The Wilson pedigree

Mutation testing • Tumour tissue from Wanda (Wendy’s mother) was obtained from pathology lab archive and DNA extracted • Deletion in exon 18 of BRCA 2 was found. This caused a frameshift creating a stop codon • To confirm this was the ‘first hit’ mutation Wanda’s sister (Wendy’s aunt) was contacted for a blood sample. She also carried this mutation • Family mutation was identified

Mutation testing • Other family member blood samples were tested • Veronica and William carried the mutation but Wendy did not

Genetic counselling for female with no BRCA 2 mutation: Wendy • Important for her to realise that she could still develop sporadic forms of breast cancer • She should still attend the standard mammogram screening program • Risk is strongly influenced by lifestyle – reduce risk by 40% by: • • • Maintaining a healthy weight Physical exercise Healthy diet Not smoking Reducing alcohol consumption

Genetic counselling for BRCA 2 mutation carrier (female): Veronica • Carried mutation so at high risk of developing breast cancer • Increased risk of ovarian cancer • Options • Do nothing • Lifestyle changes • Enhanced surveillance program – annual mammography • Tamoxifen – may reduce risk • Prophylactic mastectomy (breast removal) • Prophylactic salpingectomy (removal of ovaries and fallopian tubes)

Genetic counselling for BRCA 2 mutation carrier (male): William • Breast cancer is very rare in males so although he is a carrier his absolute risk is low • Increased risk of prostate cancer – attend regular screening • His daughters would need counselling (plus testing if they choose) as they are at substantial risk of breast cancer • If they inherit the gene his sons are at increased risk of prostate cancer and risk passing the mutation onto their children

BRCA 1 and BRCA 2 genetic testing https: //www. youtube. com/watch? v=Dpb 0 Vzti. Drk

Resource Chapter 12

Self study (link on Blackboard)