Describe the clinical features, the genes involved and briefly the testing strategies for familial breast and ovarian cancer. Cancer Genetics Session FRCPath Preparation Course 12/1/10.
Cancer Genetics Session
FRCPath Preparation Course
Clinical features: cancer and familial ovarian cancer accounts for ~8% of all ovarian cancer.
Predisposition to breast and ovarian cancer
BRCA1: Increased risk of colon cancer, pancreatic cancer, gastric cancer, fallopian tube cancer, some association with prostate cancer.
BRCA2: Increased risk of male breast cancer, prostate cancer, pancreatic cancer, cancer in bile duct, gall bladder, stomach and melanoma
Based on high risk families
Risk of breast cancer by 70yrs: 71% for BRCA1, 84% for BRCA2
Risk of ovarian cancer by 70yrs: 47-63% for BRCA1, 27% for BRCA2
Risk is reduced in estimates based on population based studies:
Risk of breast cancer by 70yrs: 65% for BRCA1, 45% for BRCA2
Examples of genetic modifiers:
RAD51: A SNP (135G>C) in 5’UTR has been shown to significantly modify breast cancer risk in BRCA2 carriersesp. in homozygotes.
SNPs in FGFR2,TNRC9 and MAP3K1 have been associated with increased breast cancer risk inthe general population and BRCA2 carriers (FGFR2 & MAP3K1) and both BRCA1 and BRCA2 carriers (TNRC9).
BRCA1 and BRCA2 implicated in many cellular processes
Required for development: embryonic lethality in mice with homozygous deletions
Essential role in DNA damage response and maintenance of genome integrity
Both genes are expressed in most tissues
Precise mechanism of tissue specific tumourigenesis not fully elucidated
BRCA1 cellular functions (633–645)
BRCA2 cellular functions (633–645)
Involvement in DNA damage repair of DBS by homologous recombination
Direct interaction of BRCA2 with RAD51 protein which is essential for DBS by HR.
BRCA2 regulates the availability and activity of RAD51, which coats ssDNA to form a nucleoprotein filament that invades and pairs with a homologous DNA duplex to initiate strand exchange in HR
BRCA2 contains a region that is capable of inducing transcription and has histone acetylase activity.
Mutation Spectrum in BRCA1 and BRCA2 (633–645)
Approximately 2% for BRCA1 and BRCA2 from population based case control studies. Increased in families with early onset breast cancer, family history of ovarian cancer and Ashkenazi Jewish ancestry.
Ashkenazi Jewish: BRCA1: 185delAG & 5382insC, BRCA2: 6174delT
Icelandic: BRCA2: 999del5
Dutch: BRCA1 large deletions
Exon 11 of BRCA1 and exon 10 & 11 of BRCA2 screened in overlapping fragments due to size.
Testing for founder mutations if case known to be from relevant population
Screening for large rearrangements
Sequencing of coding exons of both BRCA1/2 in a high throughput manner
Referral criteria (633–645)
Scottish clinical genetics: (633–645)
Different algorithms to assess score
Account for other cancers in the family
Combination of NICE and table below used for scoring (aim: mutations detected in 20% of samples tested)
Jong et al 2002. Genes other than BRCA1 and BRCA2 involved in breast cancer susceptinility. Journal of Medical Genetics 39:225-242.
EMQN best practice guidelines for molecular genetic analysis in hereditary breast/ovarian cancer 2007
Boulton 2006. Cellular functions of the BRCA tumour-suppressor proteins Biochemical Society Transactions 34, (633–645)
Mullan et al 2006. The role of BRCA1 in transcriptional regulation and cell cycle control. Oncogene 25, 5854–5863
Gudmundsdottir and Ashworth 2006.The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability Oncogene 25, 5864–5874