lecture 8 - population genetics 2 Flashcards
what are GWAS?
As GWAS analyse common variants, usually typed on commercial SNP arrays, they do not generally identify causal variants. GWAS identify common variants which tag a region of linkage disequilibrium (LD) containing causal variant(s).
Additional or follow-on studies are usually required to narrow the region of association and identify the causal variant.
Quantitative trait loci (QTL) mapping.
what is the general trend of cancer as age increases?
it increases as age increases
how are cancers two chance events as somatic mutations
Most mutations are recessive, so a single diploid cell needs two hits in the same gene (one in each chromosomal copy) to cause a mutant phenotype.
a, a normal cell at conception
b, at some point in development a mutation arises. This will be passed onto all daughter cells in a heterozygous state. This cell has a wild-type phenotype.
C, a second mutation occurs in the homologous gene. This cell is homozygous mutant. This mutant cell may lead to cancer.
what are germline mutations?
Familial cancers have a specific gene with a defined inheritance pattern.
A person inherits a bad p53 gene, for example, (first hit), but still has another functional copy of this gene on the other chromosome.
Sometime later, a mutation wipes out the good gene (second hit) and growth control is lost, allowing a clone of neoplastic cells to arise.
what are the red flags for hereditary breast cancer?
5-10% of all breast cancer cases are hereditary.
Onset younger than 50yr old
B/L breast cancer
Ovarian cancer at any age
Multiple family members with early onset breast cancer
Ashkenazi Jewish ancestry with breast cancer
Multiple affected genes
what is the early onset of breast cancer?
Breast cancer is rare in women under 40
Why?
Because cancers require two somatic mutations
However, in some family’s breast cancer is at a high frequency and often at a young age due to a germline mutation in BRCA.
Are there breast cancer pre-disposition genes?
BRCA1 and BRCA2 were identified in 1990 and 1994 respectively, by gene mapping.
what is the breast cancer gene?BRCA
BRCA1 and BRCA2 are normally expressed in the cells of breast and other tissue, where they help repair damaged DNA or destroy cells if DNA cannot be repaired. If BRCA1 or BRCA2 itself is damaged by a BRCA mutation, damaged DNA is not repaired properly, and this increases the risk for breast cancer..
Around 1 in 20 (5%) people diagnosed with breast cancer may have an inherited BRCA mutation, accounting for around 2,500 of the 50,000 cases diagnosed every year in the UK
Risk if there is a germline (verses somatic) mutation:
85% (vs 10%) lifetime risk – (High penetrance)
37% (0.4%) risk by 40yrs, 66% (3.0%) by 55yrs, 85% (8.0%) by
80yrs
Increases risk of ovarian (37-62%) and prostrate (16%) cancer
what is the structure of BRCA1?
Exons 11-13 cover over 65% of the sequence of BRCA1
Encodes binding sites for several proteins including retinoblastoma protein
(RB), cMyc, Rad50 and Rad51.
Myc is a transcription factor for a large number of genes
Rad50, Rad51 are involved in DNA repair.
RB controls cell cycle progression
The high rate of mutation occurring between exon 11-13 suggest it is very important
for the tumour suppression function of BRCA1
what is the Founder Effect on BRCA1 and BRCA2 part 1?
Prevalence of BRCA1/2 mutation carriers in the general population is around 0.2% (1/500), however it can vary significantly among different countries or some ethnic groups due to founder effect.
The knowledge of the genetic structure of particular populations is important for the developing of effective screening protocol and may provide more efficient approach for the individualization of genetic testing.
GWAS has identified different mutations within BRCA1 and BRCA2 that are population specific.
Elucidation of the founder effect in BRCA1/2 genes can have an impact on the management of hereditary cancer families.
what is the Founder Effect on BRCA1 and BRCA2 on specific countries?
Ireland
A single BRCA1 c.427G>T mutation accounts for about 22% of all hereditary breast cancer patients.
United Kingdom
Scotland and Northern Ireland 10 specific recurring mutations (five in each gene) accounted for almost 50% of the total mutations detected.
In the North-west of England two recurrent mutations accounted for 16% of identified BRCA1 mutations in breast/ovarian cancer families and for 20% of BRCA2 positive male breast cancer families, respectively.
The Netherlands
30% of the BRCA1 related cases of hereditary breast cancer are due to copy number changes of one or more exons in this gene. 3.8-kb deletion of exon 13 or 510-bp deletion of exon 22. There are additional SNP founder mutations for BRCA1 and BRCA2.
what is the Founder Effect on BRCA1 and BRCA2 part 2?
These 3 mutations account for 98–99% of identified mutations and are carried by about 2.6% (1/40) of the Ashkenazi Jewish population.
There are differences between particular mutations and breast/ovarian cancer risk by 70yrs.
Similar risk for BRCA1 c.185delAG and c.5382insC mutations (64% and 67% respectively),
Much lower for the BRCA2 c.6174delT mutation (43%).
The corresponding values for ovarian cancer lifetime risk are 14%, 33% and 20% in carriers, respectively.
Screening for these three founder mutations alone is now part of routine clinical practice for Ashkenazi Jewish individuals.
KNOWING THE RISK % MAY INFLUENCE TREATMENT
what are the modifier genes for BRCA1 and 2
Several common polymorphisms in candidate genes have been investigated as potential modifiers of breast cancer risk for BRCA1 and BRCA2 mutation carriers.
RAD51 -135G→C BRCA2 mutation carriers who have two copies of the ‘C’ allele at this locus have a threefold increased breast cancer risk compared with carriers with two copies of the ‘G’ allele
CASP8 -D302H. apoptosis-related gene. Results indicate that CASP8-D302H confers a reduction in breast cancer risk for BRCA1 mutation carriers. (Antoniou et al., 2008).
what are modifier genes for breast cancer and ovarian cancer?
Breast Cancer
Loci 1q32 andTCF7L2at 10q25.3
Loci 1q32 contains MDM4 oncogene which plays a role in p53 regulation.
TCF7L2 – Transcription factor involved in Wnt signalling.
Ovarian cancer
Two loci at 4q32.3 and 17q21.31.
4q32.3 - first indication of aBRCA1-specific risk locus for either breast or ovarian cancer. Contains members of TRIM (Triparite motif containing) family which are expressed in ovarian epithelium
17q21.31 – contains 17 genes – work ongoing.
Fine mapping of these loci will aim to identify causal variants for the observed associations.
what are the Modifier Genes – BRCA1 and BRCA2
The Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) aims to identify genetic modifiers of breast and ovarian cancer risk in BRCA1 and BRCA2 carriers. This information might be useful for more precise risk estimation in the near future.
Design of GWASWhat do you need to think about?
-Association does not necessarily equate to a causative effect of the gene variant
-Relationship between genetic variants and disease status depends on may confounding factors, such as:
a - Cohort size
b - Type of cases and controls
c - Ethnic differences
d - Selection bias in recruiting the subjects
e - Varying risk genes in different populations
f - Varying risk alleles in different ethic groups
g - Environmental factors
h - Different genotyping platforms may provide variable coverage pre genome
i - Genetic marker selection and data interpretation
j - Replication of the data is the real litmus test of any GWAS
what is the future?
personalised medicine which is providing the right treatment, the right dose, the right time for the right person
GWAS of varying phenotypic scales.understanding Human Variation in Disease Susceptibility through Clinical and Cellular GWAS
“Clinical GWAS” search for associations between genetic differences and human disease traits such as disease risk, severity of disease, disease progression, and response to treatment.
“Molecular GWAS” search for associations between SNPs and molecular phenotypes such as levels of mRNAs, proteins, or metabolites.
“Cellular GWAS” connect SNPs to particular cellular processes. Phenotypic variation in these cellular processes can be examined by pharmacological manipulation
