L13 - cancer epidemiology

Question 1

Why do we want to identify genes that are suceptability factors?

Answer 1

Understand mechanisms of the cancer, identify people at risk, personalise treatments

Question 2

What is positional cloning?

Answer 2

Linkage analysis followed by cloning and sequencing. Assemble families with affected individuals and genotype these families to find associated mutated genes

Question 3

What is a lod score?

Answer 3

A measure of how likely it is that a disease allele and marker are linked

Question 4

What is BRCA1?

Answer 4

A multifunctional protein that is commonly mutated in breast cancer. It shares many features with BRCA2 e.g. 1 non-coding exon, large exon 11, 60% identity with the mRNA

Question 5

What is the function of BRCA1?

Answer 5

Associates with a complex (MRN) that binds at sites of DNA damage (DSB) and initiates repair. It is phos by ATM

Question 6

What is the purpose of SNP and GWAS analysis?

Answer 6

Allows identification of alleles that are commonly mutated in sporadic cancer

Question 7

What is the spectrum of genetic risk?

Answer 7

Some genetic mutations cause an increased risk of cancer
Rare syndromes - high penetrance e.g. Rb, APC, XP - increase risk 1000 fold
Familial forms - breast and colon, increase risk 10-100 fold
Sporadic cases - breast, colon, increase risk 1-1.5 fold

Question 8

What made researchers think that breast cancer may be familial?

Answer 8

Some families had a higher incidence of breast cancer. These families also showed an early onset, breast and ovarian cancer, bilateral cancers and higher frequency in males

Question 9

What chromosome was breast cancer linked to?

Answer 9

23 multicase families - LOD score of 5.98 in families with marker at chr 17q12
Breast cancer linked to chr 17

Question 10

What did Skolnick fail to show?

Answer 10

Linkage at the marker for chr 17 previously identified in breast cancer

Question 11

How does the cell respond to DNA damage?

Answer 11

ATM phos in repsonse to DBS
ATM phosph MRE11/NBS1
MRE11/NBS1/RAD50 (MRN) complex binds at DSB and initiates DNA repair

Question 12

What is the phenotype of mutations in ATM and NBS?

Answer 12

One of failing to signal DNA damage - increased sensitivity to ionising radiation, failure to induce p53, failure to stop DNA synthesis