Some Terms: AFTER midterm 1 content

Which locus is linked to breast cancer?

D17S74

At approximately what age does the LOD score start to decrease for linkage between D17S74 and breast cancer?

Around 55 years

What LOD score thresholds are used for linkage analysis in breast cancer families based on mean age of diagnosis (M)?

• If M ≤ 48 (younger-onset families): LOD score must be ≥ 5.0

• If M ≤ 50 (broader group): LOD score must be ≥ 3.0

What is BRCA1 and what happens when it loses function?

A 1863–amino acid protein involved in a complex that repairs chromosomal DNA damage; loss of function leads to genomic instability and increased cancer risk.

How is the discovery of BRCA1/BRCA2 similar to the discovery of CFTR?

1. Have lots of mutations (indels, deletions, insertions)

2. Used in PGD with IVF to select embryos without the disease-causing mutation(e.g., BRCA1-free birth 2009)

3. Mutation prevalence varies among human

4. have inspired gene-based therapies targeting the underlying genetic defect

What is the difference between prevalence and penetrance?

• Prevalence: how common a disease is in a population

• Penetrance: the proportion of individuals with a mutation who actually show the disease phenotype

What are cohort studies

They capture the order of events( exposure→ risk of diseases associated with exposure, and use RR)

• was used to estimate BRCA1-associated risk

What is genetic counselling and what does a genetic counsellor do?

• Process of helping people understand and adapt to the impacts of genetic disease;

• assesses risk, guides testing decisions, interprets results, and provides support.

Solutions to Problems associated with the case-control approach

1. Experiment cohort

2. Prospective(observational) cohort

3. Retrospective(observational) cohort

In the BRCA1/BRCA2 multiplex heteroduplex analysis, how many patients were initially studied?

1435 breast cancer patients

What proportion of PCR reactions were successful, and what was the effective sample size?

85% successful → effective sample size ≈ 1220 patients

How many total BRCA mutations were found, and how were they distributed?

24 total mutations: 8 BRCA1 and 16 BRCA2

What was the approximate prevalence of BRCA mutations in breast cancer patients (age ≤55)?

~0.7% BRCA1 and ~1.3% BRCA2 (low overall prevalence)

What are confounding factors

A third (unknown) factor that enhances the chances of exposure and disease

What is index testing?

Genetic testing of the first affected individual in a family (the “index case”) to identify a disease-causing mutation.

Relative Risk estimates for each gene calculated using data from families that were further sorted into three age-at-diagnosis categories

• BRCA1 mutation increase breast cancer risk in women aged 20–39 58.4 times

• the estimated breast cancer risk (penetrance) for BRCA1 mutation carriers aged 20–39 is 23%

What is the prevalence and penetrance of BRCA1/BRCA2 mutations?(after retrospective cohort analysis)

BRCA1 (<1%) and BRCA2 (<2%) mutations are rare

• but have high penetrance—meaning carriers have a high likelihood of developing cancer over their lifetime.

What was the study design and sample size in Onay et al. (2006) for breast cancer SNP analysis?

Case-control study: 398 breast cancer cases and 372 controls, genotyping 18 cancer-related genes for common SNP variation.

What do an odds ratio (OR) or relative risk (RR) of 2.0 mean?

OR = 2.0 → odds of exposure are twice as high in cases vs controls
RR = 2.0 → exposed individuals are twice as likely to develop disease compared to unexposed

What does a hazard ratio (HR > 1.0) mean?

HR > 1.0 means the exposed group has a higher rate of developing the outcome over time compared to the unexposed group.