Germline Mutations and Hereditary Prevalence

Where are germline mutations found?

In all cells of the body; occur in gametes and can be passed to progeny

How are germline mutations inherited?

From egg or sperm parent (one mutant copy + one normal copy)

What explains hereditary cancer predisposition in tumor suppressor genes?

The two-hit model: one inherited mutation + one somatic mutation → cancer risk

What cancers are associated with HBOC?

Breast, ovarian, pancreatic, prostate cancers

Which genes are primarily mutated in HBOC?

BRCA1 and BRCA2

What proportion of breast cancers in BRCA1 carriers are triple-negative?

About 70%

What is the lifetime breast cancer risk in the general population vs BRCA1/2 carriers?

General: ~13% (1 in 8). BRCA1: 55–72%. BRCA2: 45–69%

What percent of men with advanced prostate cancer carry a BRCA mutation?

~12%

On which chromosomes are BRCA1 and BRCA2 located?

BRCA1 → chromosome 17; BRCA2 → chromosome 13

What are the 3 common founder BRCA mutations?

BRCA1: 185delAG, BRCA1: 5382insC, BRCA2: 6174delT

In what population are BRCA founder mutations most common?

Ashkenazi Jewish (1 in 40)

What do BRCA1/2 normally do?

DNA repair; help RAD51 protein repair broken DNA

What happens when BRCA1/2 are mutated?

Loss of DNA repair, increasing cancer risk

What other genes are linked to hereditary breast cancer?

CHEK2, ATM, PALB2, RAD51C, BARD1

Which gene is the 3rd most common HBOC gene?

PALB2 (Partner and Localizer of BRCA2)

What is Lynch syndrome?

Hereditary colorectal cancer syndrome with early onset and other associated cancers

Which DNA repair process is defective in Lynch syndrome?

Mismatch repair (MMR)

Which MMR genes are mutated?

MLH1, MSH2, MSH6, PMS2, EPCAM

How common is Lynch syndrome?

About 1 in 300 people

What gene is mutated in MAP?

MUTYH (DNA repair enzyme)

What inheritance pattern does MAP follow?

Autosomal recessive (mutations in both copies)

What is the colorectal cancer risk for MAP patients?

Nearly 100% by age 65

How common is MAP?

1 in 20,000–40,000 in northern Europeans

What percent of colorectal cancer is due to MAP?

About 0.7%

What gene is mutated in FAP?

APC gene

How common is FAP?

1 in 6,000–30,000

What is the cancer risk for FAP patients?

100% chance of colorectal cancer

When do polyps usually appear in FAP?

Early teens

What gene is mutated in LFS?

TP53 gene

What cancers are associated with LFS?

Bone/visceral sarcomas, breast cancer, leukemias, brain tumors

What is the cancer risk by age 40 and 60?

50% by 40; up to 90% by 60

How common is LFS?

1 in 5,000–20,000 families

What gene is mutated in PTEN Hamartoma Syndrome?

PTEN gene

What are hamartomas?

Benign tumor-like growths on skin/mucous membranes

What cancers are increased in PTEN Hamartoma Syndrome?

Breast, thyroid, uterus, colon, kidney

What genes are mutated in neurofibromatosis?

NF1 or NF2 (neurofibromin)

What do NF mutations affect?

Nerve cells, causing benign tumors (neurofibromas)

What gene is mutated in VHL syndrome?

VHL gene

What is the function of VHL protein?

Binds HIF proteins to block angiogenesis

What happens when VHL is mutated?

Loss of VHL → HIF activation → angiogenesis and oncogenesis

What tumors are common in VHL syndrome?

Hemangiomas (benign vascular tumors)