Hereditary Breast/Ovarian Cancer Syndromes - High Penetrance

Week 4

High Penetrance Breast Cancer Genes?

TP53

BRCA1

BRCA2

PALB2

PTEN

CDH1

SKT11

Moderate Penetrance Breast Cancer Genes?

ATM

CHEK2

NF1

BARD1

RAD51C

RAD51C

How much breast and ovarian cancer is hereditary?

5-10%, 10-20%

Which breast-cancer predisposing gene is most likely to be triple negative?

BRCA1

BRCA1/2 location, prevalence, primary cancer risks, recommendations?

chr 17 and 13

1/400, 1/40 in AJ because founder mutations

female breast, new primary female breast, ovarian, prostate, pancreatic, male breast, melanoma

breast screening (mammogram and breast MRI), RRM, RRSO, salpingectomy

Why no screening for ovarian cancer in BRCA?

ineffective, cannot detect until ovarian cancer is late stage

PARP? PARP Inhibitor? PARP inhibitor mechanism of action?

PARP: detects and repairs SSB

PARP Inhibitor: prevents PARP

PARP Inhibited → SSBs not repaired → DNA replicate → DSBs accumulate→ HR-deficient cell (BRCA1/2-/-) → impaired HR-mediated DNA repair → cell death

TP53 location, prevalence, syndrome, primary cancer risks, recommendations?

chr 17

1/5000-1/20,000, increased in Brazilian population because founder mutation; significant rate of de novo (7-20%)

Li Fraumeni syndrome

female breast, adenocortical carcinomas, CNS, osteosarcomas, rhabodymyomas

breast screening (mammogram and breast MRI), RRM, whole body MRI, avoid radiation

Does TP53 have an increased risk of ovarian cancer?

No

PTEN location, prevalence, syndrome, classic features, primary cancer risks, recommendations?

chr 10

1/20,000

Cowden syndrome/PTEN hamartomas tumor syndrome

hamartomas, macrocephaly

female breast, thyroid, endometrial (uterine, not ovarian), colorectal, renal, melanoma

breast screening (mammogram and breast MRI), RRM, endometrial biopsy (screening not effective), transvaginal U/S, hysterectomy

CDH1 location, prevalence, syndrome, classic features, primary cancer risks, recommendations?

chr 16

1-3% of gastric cancers

Hereditary Diffuse Gastric Cancer Syndrome

cleft palate

lobular breast, diffuse gastric

breast screening (mammogram and breast MRI), RRM, prophylactic gastrectomy

SKT11 location, prevalence, syndrome, classic features, primary cancer risks, recommendations?

chr 19

rare (1/25,000-1/280,000)

Peutz-Jehgers Syndrome

hamartomatous polyps of small intestine and stomach and other gI organs (often causing intussusception, hyperpigemented spots on mucosal surfaces (hands and feet)

female breast, colon, pancreas

breast screening (mammogram and breast MRI), colonoscopy, imaging of pancreas

PALB2 location, prevalence, primary cancer risks, recommendations?

chr 16

0.5-1% of breast cancer

female breast, ovary, pancreas

breast screening (mammogram and breast MRI), RRM, RRSO, screening of pancreas

PALB2 is considered a moderate gene. How can breast cancer risks approach levels similar to high penetrance genes?

family history impacts/modifies risk

Which genes often appear triple-negative in histology?

PALB2 and BRCA1

Which genes are PARP inhibitors beneficial for?

PALB2 and BRCA1/2

Which genes are more likely to increase risk of ductal cancer? What about lobular cancer?

BRCA1/2, TP53, PTEN, SKT11, PALB2

CDH1

Penetrance? What can it describe?

probability of a disease given presence of mutation (AKA probability of phenotype given specific genotype)

gene, mutation in a gene, or risks of developing cancer by a specific age

What influences penetrance?

age

family hx

exposures, environmental risk/protective factors

polygenic risk

epigenetics/variation in gene expression of wildtype vs mutant allele

underlying mutation rate, risk of getting second hit or loss of heterozygosity

mutation type (nonsense, missense, splice site, large deletion)

functional domain/mutation location (activating vs inactivating)

Will we ever be able to give a precise numerical estimate of risk to an individual?

No. Use average risks of individuals in penetrance studies.