Hereditary cancer syndromes Flashcards
How many ovarian cancers are attributed to genetic mutations?
30%
What chromosomes are BRCA mutations on?
BRCA1- 17q21
BRCA2- 13q12-13
What kind of gene is BRCA?
tumor suppressor gene, 80% of patients have a frameshift mutation, which causes a defect in double stranded DNA repair and E3 ubiquitination
How is BRCA inherited?
Autosomal dominant
What is the lifetime risk of HGSTOC for BRCA?
BRCA1- 25-40%
BRCA2- 18-27%
Penetrance ranges from 41-90%
What is the risk of a BRCA mutation in the ashkenazi jewish population?
1/40, compared to general population risk of (BRCA1- 1/300, BRCA2 1/800)
When is BSO recommended for BRCA patients?
BRCA1- 35-40yo
BRCA2- 40-45yo or when childbearing is complete
How many patients have fallopian tube cancer found at time of RR-BSO?
2-17%
How much is the risk reduction with rr-BSO?
> 80%, but still risk of primary peritoneal cancer due to an unrecognized STIC (2-4.3%)
How much do OCPs reduce risk of HGSTOC for BRCA patients?
60% risk reduction if taken for at least 6 years
How much is breast cancer risk reduced with BSO in BRCA patients?
BRCA1- 56%
BRCA2-46%
What is SEE-FIM pathological protocol for RR-BSO
examined at 5 micrometer sections per 2mm thick tissue block; an occult STIC may measure 1mm or less
What is the lag time from diagnosis of STIC to invasive disease?
4 years
Which genes are considered high penentrance?
BRCA1, BRCA2, CDH1, PALB2, PTEN, TP53
EOC genetic testing criteria
-Personal hx of EOC at any age
-A FamHx of EOC: only needed if first or second degree relative had EOC at any age
-Family member with a probability of >5% of a BRCA1/2pv based on probability models
Breast cancer genetic testing criteria
-Personal hx of breast cancer:
-if dx before age 46
-if dx ages 46-50 and have unknown/limited famhx or multiple prior familial breast cancers with metachronous or synchronous cancers in more than one relative with breast, ovarian, pancreatic, or prostate ca at any age
-if dx at 51 or older and one or more relatives with any breast cancer </= 50yo or male breast cancer at any age
-Dx at any age: to guide PARP or herceptin use, if triple negative, lobular breast cancer w/ personal or family hx of gastric cancer, one or more blood relatives with male breast cancer, ovarian or pancreatic cancer at any age, 3 or more total dx of breast cancer in parent or close relative, two ore more close blood relatives with breast or prostate cancer at any age
-Ashkenazi Jewish
Breast screening for BRCA patients
18yo- Breast awareness
25yo- clinical breast exam q6-12mo
25-29yo- annual MRI w/ contrast
30-75yo- annual MRI and mammogram
>75yo- individual
Ovarian/uterine screening for BRCA patients
No exam, US, or CA125 has been proven useful
BRCA1- RRSO 35-40yo
BRCA2- RRSO 40-45yo
Lynch syndrome genes
MLH1, MSH2, MSH6, PMS2 EPCAM
How many patients have MLH1 silencing
20-30% have MLH1 silenced by non-inherited methylation of the MLH1 promoter
Bethesda guidelines for lynch syndrome
-Diagnosed in patient under 50yo
-Presence of synchronous or metachronous, CRC or other lynch related tumor regardless of age
-CRC with IHC deficient MSI histology dx in a patient younger than 60yo
-CRC dx in a patient with one or more first degree relatives with a LS related cancer, with one of the cancers being dx before age 50
-CRC dx in a patient with 2 or more 1st or 2nd degree relatives with LS related cancers regardless of age
Lynch screening- MLH1, MSH2, and EPCAM
-colonoscopy btwn 20-25yo, or 2-5y prior to the earliest dx
proband, every 1-2 years
-TLH/BSO in 40s
-Annual EMB 30-35yo
-EGD with duodenoscopy q2-3y starting at 30-35y
-UA w/ cytology at 25-30yo annually
-annual CNS exam starting 25-30yo
Lynch screening- MSH6, PMS2
-colonoscopy 25-30yo or 2-5y prior to earliest proband colon cancer if dx before age 30, q 1-2y
-endometrial and ovarian cancer surveillance as other lynch mutations
ATM gene- risk of cancer
EOC: <3%
insufficient evidence for RRSO
Breast: 15-40%
PALB2 gene- risk of cancer
EOC: 3-5%
insufficient evidence for RRSO
Breast: 41-60%
RAD51C gene- risk of cancer
EOC: >10%
consider RRSO between 45-50yo
Breast: 15-40%
RAD51D gene- risk of cancer
EOC: >10%
consider RRSO between 45-50yo
Breast: 15-40%
BRIP1 gene- risk of cancer
EOC: >10%
consider RRSO between 45-50yo
Breast: >10%
MLH1/MSH2 genes- risk of cancer
EOC: >10%
consider RRSO w/ hysterectomy
Uterine: 60%
Colon: 60%
MSH6 gene- risk of cancer
EOC: <13%
Breast: <15%
PMS2 gene- risk of cancer
EOC: <3%
Breast: <15%
