family cancer syndromes Flashcards
Retinoblastoma
• Heritable
(autosomal dominant)
and Sporadic forms
• Heritable form often
bilateral & earlier onset
• Sporadic form always
unilateral
• Studied by Knudson as
a model for genetic basis
of cancer
• “Whiteness” in pupil
(loss of “red reflex”)
genetic mechanism for retinoblastoma
gene testing for retinoblastoma
• Rb mutation analysis (blood sample from
affected family member)
• Mutation test for new born babies (and for
untested children and unaffected adults)
• Surveillance of gene carrier
babies/children (EUA)
• Pre-natal and pre-implantation diagnosis
familial colorectal cancer
familial adenomatous polyposis
FAP - autosomal dominant
• Germline APC mutations (tumour suppressor)
• Prevalence 1 : 8500
• Fully penetrant
• 100’s-1000’s adenomatous polyps in large
bowel, usually develop in ‘teens
• CRCa average age 39 yr (20-70)
• Duodenal polyps/cancer, desmoid tumours,
osteomas, sebaceous cysts, dental & retinal
anomalies
FAP clinical genetic management?
• Regional (National) registers, family-based
• Confirm pathology in proband
• Confirm mutation in APC
• Predictive genetic testing from secondary
school age
• Annual surveillance (colonoscopy)
• Planned surgery (colectomy)
• Ongoing surveillance of pouch / rectum
• Upper GI surveillance
MUTYH-Associated polyposis (MAP)
- Autosomal recessive, FAP-like disorder
- Inherited mutations in MUTYH cause deficient Base Excision Repair of DNA
- Somatic APC (and other) mutations accumulate rapidly in colonic cells
- Clinical genetic management – same principles as for FAP – BUT SIBLINGS !
lynch syndrome?
• AKA Hereditary Non-Polyposis Colorectal
Cancer, HNPCC
can occur in the endometrium and colon (most common)
uncommon sites - stomach, biliary tract, urinary tract, ovarian
• Mutation in DNA mismatch repair genes
(tumour suppressor mechanism)
• Tumours show MSI (microsatellite instability)
and accelerated growth
• Test for germline MMR gene (MLH1, MSH2,
MSH6, PMS2) mutations
• Mutation carriers: colonoscopy every 1-2 years
from 25 years
• Screening for other cancers unproven
asprin can protect against it
hereditory breast and ovarian cancer
• Due to mutations in BRCA1 & BRCA2 and
rarely other genes
• BRCA1 & BRCA2 involved in DNA repair,
recombination & cell cycle control
• Autosomal dominant inheritance
• In some families only breast OR ovarian
cancer may be present
featyurwes suggesting familial germline brca mutation
• Multiple cases of early onset breast cancer
• Multiple cases of breast and / or ovarian
cancer
• Breast and ovarian cancer in same woman
• Bilateral breast cancer
• Breast cancer & Ashkenazi Jewish heritage
• Male breast cancer (BRCA2)
brca1 risks
Breast cancer 50%85% (often early age at onset)
Second primary breast cancer 40%60%
Ovarian cancer 15%45%
brca2 risk
Breast cancer
(50%85%)
Ovarian cancer
(10%20%)
Male breast cancer
(6%)
Increased risk of prostate,
laryngeal, and pancreatic cancers
brca1 and 2 in jews
An estimated 1 in 40 Ashkenazi Jews
carries a BRCA1 or BRCA2 mutation
however non jew BRCA1 carriers and sufferes have more change of deleveping the cancers
brca1 testing?
• In NHS:
Those at 10% lifetime risk by family history
(computer programmes calculate risk)
NICE (2013)
• In USA:
A free for all
Commercial companies offer testing
option for gene carriers once identified?
Do Nothing
Screening
Annual BREAST MRI from 20 - 49 years
Annual mammograms from 50 - 69 years
Chemoprevention
Tamoxifen or raloxifene for 5 years in
women 30 - 49 years
Risk Reducing Surgery
Mastectomy / oophorectomy
