Hereditary Cancer Syndromes Flashcards
CHEK2
Considered a moderate-risk mutation, it may double or triple the carrier’s lifetime risk of breast cancer, and also increase the risk of colon cancer and prostate cancer.
Mutation associated with Cowden syndrome
PTEN
Gene’s most commonly implicated in hereditary cancer syndromes
BRCA1/2, cadherin 1 (CDH1), partner and localizer of BRCA2 (PALB2), phosphatase and tensin homolog (PTEN), and tumor protein p53 (TP53) [17]. We also include other genes such as ataxia-telangiectasia mutated (ATM), checkpoint kinase 2 (CHEK2),
Term for the extension of testing in families after the identification of a pathogenic variant is
cascade testing
Hereditary cancer syndrome associated with p53 mutation
Li Fraumeni syndrome
Cancers associated with lynch syndrome
CRC, uterine, renal, pancreatic
Management of patient with pMMR testing and high pre-test for lynch
Check for MSI status (MMR IHC testing has significant false negative rate of 5-10%)
Initial testing for Lynch syndrome
IHC testing for protein expression of 4 MMR genes or PCR
BRCA type associated with triple negative breast cancer
BRCA1
CDH1 is associated with
Hereditary diffuse gastric cancer
p53 mutation and breast cancer association
HER2-positive breast cancer
Cowden syndrome pathophys
upregulation of MTOR pathway
Cowden syndrome inheritance
Autosomal dominant
Cowden syndrome malignancies
endometrial, colon, breast, follicular thyroid
Cowden syndrome management
- mammography by age 30 or 5 years before earliest diagnosed BC in family
- annual thyroid US
- C-scope by age 35
- NO endometrial cancer screening
Other clinical features of FAP syndrome
- papillary thyroid cancer
- CHRPE (congenital hypertrophy of the retinal pigment epithelium – dark spot in eye)
- benign bone tumors, Desmond tumors, sebaceous cysts, supernumerary teeth
Mutation in Peutz-Jeghers syndrome
STK11
Peutz-Jeghers presentation
- hyper pigmented macules in mouth, nose, eyes, genitalia, and fingers
- harmatomatous polyps in GI tract
Cancers associated with Peutz-Jeghers
breast (most common), CRC, stomach, small bowel, pancreas
Peutz-Jeghers inheritance
Autosomal dominant
Peutz-Jeghers surveillance
- annual mammogram starting around age 25
- C-scope and EGD q2 years
- small bowel examination starting at age 8
- MRCP q1 year around 30
- pap smears, testicular exams
most common inheritance pattern of hereditary cancer syndrome
autosomal dominant
typical underlying genetic defect in hereditary cancer syndrome
typically it’s an inactivating mutation in a tumor suppressor gene rather than an activating mutation in an oncogene
penetrance of hereditary cancer syndromes
- there’s often incomplete penetrance
2 main hereditary colorectal cancer syndromes
1) lynch syndrome
2) hereditary polyposis syndrome
categories of hereditary polyposis syndrome
1) Adenomatous (FAP, MUTYH polyposis syndrome)
2) hamartomatous (peutz-jeghers, juvenile polyposis, cowden syndrome)
Lynch syndrome inheritance
autosomal dominant
mechanism of lynch syndrome
- germline mutation in any of the 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)
Most common cancers in lynch
colon
endometrial
other cancer types of lynch
ovarian prostate gastric urothelial and bladder pancreatic sebaceous skin tumors
When to test for lynch
- guidelines now recommend universal screening of ALL CRC and endometrial cancers for MMR deficiency
how tumors are tested for lynch
1) MSI testing
2) IHC for MMR protein expression/deficiency
* some path labs do MSI or MMR testing or both
what does “variant of uncertain significance mean” or VUS
Gene mutation that could just be benign polymorphism (mostly) or could be malignant but we don’t really know its clinical significance
what is the proband
first family member with early onset cancer
who do you typically test?
the proband
Malignancies associated with VHL
- retinal and CNS hemangioblastomas
- clear cell kidney cancers
- pancreatic neuroendocrine tumors
- pheochromocytomas
Birt-Hogg-Dube syndrome
chromophobe and oncocytoma kidney cancer + pulmonary cysts that may lead to spontaneous pneumothorax + hair follicle tumor
Histology associated with VHL mutation
Clear cell
Tuberous sclerosis syndrome clinical features
CNS tubers + angiomyolipomas + clear cell RCC + ASD + subpendymal giant cell astrocytoma + retinal hamartomas
management of patients with tuberous sclerosis and RCC
mTOR inhibitors
Most commonly identified gene mutation in familial forms of melanoma
CDKN2A
Fanconi anemia clinical features
- short stature
- skeletal defects
- bone marrow failure
- early onset head and neck SCC
How to screen for fanconi anemia AND why it’s important before treatment
Chromosome breakage test
- can have severe toxicities from chemotherapy and radiation
Li Fraumeni associated malignancies
***Early onset tumors (before age 45)
breast cancer
Soft tissue sarcoma ->
osteosarcoma ->
CNS tumors ->
adrenocortical carcinoma ->
