Hereditary Cancer Syndromes

Question 1

CHEK2

Answer 1

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.

Question 2

Mutation associated with Cowden syndrome

Answer 2

PTEN

Question 3

Gene’s most commonly implicated in hereditary cancer syndromes

Answer 3

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),

Question 4

Term for the extension of testing in families after the identification of a pathogenic variant is

Answer 4

cascade testing

Question 5

Hereditary cancer syndrome associated with p53 mutation

Answer 5

Li Fraumeni syndrome

Question 6

Cancers associated with lynch syndrome

Answer 6

CRC, uterine, renal, pancreatic

Question 7

Management of patient with pMMR testing and high pre-test for lynch

Answer 7

Check for MSI status (MMR IHC testing has significant false negative rate of 5-10%)

Question 8

Initial testing for Lynch syndrome

Answer 8

IHC testing for protein expression of 4 MMR genes or PCR

Question 9

BRCA type associated with triple negative breast cancer

Answer 9

BRCA1

Question 10

CDH1 is associated with

Answer 10

Hereditary diffuse gastric cancer

Question 11

p53 mutation and breast cancer association

Answer 11

HER2-positive breast cancer

Question 12

Cowden syndrome pathophys

Answer 12

upregulation of MTOR pathway

Question 13

Cowden syndrome inheritance

Answer 13

Autosomal dominant

Question 14

Cowden syndrome malignancies

Answer 14

endometrial, colon, breast, follicular thyroid

Question 15

Cowden syndrome management

Answer 15

• 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

Question 16

Other clinical features of FAP syndrome

Answer 16

• papillary thyroid cancer
• CHRPE (congenital hypertrophy of the retinal pigment epithelium – dark spot in eye)
• benign bone tumors, Desmond tumors, sebaceous cysts, supernumerary teeth

Question 17

Mutation in Peutz-Jeghers syndrome

Answer 17

STK11

Question 18

Peutz-Jeghers presentation

Answer 18

• hyper pigmented macules in mouth, nose, eyes, genitalia, and fingers
• harmatomatous polyps in GI tract

Question 19

Cancers associated with Peutz-Jeghers

Answer 19

breast (most common), CRC, stomach, small bowel, pancreas

Question 20

Peutz-Jeghers inheritance

Answer 20

Autosomal dominant

Question 21

Peutz-Jeghers surveillance

Answer 21

• • 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

Question 22

most common inheritance pattern of hereditary cancer syndrome

Answer 22

autosomal dominant

Question 23

typical underlying genetic defect in hereditary cancer syndrome

Answer 23

typically it’s an inactivating mutation in a tumor suppressor gene rather than an activating mutation in an oncogene

Question 24

penetrance of hereditary cancer syndromes

Answer 24

• there’s often incomplete penetrance

Question 25

2 main hereditary colorectal cancer syndromes

Answer 25

1) lynch syndrome

2) hereditary polyposis syndrome

Question 26

categories of hereditary polyposis syndrome

Answer 26

1) Adenomatous (FAP, MUTYH polyposis syndrome)

2) hamartomatous (peutz-jeghers, juvenile polyposis, cowden syndrome)

Question 27

Lynch syndrome inheritance

Answer 27

autosomal dominant

Question 28

mechanism of lynch syndrome

Answer 28

• germline mutation in any of the 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM)

Question 29

Most common cancers in lynch

Answer 29

colon

endometrial

Question 30

other cancer types of lynch

Answer 30

ovarian
prostate
gastric
urothelial and bladder
pancreatic
sebaceous skin tumors

Question 31

When to test for lynch

Answer 31

• guidelines now recommend universal screening of ALL CRC and endometrial cancers for MMR deficiency

Question 32

how tumors are tested for lynch

Answer 32

1) MSI testing
2) IHC for MMR protein expression/deficiency
* some path labs do MSI or MMR testing or both

Question 33

what does “variant of uncertain significance mean” or VUS

Answer 33

Gene mutation that could just be benign polymorphism (mostly) or could be malignant but we don’t really know its clinical significance

Question 34

what is the proband

Answer 34

first family member with early onset cancer

Question 35

who do you typically test?

Answer 35

the proband

Question 36

Malignancies associated with VHL

Answer 36

• retinal and CNS hemangioblastomas
• clear cell kidney cancers
• pancreatic neuroendocrine tumors
• pheochromocytomas

Question 37

Birt-Hogg-Dube syndrome

Answer 37

chromophobe and oncocytoma kidney cancer + pulmonary cysts that may lead to spontaneous pneumothorax + hair follicle tumor

Question 38

Histology associated with VHL mutation

Answer 38

Clear cell

Question 39

Tuberous sclerosis syndrome clinical features

Answer 39

CNS tubers + angiomyolipomas + clear cell RCC + ASD + subpendymal giant cell astrocytoma + retinal hamartomas

Question 40

management of patients with tuberous sclerosis and RCC

Answer 40

mTOR inhibitors

Question 41

Most commonly identified gene mutation in familial forms of melanoma

Answer 41

CDKN2A

Question 42

Fanconi anemia clinical features

Answer 42

• short stature
• skeletal defects
• bone marrow failure
• early onset head and neck SCC

Question 43

How to screen for fanconi anemia AND why it’s important before treatment

Answer 43

Chromosome breakage test
- can have severe toxicities from chemotherapy and radiation

Question 44

Li Fraumeni associated malignancies

Answer 44

***Early onset tumors (before age 45)
breast cancer
Soft tissue sarcoma ->
osteosarcoma ->
CNS tumors ->
adrenocortical carcinoma ->