Cancer syndromes

Question 1

Birt-Hogg-Dube
gene(s)
common mutations
inheritance

Answer 1

FLCN gene
half have either del or dup of 1285C
AD inheritance

Question 2

Cowden
gene(s)
inheritance

Answer 2

PTEN gene responsible for most

AD inheritance

Question 3

FAP
gene(s)
inheritance

Answer 3

APC gene

AD inheritance

Question 4

Fanconi anemia
gene(s)
inheritance

Answer 4

> 15 genes associated; this pathway repairs interstrand cross-link DNA damage
usually AR, can be XLR

Question 5

HBOC
gene(s)
inheritance

Answer 5

BRCA1 and BRCA2

AD inheritance

Question 6

Lynch syndrome
gene(s)
inheritance

Answer 6

[most to least common] MLH1, MSH2, MSH6, PMS2, EPCAM
^mismatch repair genes
this does not account for all clinically diagnosed Lynch syndrome
AD inheritance

Question 7

MAP/MUTYH
gene(s)
inheritance

Answer 7

MUTYH gene

AR inheritance

Question 8

MEN2
gene(s)
inheritance

Answer 8

RET gene

AD inheritance

Question 9

Li Fraumeni
phenotype
natural history

Answer 9

increased risk for cancers of: [in order of decreasing relative risk] bone, connective tissue, brain, pancreas, breast, colon, liver

Question 10

Li Fraumeni
gene(s)
inheritance

Answer 10

TP53 gene

AD inheritance

Question 11

Peutz-Jeghers
gene(s)
inheritance

Answer 11

STK11 gene

AD inheritance

Question 12

Retinoblastoma
gene(s)
inheritance

Answer 12

RB1 gene (accounts for 40%)
AD inheritance (w/usually full penetrance)

Question 13

Tuberous sclerosis
gene(s)
inheritance

Answer 13

TSC1 (1/3) and TSC2 (2/3) genes

AD inheritance

Question 14

Von Hippel-Lindau
gene(s)
inheritance

Answer 14

VHL gene

AD inheritance

Question 15

Birt-Hogg-Dube
phenotype
natural history

Answer 15

benign skin tumors (face, neck, upper chest)
increased chance of lung cysts and pneumothorax
first appear in 20s-30s

Question 16

Cowden
phenotype
natural history

Answer 16

breast (85% ltr), thyroid (follicular, non-medullary) (35% ltr), endometrial (28% ltr) cancers
macrocephaly (HC >97th%ile)
skin findings in early adulthood

Question 17

FAP
phenotype
natural history

Answer 17

hundreds - thousands colonic adenomatous polyps
usually appear between age 7-40y and rapidly increase in number
untreated, almost all develop colon cancer between ages 21-50y

Question 18

Fanconi anemia

carrier frequency

Answer 18

general population: 1/300

Ashkenazi Jewish: 1/90

Question 19

Fanconi anemia
phenotype
natural history

Answer 19

bone marrow failure
physical abnormalities (thumbs, forearms)
organ defects (kidney, heart)
increased risk of certain cancers (AML; genital, head, neck tumors)

Question 20

HBOC
phenotype
natural history

Answer 20

BRCA1: triple neg breast cancer, ovarian cancer, prostate cancer
BRCA2: breast, ovarian, male breast, pancreatic, prostate, stomach cancers, melanoma

Question 21

HBOC

lifetime risk of breast and ovarian cancers

Answer 21

breast: up to 65%
ovarian: up to 40%

Question 22

Lynch syndrome
phenotype
natural history

Answer 22

increased risk of colon (50-80%), endometrial (25-60%), stomach (10%), ovarian (10%) cancers; and others

Question 23

MAP/MUTYH
phenotype
natural history

Answer 23

test those with over 10 polyps who are negative for FAP

no other cancers associated

Question 24

MEN2
phenotype
natural history

Answer 24

3 subtypes, all with near 100% risk of medullary thyroid cancer, 2 have increased risk for pheochromocytoma

Question 25

Peutz-Jeghers
phenotype
natural history

Answer 25

gastrointenstinal polyposis (hamartomatous polyps), mucocutaneous pigmentation (on face, presenting in childhood), cancer predisposition

Question 26

Retinoblastoma
phenotype
natural history

Answer 26

bilateral or unilateral retinoblastoma presenting in first year of life up to 30 months of life

Question 27

Tuberous sclerosis
phenotype
natural history

Answer 27

abnormalities of skin (almost 100%), brain (seizures, ID, DD), kidney, heart, and lungs w/CNS tumors as the leading cause of morbidity and mortality

Question 28

Von Hippel-Lindau
phenotype
natural history

Answer 28

hemangioblastomas; endolymphatic sac tumors (hearing loss); renal cell carcinoma; pheochromocytomas
“hippo w/HERP”

Question 29

MSI

Answer 29

microsatellites are particularly susceptible to acquiring errors when MMR gene function is impaired so this testing helps assess likelihood of MMR mutation

Question 30

IHC for Lynch syndrome

Answer 30

detects presence/absence of proteins
dimers: 
-MSH2 w/MSH6 or MSH3
-MLH1 w/PMS2 or PMS1
note: MSH6 and PMS2 are unstable when not dimerized
so...
mutation in MSH2: loss of it and MSH6
mutation in MLH1: loss of it and PMS2

Question 31

function of mismatch repair genes (MMR)

Answer 31

correction of mismatched base pairs

loss of function mutations lead to Lynch syndrome

Question 32

function of tumor suppressor genes

Answer 32

regulate when cells divide, die

loss of function mutations lead to cancer predisposition

Question 33

function of oncogenes

Answer 33

mutated proto-oncogenes (which promote normal growth and survival of cells)
generally not inherited mutations

Question 34

Hereditary paraganglioma/pheochromocytoma syndromes

gene(s)

Answer 34

• SDHB gene: body
• SDHC gene: head
• SDHD gene: paternal mutations cause disease (maternal is inactivated/imprinted)

Question 35

Gorlin syndrome
features
gene(s)
inheritance

Answer 35

aka nevoid basal cell carcinoma syndrome (NBCCS)

• jaw keratocysts; macrocephaly, coarse facial features; skeletal anomalies
• PTCH1 gene
• AD inheritance

Question 36

Juvenile Polyposis
features
gene(s)
inheritance

Answer 36

• GI hamartomatous polyps, mostly benign (5-100 over lifetime); cancer risk up to 50%
• screen by age 15y
• BMPR1A, SMAD4 genes
• AD inheritance

Question 37

Hereditary Diffuse Gastric Cancer
features
gene(s)
inheritance

Answer 37

• high risk for cancer over lifetime; average age at onset 38y; females have 50% risk of lobular breast cancer
• CDH1 gene
• AD inheritance

Question 38

Familial atypical multiple mole melanoma
features
gene(s)
inheritance

Answer 38

• melanoma, pancreatic cancer
• CDKN2A gene
• AD inheritance