Cancer syndromes Flashcards
Birt-Hogg-Dube
gene(s)
common mutations
inheritance
FLCN gene
half have either del or dup of 1285C
AD inheritance
Cowden
gene(s)
inheritance
PTEN gene responsible for most
AD inheritance
FAP
gene(s)
inheritance
APC gene
AD inheritance
Fanconi anemia
gene(s)
inheritance
> 15 genes associated; this pathway repairs interstrand cross-link DNA damage
usually AR, can be XLR
HBOC
gene(s)
inheritance
BRCA1 and BRCA2
AD inheritance
Lynch syndrome
gene(s)
inheritance
[most to least common] MLH1, MSH2, MSH6, PMS2, EPCAM
^mismatch repair genes
this does not account for all clinically diagnosed Lynch syndrome
AD inheritance
MAP/MUTYH
gene(s)
inheritance
MUTYH gene
AR inheritance
MEN2
gene(s)
inheritance
RET gene
AD inheritance
Li Fraumeni
phenotype
natural history
increased risk for cancers of: [in order of decreasing relative risk] bone, connective tissue, brain, pancreas, breast, colon, liver
Li Fraumeni
gene(s)
inheritance
TP53 gene
AD inheritance
Peutz-Jeghers
gene(s)
inheritance
STK11 gene
AD inheritance
Retinoblastoma
gene(s)
inheritance
RB1 gene (accounts for 40%) AD inheritance (w/usually full penetrance)
Tuberous sclerosis
gene(s)
inheritance
TSC1 (1/3) and TSC2 (2/3) genes
AD inheritance
Von Hippel-Lindau
gene(s)
inheritance
VHL gene
AD inheritance
Birt-Hogg-Dube
phenotype
natural history
benign skin tumors (face, neck, upper chest)
increased chance of lung cysts and pneumothorax
first appear in 20s-30s
Cowden
phenotype
natural history
breast (85% ltr), thyroid (follicular, non-medullary) (35% ltr), endometrial (28% ltr) cancers
macrocephaly (HC >97th%ile)
skin findings in early adulthood
FAP
phenotype
natural history
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
Fanconi anemia
carrier frequency
general population: 1/300
Ashkenazi Jewish: 1/90
Fanconi anemia
phenotype
natural history
bone marrow failure
physical abnormalities (thumbs, forearms)
organ defects (kidney, heart)
increased risk of certain cancers (AML; genital, head, neck tumors)
HBOC
phenotype
natural history
BRCA1: triple neg breast cancer, ovarian cancer, prostate cancer
BRCA2: breast, ovarian, male breast, pancreatic, prostate, stomach cancers, melanoma
HBOC
lifetime risk of breast and ovarian cancers
breast: up to 65%
ovarian: up to 40%
Lynch syndrome
phenotype
natural history
increased risk of colon (50-80%), endometrial (25-60%), stomach (10%), ovarian (10%) cancers; and others
MAP/MUTYH
phenotype
natural history
test those with over 10 polyps who are negative for FAP
no other cancers associated
MEN2
phenotype
natural history
3 subtypes, all with near 100% risk of medullary thyroid cancer, 2 have increased risk for pheochromocytoma
Peutz-Jeghers
phenotype
natural history
gastrointenstinal polyposis (hamartomatous polyps), mucocutaneous pigmentation (on face, presenting in childhood), cancer predisposition
Retinoblastoma
phenotype
natural history
bilateral or unilateral retinoblastoma presenting in first year of life up to 30 months of life
Tuberous sclerosis
phenotype
natural history
abnormalities of skin (almost 100%), brain (seizures, ID, DD), kidney, heart, and lungs w/CNS tumors as the leading cause of morbidity and mortality
Von Hippel-Lindau
phenotype
natural history
hemangioblastomas; endolymphatic sac tumors (hearing loss); renal cell carcinoma; pheochromocytomas
“hippo w/HERP”
MSI
microsatellites are particularly susceptible to acquiring errors when MMR gene function is impaired so this testing helps assess likelihood of MMR mutation
IHC for Lynch syndrome
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
function of mismatch repair genes (MMR)
correction of mismatched base pairs
loss of function mutations lead to Lynch syndrome
function of tumor suppressor genes
regulate when cells divide, die
loss of function mutations lead to cancer predisposition
function of oncogenes
mutated proto-oncogenes (which promote normal growth and survival of cells)
generally not inherited mutations
Hereditary paraganglioma/pheochromocytoma syndromes
gene(s)
- SDHB gene: body
- SDHC gene: head
- SDHD gene: paternal mutations cause disease (maternal is inactivated/imprinted)
Gorlin syndrome
features
gene(s)
inheritance
aka nevoid basal cell carcinoma syndrome (NBCCS)
- jaw keratocysts; macrocephaly, coarse facial features; skeletal anomalies
- PTCH1 gene
- AD inheritance
Juvenile Polyposis
features
gene(s)
inheritance
- GI hamartomatous polyps, mostly benign (5-100 over lifetime); cancer risk up to 50%
- screen by age 15y
- BMPR1A, SMAD4 genes
- AD inheritance
Hereditary Diffuse Gastric Cancer
features
gene(s)
inheritance
- high risk for cancer over lifetime; average age at onset 38y; females have 50% risk of lobular breast cancer
- CDH1 gene
- AD inheritance
Familial atypical multiple mole melanoma
features
gene(s)
inheritance
- melanoma, pancreatic cancer
- CDKN2A gene
- AD inheritance
