Inherited Cancer Flashcards
(37 cards)
BRCA1/2
BRCA1: higher risk of breast & ovarian ca
BRCA2: higher risk of male breast ca, prostate, pancreas
AJ founder variants in BRCA1 (c185delAG and c.5382insC) and BRCA2 (c.6174delT) are responsible for >50% of BRCA in the population
Surveillance: breast MRI (25-29y); MRI+mammogram (30-75)
tx: PARP inhibs (olaparib); mastecomy/oophorectomy 35-45
risk prediction: Gail model (not for high risk)
Familial Adenomatous Polyposis:
AD, APC
100’s of colon polyps, jaw osetoma, abdominal desmoid tumors, hepatoblastoma, upper gastric
100% lifetime cancer risk
Attenuated FAP: fewer polyps, more proximal; but lifetime risk of CRC is still 70%
Gardner syndrome: colonic polyposis + osteomas & soft tissue tumors
Turcot syndrome: colon ca + CNS tumors
tx; colectomy (early 20’s_
surveillance: colonoscopy @ 10-15y (every 1-2y after) + annual thyroid exam
Lynch Syndrome
: AD, MLH1, MSH2, MSH6, PMS2
most common hereditary colon ca. syndrome; not alot of polyps here
colon cancer>endometrial>prostate>ovarian>stomach, urinary, small bowel, CNS
80% lifetime cancer risk
surveillance: MSI of tumor tissue (high MSI + High burden= better response to immunotherapy) or MMR protein IHC
MSI-H=>2 unstable markers
colonoscopies starting at 20y or 2-5y before earliest diagnosis in family
tx: full colectomy if CRC present, prophylactic hysterectomy/salpingoectomy if childbearing complete
tx: immune checkpoint inhib if MSI present
Biallelic variants: very early onset of cancer (PMS2 most common)
Li-Fraumini:
AD, TP53
70-90% lifetime cancer risk
Multipel tumor types in same pedigree
sarcoma, rhabdomyosarcoma, breast, CNS, adrenocortical, Wilms tumors
also inc. risk for liquid tumors; GI cancer, head/neck
avoid radiotherpay & ionizing radiation
low-hypodiploid ALL need to screen for TP53
surveillance “Torotono protocol”: start in infancy (annual brain MRI, whole body MRI, breast MRI, colonoscopy)
dx: LFS tumor < 45y AND 1st or 2nd deg. relative w/ LFS <56 OR >2 LFS tumors starting <46 (not a genetic diagnosis, its based on fhx)
Multiple endocrine neoplasia type 1:
AD, MEN1
90% cancer risk by 45y
Parathyroid, pancreas, pituitary (PaPaPi) cancers
hyperparathyroidism, facial angiofibromas, CALMs, Lipomas
LOF (tumor suppressor)
Multiple endocrine neoplasia type 2:
AD, RET
MEN2A: Parathyroid, medullary throid, pheochromocytoma (PaMePhe)
MEN2B: mucosal neuromas on lips/tongue, marfanoid habitus, medullary thyroid carcinoma, pheochromocytoma
Tx: 2A thyroidectomy <5y; 2b thyroidectomy <1y
clinical tests: inc. calcitonin, inc catecholamines (2b only)
allelic to hirschsprung dx
Neurofibromatosis type 2
: AD NF2
think brain tumors in young adults w/o skin findings
vestibular schwannoma, benign nerve tumors (cranial/peripheral schwannomas, meningiomas, ependyomas); death by 36y
HL, cataracts, balance problems, CALMs
in kids: skin tumors, retinal hamartoma, thick optic nerve, cranial nerve palsy, mononeuropathy (hand/foot drop)
txL bevacizumab (chemo)
PTEN Hamartoma syndrome:
Cowden: onset 2nd-3rd decade, mucocutaneous facial and oral papules, macrocephaly, goiter, doliocephaly, lipomas
Cancer risk: breast>thyroid>renal>endometrial (85% lifetime BC risk)
Bannayan-Riley-Ruvalcaba: macrocephaly, polyposis, lipomas, pigmented macule of glans penis
Proteus (somatic): disproportionate overgrowth, dysregulated adipose tissue, vascular malformation
ovarian ca risk in 2nd decade
Lhermitte-Duclos disease: cerebellar dysplastic gangliocytoma
surveillance: annual derm, brast MRI at age 30, annual thryoid at 18y, annual endometrial biopsy 35y
Tuberous Sclerosis complex:
AD, TSC1/2
Skin: facial angiofibroma, hypopigmented macules, shagreen patches, ungual fibromas (red papules around nails)
CNS: cortical tubers, giant cell astrocytoma, seizures
Cardio: rhabdomyomas (regress in infancy w/o intervention)
Eye: hamartomas
Renal: angiomyolipomas (not cancerous, but can cause internal bleeding)
Contiguous gene del syndrome w/ PCKD= TSC + polycystic kidney disease
tx: mTOR inhib, everolimus, sirolimus
Von Hippel Lindau syndrome
AD, VHL
Renal CCC, hemangioblastoma, pheochromocytoma
reduced ca. risk w/ full gene del
surveillance: start evals at age 1
16y, start abdominal US + MRI, brain & spine MRI every 2y
missense vars are common
Hereditary leiomyomatosis & RCC
: AD FH gene
Birt-hogg-dube syndrome:
AD FLCN
RCC
Peutz-Jeghers:
AD STK11
Hamartomatous polyps, mucucutaneous pigmentation (lips)
CRC=Breast>pancreas>stomach
acute intussusception (intestines sliding)
Heriditary diffuse gastric cancer;
AD CDH1
gastric, breast
tx: total gastrectomy
Familial Pancreatic Cancer
BRCA1/2, PALB2, CDKN2A, STK11, APC, Lynch genes, TP53
Gorlin syndrome:
AD PTCH1
Multiple Basal cell carcinoma, medulloblastoma, jaw odontogenic kerato cysts, palmar pits, bifid ribs, calicification of falx cerebri
Schwannomatosis
NF2-Schwannomas (bilateral, 8th cranial nerve), balance and hearing issues
SMARCB1-Hypomorph a/w schwannomas, LOF=rhabdoid tumors
LZTR1
Rhabdoid tumor predisopositon
SMARCB1 (LOF only)
poor prognosis, brain tumors <3y; consider in any patient w/ multiple primary tumors
Retinoblastoma
RB1
“Tumors very young, ~15-24months. Look for white pupils, strabismus, reduced vision
bilateral RB=100% heritable
90% penetrant”
Juvenile Polyposis
BMPR1A
SMAD4
“juvenile refers to histology, not age of proband;
dx: colonoscopy @ 15y
tx: colectomy not recommended”
GREM1 polyposis
Pheochromocytoma
Paraganglioma
SDHx
VHL
RET (oncogene
FH
MAX rare, on ACMG)
TMEM2178 (rare, on ACMG)
“Sympathetic para- catecholamine excess; parasymp- non secretory
pheo- catecholamine excess;
SDHB=bad; A low maligancy, D low malignancy, usually paternal”
Mut GIST (90% of cases)
KIT
PDGFRA
GIST, skin hyperpigmentation, melanoma, (LOF= piebaldism)
treat w/ imantinib
WT GIST (No kit/pdgfra) (10% of GIST)
SHDx-“Carney stratakis (GIST & para)- SDHx germline
Carney triad (GIST, para, pulmonary chonrdromas)-SDHC hypermeth”
SDH competent-NF1, BRAF, RAS
