Rare and Peds Cancer syndromes Flashcards
what are the details/mechanisms of proto-oncogenes with cancer? ex?
MEN
dominant (1-hit) -> growth factors, kinases, transmembrane signaling
activated -> cancer
not inherited
what are the details/mechanisms of tumor suppressors with cancer? ex?
dominant (2 hit)
represses cancer
cancer action when lose
inherited or not
warning signs with hereditary pancreatic cancer?
risk factors?
when is panc considered familial?
abdominal pain, loss of appetite, jaundice, weight loss, nausea, changes in stool, recent-onset diabetes
FHx, diet, obesity, race, smoking, gender (more men), age, diabetes, pancreatitis
two or more F/SDRs
what pancreatic syndromes are associated with adenocarcinoma?
familal pancreativ, CDKN2A, BRCA1/2, Lynch, PALB2, STK11
what pancreatic syndromes are associated with neuroendocrine?
VHL, MEN1
what do we know about pancreatic cancer screening?
some argue that there’s limited medical management use
can include endoscopic U/S or MRI, ** no screening has been shown to reduce mortality
Nevoid basal cell carcinoma syndrome is also known as:
Gorlin syndrome
what are the characteristic features of Gorlin syndrome?
BCC beginning in 3rd decade
Jaw cysts (keratocysts)
macrocephaly, frontal bossing, coarse face
calcification of the falyx by age20y (90%)
medulloblastoma in 5% of children
how do we dx people with Gorlin syndrome?
2 major and 1 minor feature OR 1 major and 3 minor features
what are the major features of Gorlin syndrome?
> 5 BCC (or 1 before 30y)
FDR with NBCCS
> 2 pits in the palms or soles
jaw keratocysts
calcium deposits in falx or brain calcium deposits in person <20y
what % of melanoma is sporadic?
90%
what are the risk factors for melanoma?
melanoma prone family
previous primary melanoma
FHx
skin type
freckling
blue eyes
red hair
blistering sunburn
multiple moles or atypical moles
what are the high penetrance genes associated with melanoma? intermediate?
H: CDK2NA, CDK4, TERET POT1
M: MC1R, MITF
what syndromes (besides familial melanoma) have melanoma?
Cowden, HBOC, and smaller risk with Lynch
what is paraganglioma (PGL)? what other cancer is it associated within a hereditary syndrome?
neuroendocrine tumor
abdomen: adrenal/extra adrenal
head and neck (glomus tumor)
Hereditary paraganglioma-pheochromocytoma
what is pheochromocytoma (PCC)?
neuroendocrine tumor
functional and secrete catecholamines
what genes are associated with PGL/PCC? what percentage of PGL/PCC are hereditary?
SDH_ genes (D,C,B,AF2)
40%
what is unique about the SDHD gene in PGL/PCC?
nonpenetrant maternal inheritance
30% of PGL/PCC
40-50% of skull base and neck PGL
15% of chest, abdomen, pelvic PGL/PCC
when should you consider SDHx genes?
primary cancer is PGL
what other red flags should direct us to PGL/PCC? what about IHC?
SDH deficient GIST (hereditary diffuse gastric cancer)
SDH deficient RCC
typical RCC red flags
all PGL/PCC should be referred no matter iHC
what are PGL/PCC testing criteria?
multiple PGL or PCC (including bilat pheo)
multifocal w/ mult synchronous or metachronous tumors
recurrent
early-onset (<45y)
what would you expect if IHC was deficient for SDH_ but no germline mutation was detected?
SDHC promoter methylation
what conditions other than PGL/PCC can have pheo?
VHL and NF1
when does someone have CMMRD? what does it mean for their parents?
two inherited mutations in a lynch syndrome gene
their parents have lynch syndrome
what features do you see in someone with CMMRD?
hematologic malignancies -> tend to be T cell instead of B cell typically
brain tumors (gliomas, medulloblastoma)
CAL spots
small # of people meet dx criteria for NF1 even if they don’t have NF1
multiple polyps at young age
how many types of MEN are there?
2
what types of cancers are associated with MEN1? gene?
MEN1 gene (chr 11)
pituitary, parathyroid, adrenal cortex, pancreatic islets
what cancers are associated with MEN2? gene? subtypes of MEN2?
thyroid (T cells), parathyroid, adrenal medulla
RET gene
2A: medullary thyroid carcinoma, pheo, hyperparathyroidism, parathyroid adenoma
2B: MTC, pheo, marfanoid habitus, no HPT, 50% de novo rate
What is unique about familial medullary thyroid carcinoma?
at least two people with MTC, no pheos or parathyroid disease, later age of onset, specific mutations in RET
how common is MTC? breakdown of syndromes? what other syndrome has thyroid cancer?
10% of all thyroid
75% of MTC is sporadic
- 20% MEN2A
- 2% MEN2B
- 2% FMTC
Cowden syndrome
What gene is associated with Li-Fraumeni syndrome?
how many individuals that meet clinical dx criteria have a detectable mutation in this gene?
TP53
70%
what differenty types of LFS are there?
classic LFS and Li Fraumeni like
to meet the classic LFS criteria someone must have all of the following:
sarcoma <45y
1stDR with any cancer <45y
1st/2ndDR with cancer <45y or sarcoma at any age
what is the de novo rate for LFS/TP53?
who should we consider testing for LFS?
how effective is sequencing?
7-20%
young women with brca <30y, TNBC
detects 95% of mutations
what are the criteria used to screen for individuals with LFS?
Chompret criteria
what gene is associated with Cowden syndrome? facial features?
PTEN (10q23)
facial trichilemmomas, acral keratoses, papillomatous papules, mucosal lesions
what are the major features associated with Cowden/ PTEN Hamartoma tumor syndrome? minor?
brca, thyroid cancer, macrocephaly, Lhermitte-Duclos disease, endo cancer
thyroid lesions, MR, GI hamartoma, fibrocystic breasts, lipomas, fibromas, GU tumors or malformations
those with Cowden/PHTS have lifetime risks for?
brca (25-50%) benign breast disease (67%) tyroid cancer (usually follicular, rarely papillary; 10%) benign thyroid lesions (75%) endometrial cancer (5-10%) uterine fibroids (common)
What syndromes/genes are a part of the DDx list if you suspect hereditary breast cancer?
HBOC (BRCA1/2) LFS (TP53) Cowden (PTEN) Hereditary diffuse gastric cancer -- lobular ( CDH1) Peutz-Jegher (STK11) CHEK2 (CHEK2) Lynch (MMR) Ataxia telangiectasia (ATM) Bloom's syndrome (BLM)
other? RAD51C/D, BRIP1
What syndromes/genes are a part of the DDx list if you see male breast cancer?
HBOC (6-10%, less with BRCA1)
Klinefelter syndrome
Cowden (PTEN - some cases)
What syndromes are a part of the DDx list if you suspect hereditary ovarian cancer?
HBOC (adenocarcinoma)
Lynch (MMR, adenocarcinoma)
PJS (STK11, sex cord tumors)
other: BRIP1, RAD51C/D
TBD -> PALB2, CHEK2, others
What syndromes/genes are a part of the DDx list if you suspect hereditary uterine/endometrial cancer?
Cowden (PTEN)
Lynch (MMR)
PJS (STK11)
TBD -> BRCA1/2?
What syndromes/genes are a part of the DDx list if you suspect hereditary colon cancer?
Lynch (MMR FAP (APC) MYH polyposis (MYH) LFS (TP53) PJS (STK11/LKB1) Juvenile Polyposis (BMPR1A, SMAD4) Birt-Hogg-Dube (FLCN, low risk)
What syndromes/genes are a part of the DDx list if you suspect hereditary gastric cancer?
Lynch (MMR) FAP (APC) LFS (TP53) PJS (STK11/LKB1) hereditary diffuse gastric cancer (CDH1) Juvenile polyposis (BMPR1A, SMAD4)
What syndromes/genes are a part of the DDx list if you suspect hereditary pancreatic cancer?
adenocarcinoma:
- familial pancreatic cancer (??? gene)
- FAMMM -> CDKN2A
- HBOC (BRCA1/2)
- PALB2 (PALB2)
- PJS (STK11)
- Lynch and FAP (MMR and APC)
Neuroendocrine:
- VHL )VHL)
- MEN1 (MEN1)
What syndromes/genes are a part of the DDx list if you suspect hereditary RENAL cancer?
VHL (VHL, clear cell) BHD -> (FLCN, oncocytic chromophobe) HPRCC (C-MET, Papillary RCC type 1) HLRCC (FH, Papillary RCC type 1) Cowden (PTEN, papillary RCC) TS (TSC1/2, angiomyolipoma/oncocytoma/RCC)
What syndromes/genes are a part of the DDx list if you suspect hereditary pheochromocytoma?
hereditary PGL/PCC (SDH genes)
VHL (VHL)
MEN2A and 2B (RET)
NF1 (NF1)
what pediatric cancers typically warrant a genetics eval?
retinoblastoma (RB1) bilateral Wilms tumor (WT1) adrenocortical carcinoma (TP53) choroid plexus tumor (TP53) rhabdomyosarcoma < 3y (TP53) osteosarcoma < 10y (TP53) medullary thyroid cancer (RET) atypical teratoid and malignant rhabdoid tumor (INI1/SNF5) hepatoblastoma (APC) PCC/PGL (VHL, NF1, RET, SDHB, SDHC, SDHD) endolymphatic sac tumors (VHL) optic pathway tumor (NF1) acoustic or vestibular schwannomas (NF2) BCC/medulloblastoma (PTCH) bilateral neuroblastoma (ALK, PHOX2B)
what are some hereditary cancer syndromes that are associated with childhood cancers?
Retinoblastoma, Wilms tumor, FAP, MEN2/S, LFS, Rhabdoid predisposition syndrome, VHL, Nevoid BCC syndrome/Gorlin syndrome, PJS, Cowden, Familial melanoma, NF1 and NF2, TSC, PGL/PCC
