Cancer Syndromes Flashcards
What gene is associated with ataxia-teangiectasia?
ATM (recessive form)
What’s the prevalence of AT?
1:40,000-1:100,000 live births
When does AT typically present? Life expectancy?
infancy to childhood
roughly 20 years
What’s the less severe form of AT?
AT Variant (later onset and slower progression)
What biochemical testing is done to diagnose AT? Genetic analysis?
ATM protein levels
AFP levels
radiosensitivity
chromosome analysis
full-gene of both alleles for ATM variants
What are some of the main manifestations of AT?
CNS manifestations (early-onset cerebellar ataxia)
telangiectasias (oculocutaneous)
immunodeficiency
25-40% lifetime risk fo malignancies (hematologic and some solid)
ectodermal, respiratory, and endocrine manifestations
What percent of the population have one germline ATM variant?
0.5-1%
What cancers are associated with germline variants in ATM? Risks?
Breast (15-40%)
Pancreatic (5-10%)
Ovarian (<3%)
some evidence for prostate, colorectal, melanoma, and gastric
When would you test for ATM variants?
FHx or personal history of ovarian, breast, and/or pancreatic cancer
Where is ATM mainly expressed?
lymph nodes, spleen, and appendix, found in many other tissues
What is the ATM gene involved in? product?
coordinating cellular signaling pathways (double-stranded DNA repair, oxidative stress, cell-cycle checkpoint)
produces a protein kinase
What types of variants are most common in ATM? Which one confers most breast cancer risk?
missense or nonsense, splicing, small deletions
c.7271T>G
What types of screening is performed for AT? treatment?
screening:
- blood testing, avoiding radiography, abdominal US in adulthood, breast MRI for females starting at age 25
treatment:
avoid radiotherapy
avoid chemotherapy and other harsh pharmaceuticals (reduced dosage)
Do those with ATM variants require risk-reducing surgery?
no they do not
What type of gene is PALB2?
partner and localizer with BRCA2 and aids in tumor suppression
also works with BRCA2 to repair damaged DNA
What happens to DNA in the absence of PALB2?
increased chromosomal instability (more breaks)
What penetrance is associated with PALB2?
moderate-high
What types of diagnostic testing can be performed for PALB2?
known familial mutation
full sequence analysis
del/dup analysis
What is the lifetime brca risk in women with a PALB2 variant? ovca? pancreatic?
40-60%
slightly increased ovca
5-10% pancreatic risk in M and W
How can we manage risk in someone with a PALB2 variant?
mamm. and MRI every 12mo starting @ 30 and/or prophylactic mastectomy
ocva: manage based on FHx, salpingo-oophorectomy after 50y
Panc: beginning at 50y (or 10y younger than age of dx) annual MRI or endoscopic US
How do we treat cancer in those with PALB2 variants?
PARP inhibitors
surgical considerations in brca
Homozygous for PALB2 = ______. Leads to?
fanconi anemia subtype
physical differences and DD, malignancy (leukemia and lymphoma in childhood)
PALB2 can resemble what other genes ina. FHx?
BRCA1/2
POLD1/POLE code for: _________. Most pathogenic variants are:
DNA polymerases
missense and LoF
Variants in POLD1/POLE impact proofreading and are associated with what types of conditions?
polymerase proofreading associated polyposis (PPAP)
Are there any extracolonic cancers associated with POLD1/POLE?
brain, endometrial, breast, stomach, pancreas, and skin
When should we test for POLD1/POLE?
if there are at least 10 adenomas in a FHx
What types of management would someone with a POLD1/POLE variant receive?
colonoscopy started btwn 14-20y and repeated as indicated by polyp burden
- 25-30y (NCCN)
Upper GI endoscopy should start btwn 25-30y
What type of gene is STK11? Aka?
tumor suppressor gene
LKB1
What syndrome is associated with STK11? prevelance? how many experience symptoms <10y?
Peutz-Jehgers syndrome
1/25,000-1/280,000
1/3
What are the characteristic features of PJS?
hamartomatous poylposis
mucocutaneous hyperpigmentation
cancer predisposition
What are the lifetime cancer risks associated with PJS?
CRC: 39-57% Brca: 45-54% Pancreatic: 11-36% Stomach: up to 29% Small bowel: up to 13% Lung: increased GYN: increased
What types of treatments are effective in PJS?
PD-1 inhibitors (highly dependent on type of cancer)
Other than PJS, what can STK11 be associated with?
a biomarker for non-small cell lung cancer
What process is CHEK2 involved in? What type of gene?
regulates cell cycle in response to DNA damage
tumor suppressor
What is one of the most described CHEK2 variants?
1100delC
What indicated testing for CHEK2?
personal hx of CHEK2-related cancer
FHx of CHEK2 related cancer
Family member with known CHEK2 variant
CHEK2 has been said to increase the risk for these cancers: ______. What determines individual cancer risk?
breast (15-40%), colorectal, prostate, thyroid, kidney (maybe)
FHx
What syndrome can be associated with CHEK2? Inheritance? What other risks?
LFS2 (mostly TP53)
osteosarcoma, breast cancer, brain cancer, adrenal cortical tumors
What screening is completed for CHEK2?
What about RRM?
mammogram starting @ 40y
possible breast MRI
consider tomosynthesis
RRM not recommended by NCCN
What surgical intervention is recommended for CHEK2 carriers?
bilat mastectomy rather than lumpectomy/radiation
What types of treatments are available to those with CHEK2 variants?
PARP inhibitors
What two genes are associated with Juvenile Polyposis syndrome?
SMAD4 and BMPR1A
What type of gene is SMAD4? Function? How many variants have been associated with JPS?
tumor suppressor and transcription factor
regulates cell cycle proliferation
at least 78
What type of gene is BMPR1A? Function? How many variants have been associated with JPS?
activated SMAD proteins (signalling)
> 60
What are the characteristics of JPS? What does it mean by juvenile?
Autosomal dominant inheritance
multiple, distinct juvenile polyps in GI tract and increased risk for CRC
polpy histology, not age of onset
What are juvenile polyps?
hamartomatous polyps that develop from abn collection of tissue
How many people with JPS have a variant in SMAD4 or BMPR1A?
50-60%
What kind of polyp burden is associated with JPS?
some have a few while others have >100
What may be suggestive of a SMAD4 pathogenic variant?
more likely to have personal or FHx of upper GI polyps
gastric phenotype tends to be more aggressive with more polyps and a higher risk for gastric cancer
How is someone clinically diagnosed with JPS?
at least 5 juvenile polyps
multiple juvenile polyps found throughout GI tract
any # of juvenile polyps in an ind with. FHx of JPS
Are there any clinical features for individuals with JPS?
anemia, rectal bleeding, prolapse of rectal polyp
> 1 juvenile polyp
at least one juvenile polyp with FHx of JPS
What other condition may be seen with JPS?
hereditary hemorrhagic telangiectasia
what are clinical features of JPS/HHT?
manifest in early childhood
epistaxis, telangiectasias, arteriovenous malformations, digital clubbing
high frequency of pulmonary AVMs, anemia, migraine, exercise intolerance
What syndrome is associated with PTEN?
Cowden syndrome
What type of gene is PTEN? Associated with? What physical changes can be seen with variants?
tumor suppressor
PTEN hamartoma syndrome, cowden syndrome, and others
large head, skin changes, abn growth/canacer
What indications are seen with a PTEN variant?
hamartomas macrocephaly trichilemmomas papillomatous papules cancer raised skin intellectual disability (rare)
What cancers are associated with PTEN?
breast thyroid uterine kidney colorectal melanoma
Pathogenic findings in Cowden syndrome?
mucocutaneous lesins
facial trichilemmomas
acral keratoses
papillomatous lesions
What are the major criteria for cowden syndrome?
breast cancer thyroid cancer uterine cancer macrocephaly Lhermitte-duclos disease (benign brain tumor)
What are the minor criteria for cowden syndrome?
structural thyroid disease
ID/developmental delay
GI hamartomas/benign tumors
fibrocystic breast disease
lipomas
fibromas
What testing is usually completed for CS?
gene sequencing
other genes: WWP1, KLLN, PI3CA, SDH(B/C/D)
Is reducing surgery recommended with cowden syndrome?
yes
What treatments are available for Cowden syndrome?
I3C supplement
PARP inhibitors trials for triple negative
What are the cancer risks associated with a PTEN variant?
breast (85%) thryoid (35%) endometrial (28%) colorectal (9%) kidney (33%) melanoma (6%)
How many individuals have a germline variant in TP53? what condition is this associated with?
1:4,500 to 1:20,000
Li-Fraumeni syndrome
What are the most common types of pathogenic variants in TP53?
missense or small deletions in DNA-binding domain of p53 protein
Would you be suspicious of a germline finding if you saw a TP53 mutant in a tumor?
no, most commonly mutated gene in tumors
What is the tp53 founder mutation? Implications?
Southeast and Southern Brazil (c.1010G>A)
similar lifetiem risk but lower penetrance at younger ages
What are some suggestive findings of LFS?
meeting classic LFS criteria or Chompret criteria
dx of ALL before 21y
somatic tumor testing: TP53 variant with AF > 50% OR absent/decrease p53 on IHC
Is TP53 testing warranted in individuals w/o strong FHx?
yes, 7-20% of variants are de novo
What lifetime brca risk is assocaited with TP53?
> 60% in women
What are the core cancers associated with LFS? There’s a high risk for:
soft tissue sarcoma, CNS tumors, adrenocortical carcinoma, and osteosarcoma
multiple primary cancers
What are three 3 clinical criteria that must be met for LFS?
proband with sarcoma dx <45y
1st degree relative w/ any cancer dx <45y
1st or 2nd-degree rlative w/ any cancer <45 OR sarcoma dx at any age
What treatment should be avoided with LFS? What’s encoruaged?
radiation
bilateral mastectomy for those that develop brca
some literature shows TP53 assocaited cancers are often hormone and Her-2 positive so they may be treated withtthings like Herceptin
What can be done to prevent cancers in LFS?
regular screening
bilateral RRM
What is chompret criteria?
- A proband with a tumor belonging to the LFS tumor spectrum (e.g., premenopausal breast cancer, soft-tissue sarcoma, osteosarcoma, central nervous system (CNS) tumor, adrenocortical carcinoma) before age 46 years AND at least one first- or second-degree relative with an LFS tumor (except breast cancer if the proband has breast cancer) before age 56 years or with multiple tumors;
- OR A proband with multiple tumors (except multiple breast tumors), two of which belong to the LFS tumor spectrum and the first of which occurred before age 46 years;
- OR A proband with adrenocortical carcinoma, choroid plexus tumor, or rhabdomyosarcoma of embryonal anaplastic subtype, irrespective of family history;
- OR A female proband with breast cancer before age 31 years.
