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Cancer Syndromes Flashcards

1
Q

What gene is associated with ataxia-teangiectasia?

A

ATM (recessive form)

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2
Q

What’s the prevalence of AT?

A

1:40,000-1:100,000 live births

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3
Q

When does AT typically present? Life expectancy?

A

infancy to childhood

roughly 20 years

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4
Q

What’s the less severe form of AT?

A

AT Variant (later onset and slower progression)

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5
Q

What biochemical testing is done to diagnose AT? Genetic analysis?

A

ATM protein levels
AFP levels
radiosensitivity

chromosome analysis
full-gene of both alleles for ATM variants

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6
Q

What are some of the main manifestations of AT?

A

CNS manifestations (early-onset cerebellar ataxia)
telangiectasias (oculocutaneous)
immunodeficiency
25-40% lifetime risk fo malignancies (hematologic and some solid)
ectodermal, respiratory, and endocrine manifestations

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7
Q

What percent of the population have one germline ATM variant?

A

0.5-1%

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8
Q

What cancers are associated with germline variants in ATM? Risks?

A

Breast (15-40%)
Pancreatic (5-10%)
Ovarian (<3%)
some evidence for prostate, colorectal, melanoma, and gastric

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9
Q

When would you test for ATM variants?

A

FHx or personal history of ovarian, breast, and/or pancreatic cancer

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10
Q

Where is ATM mainly expressed?

A

lymph nodes, spleen, and appendix, found in many other tissues

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11
Q

What is the ATM gene involved in? product?

A

coordinating cellular signaling pathways (double-stranded DNA repair, oxidative stress, cell-cycle checkpoint)

produces a protein kinase

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12
Q

What types of variants are most common in ATM? Which one confers most breast cancer risk?

A

missense or nonsense, splicing, small deletions

c.7271T>G

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13
Q

What types of screening is performed for AT? treatment?

A

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)

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14
Q

Do those with ATM variants require risk-reducing surgery?

A

no they do not

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15
Q

What type of gene is PALB2?

A

partner and localizer with BRCA2 and aids in tumor suppression

also works with BRCA2 to repair damaged DNA

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16
Q

What happens to DNA in the absence of PALB2?

A

increased chromosomal instability (more breaks)

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17
Q

What penetrance is associated with PALB2?

A

moderate-high

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18
Q

What types of diagnostic testing can be performed for PALB2?

A

known familial mutation
full sequence analysis
del/dup analysis

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19
Q

What is the lifetime brca risk in women with a PALB2 variant? ovca? pancreatic?

A

40-60%
slightly increased ovca
5-10% pancreatic risk in M and W

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20
Q

How can we manage risk in someone with a PALB2 variant?

A

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

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21
Q

How do we treat cancer in those with PALB2 variants?

A

PARP inhibitors

surgical considerations in brca

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22
Q

Homozygous for PALB2 = ______. Leads to?

A

fanconi anemia subtype

physical differences and DD, malignancy (leukemia and lymphoma in childhood)

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23
Q

PALB2 can resemble what other genes ina. FHx?

A

BRCA1/2

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24
Q

POLD1/POLE code for: _________. Most pathogenic variants are:

A

DNA polymerases

missense and LoF

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25
Variants in POLD1/POLE impact proofreading and are associated with what types of conditions?
polymerase proofreading associated polyposis (PPAP)
26
Are there any extracolonic cancers associated with POLD1/POLE?
brain, endometrial, breast, stomach, pancreas, and skin
27
When should we test for POLD1/POLE?
if there are at least 10 adenomas in a FHx
28
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
29
What type of gene is STK11? Aka?
tumor suppressor gene LKB1
30
What syndrome is associated with STK11? prevelance? how many experience symptoms <10y?
Peutz-Jehgers syndrome 1/25,000-1/280,000 1/3
31
What are the characteristic features of PJS?
hamartomatous poylposis mucocutaneous hyperpigmentation cancer predisposition
32
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 ```
33
What types of treatments are effective in PJS?
PD-1 inhibitors (highly dependent on type of cancer)
34
Other than PJS, what can STK11 be associated with?
a biomarker for non-small cell lung cancer
35
What process is CHEK2 involved in? What type of gene?
regulates cell cycle in response to DNA damage tumor suppressor
36
What is one of the most described CHEK2 variants?
1100delC
37
What indicated testing for CHEK2?
personal hx of CHEK2-related cancer FHx of CHEK2 related cancer Family member with known CHEK2 variant
38
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
39
What syndrome can be associated with CHEK2? Inheritance? What other risks?
LFS2 (mostly TP53) | osteosarcoma, breast cancer, brain cancer, adrenal cortical tumors
40
What screening is completed for CHEK2? | What about RRM?
mammogram starting @ 40y possible breast MRI consider tomosynthesis RRM not recommended by NCCN
41
What surgical intervention is recommended for CHEK2 carriers?
bilat mastectomy rather than lumpectomy/radiation
42
What types of treatments are available to those with CHEK2 variants?
PARP inhibitors
43
What two genes are associated with Juvenile Polyposis syndrome?
SMAD4 and BMPR1A
44
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
45
What type of gene is BMPR1A? Function? How many variants have been associated with JPS?
activated SMAD proteins (signalling) >60
46
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
47
What are juvenile polyps?
hamartomatous polyps that develop from abn collection of tissue
48
How many people with JPS have a variant in SMAD4 or BMPR1A?
50-60%
49
What kind of polyp burden is associated with JPS?
some have a few while others have >100
50
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
51
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
52
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
53
What other condition may be seen with JPS?
hereditary hemorrhagic telangiectasia
54
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
55
What syndrome is associated with PTEN?
Cowden syndrome
56
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
57
What indications are seen with a PTEN variant?
``` hamartomas macrocephaly trichilemmomas papillomatous papules cancer raised skin intellectual disability (rare) ```
58
What cancers are associated with PTEN?
``` breast thyroid uterine kidney colorectal melanoma ```
59
Pathogenic findings in Cowden syndrome?
mucocutaneous lesins facial trichilemmomas acral keratoses papillomatous lesions
60
What are the major criteria for cowden syndrome?
``` breast cancer thyroid cancer uterine cancer macrocephaly Lhermitte-duclos disease (benign brain tumor) ```
61
What are the minor criteria for cowden syndrome?
structural thyroid disease ID/developmental delay GI hamartomas/benign tumors fibrocystic breast disease lipomas fibromas
62
What testing is usually completed for CS?
gene sequencing other genes: WWP1, KLLN, PI3CA, SDH(B/C/D)
63
Is reducing surgery recommended with cowden syndrome?
yes
64
What treatments are available for Cowden syndrome?
I3C supplement PARP inhibitors trials for triple negative
65
What are the cancer risks associated with a PTEN variant?
``` breast (85%) thryoid (35%) endometrial (28%) colorectal (9%) kidney (33%) melanoma (6%) ```
66
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
67
What are the most common types of pathogenic variants in TP53?
missense or small deletions in DNA-binding domain of p53 protein
68
Would you be suspicious of a germline finding if you saw a TP53 mutant in a tumor?
no, most commonly mutated gene in tumors
69
What is the tp53 founder mutation? Implications?
Southeast and Southern Brazil (c.1010G>A) similar lifetiem risk but lower penetrance at younger ages
70
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
71
Is TP53 testing warranted in individuals w/o strong FHx?
yes, 7-20% of variants are de novo
72
What lifetime brca risk is assocaited with TP53?
>60% in women
73
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
74
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
75
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
76
What can be done to prevent cancers in LFS?
regular screening bilateral RRM
77
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.

Cancer Genetics (3 decks)

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