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Cancer Genetics > Cancer Syndromes > Flashcards

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
Q

Variants in POLD1/POLE impact proofreading and are associated with what types of conditions?

A

polymerase proofreading associated polyposis (PPAP)

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26
Q

Are there any extracolonic cancers associated with POLD1/POLE?

A

brain, endometrial, breast, stomach, pancreas, and skin

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27
Q

When should we test for POLD1/POLE?

A

if there are at least 10 adenomas in a FHx

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28
Q

What types of management would someone with a POLD1/POLE variant receive?

A

colonoscopy started btwn 14-20y and repeated as indicated by polyp burden
- 25-30y (NCCN)
Upper GI endoscopy should start btwn 25-30y

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29
Q

What type of gene is STK11? Aka?

A

tumor suppressor gene

LKB1

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30
Q

What syndrome is associated with STK11? prevelance? how many experience symptoms <10y?

A

Peutz-Jehgers syndrome

1/25,000-1/280,000

1/3

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31
Q

What are the characteristic features of PJS?

A

hamartomatous poylposis
mucocutaneous hyperpigmentation
cancer predisposition

32
Q

What are the lifetime cancer risks associated with PJS?

A 
CRC: 39-57%
Brca: 45-54%
Pancreatic: 11-36%
Stomach: up to 29%
Small bowel: up to 13%
Lung: increased
GYN: increased
33
Q

What types of treatments are effective in PJS?

A

PD-1 inhibitors (highly dependent on type of cancer)

34
Q

Other than PJS, what can STK11 be associated with?

A

a biomarker for non-small cell lung cancer

35
Q

What process is CHEK2 involved in? What type of gene?

A

regulates cell cycle in response to DNA damage

tumor suppressor

36
Q

What is one of the most described CHEK2 variants?

A

1100delC

37
Q

What indicated testing for CHEK2?

A

personal hx of CHEK2-related cancer

FHx of CHEK2 related cancer

Family member with known CHEK2 variant

38
Q

CHEK2 has been said to increase the risk for these cancers: ______. What determines individual cancer risk?

A

breast (15-40%), colorectal, prostate, thyroid, kidney (maybe)

FHx

39
Q

What syndrome can be associated with CHEK2? Inheritance? What other risks?

A

LFS2 (mostly TP53)

osteosarcoma, breast cancer, brain cancer, adrenal cortical tumors

40
Q

What screening is completed for CHEK2?

What about RRM?

A

mammogram starting @ 40y
possible breast MRI
consider tomosynthesis
RRM not recommended by NCCN

41
Q

What surgical intervention is recommended for CHEK2 carriers?

A

bilat mastectomy rather than lumpectomy/radiation

42
Q

What types of treatments are available to those with CHEK2 variants?

A

PARP inhibitors

43
Q

What two genes are associated with Juvenile Polyposis syndrome?

A

SMAD4 and BMPR1A

44
Q

What type of gene is SMAD4? Function? How many variants have been associated with JPS?

A

tumor suppressor and transcription factor

regulates cell cycle proliferation

at least 78

45
Q

What type of gene is BMPR1A? Function? How many variants have been associated with JPS?

A

activated SMAD proteins (signalling)

> 60

46
Q

What are the characteristics of JPS? What does it mean by juvenile?

A

Autosomal dominant inheritance

multiple, distinct juvenile polyps in GI tract and increased risk for CRC

polpy histology, not age of onset

47
Q

What are juvenile polyps?

A

hamartomatous polyps that develop from abn collection of tissue

48
Q

How many people with JPS have a variant in SMAD4 or BMPR1A?

A

50-60%

49
Q

What kind of polyp burden is associated with JPS?

A

some have a few while others have >100

50
Q

What may be suggestive of a SMAD4 pathogenic variant?

A

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
Q

How is someone clinically diagnosed with JPS?

A

at least 5 juvenile polyps

multiple juvenile polyps found throughout GI tract

any # of juvenile polyps in an ind with. FHx of JPS

52
Q

Are there any clinical features for individuals with JPS?

A

anemia, rectal bleeding, prolapse of rectal polyp

> 1 juvenile polyp
at least one juvenile polyp with FHx of JPS

53
Q

What other condition may be seen with JPS?

A

hereditary hemorrhagic telangiectasia

54
Q

what are clinical features of JPS/HHT?

A

manifest in early childhood

epistaxis, telangiectasias, arteriovenous malformations, digital clubbing

high frequency of pulmonary AVMs, anemia, migraine, exercise intolerance

55
Q

What syndrome is associated with PTEN?

A

Cowden syndrome

56
Q

What type of gene is PTEN? Associated with? What physical changes can be seen with variants?

A

tumor suppressor

PTEN hamartoma syndrome, cowden syndrome, and others

large head, skin changes, abn growth/canacer

57
Q

What indications are seen with a PTEN variant?

A 
hamartomas
macrocephaly
trichilemmomas
papillomatous papules
cancer
raised skin
intellectual disability (rare)
58
Q

What cancers are associated with PTEN?

A 
breast
thyroid
uterine
kidney
colorectal
melanoma
59
Q

Pathogenic findings in Cowden syndrome?

A

mucocutaneous lesins

facial trichilemmomas

acral keratoses

papillomatous lesions

60
Q

What are the major criteria for cowden syndrome?

A 
breast cancer
thyroid cancer
uterine cancer
macrocephaly
Lhermitte-duclos disease (benign brain tumor)
61
Q

What are the minor criteria for cowden syndrome?

A

structural thyroid disease

ID/developmental delay

GI hamartomas/benign tumors

fibrocystic breast disease

lipomas

fibromas

62
Q

What testing is usually completed for CS?

A

gene sequencing

other genes: WWP1, KLLN, PI3CA, SDH(B/C/D)

63
Q

Is reducing surgery recommended with cowden syndrome?

A

yes

64
Q

What treatments are available for Cowden syndrome?

A

I3C supplement

PARP inhibitors trials for triple negative

65
Q

What are the cancer risks associated with a PTEN variant?

A 
breast (85%)
thryoid (35%)
endometrial (28%)
colorectal (9%)
kidney (33%)
melanoma (6%)
66
Q

How many individuals have a germline variant in TP53? what condition is this associated with?

A

1:4,500 to 1:20,000

Li-Fraumeni syndrome

67
Q

What are the most common types of pathogenic variants in TP53?

A

missense or small deletions in DNA-binding domain of p53 protein

68
Q

Would you be suspicious of a germline finding if you saw a TP53 mutant in a tumor?

A

no, most commonly mutated gene in tumors

69
Q

What is the tp53 founder mutation? Implications?

A

Southeast and Southern Brazil (c.1010G>A)

similar lifetiem risk but lower penetrance at younger ages

70
Q

What are some suggestive findings of LFS?

A

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
Q

Is TP53 testing warranted in individuals w/o strong FHx?

A

yes, 7-20% of variants are de novo

72
Q

What lifetime brca risk is assocaited with TP53?

A

> 60% in women

73
Q

What are the core cancers associated with LFS? There’s a high risk for:

A

soft tissue sarcoma, CNS tumors, adrenocortical carcinoma, and osteosarcoma

multiple primary cancers

74
Q

What are three 3 clinical criteria that must be met for LFS?

A

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
Q

What treatment should be avoided with LFS? What’s encoruaged?

A

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
Q

What can be done to prevent cancers in LFS?

A

regular screening

bilateral RRM

77
Q

What is chompret criteria?

A
  • 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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