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Block 4 - Emergency Medicine > A+P: Hereditary CA > Flashcards

A+P: Hereditary CA Flashcards

1
Q

Biggest RFs for CA

A
  • age
  • environmental exposures
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2
Q

Categories of Cancer

A
  1. Sporadic
  2. Familial
  3. Hereditary
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3
Q

Describe Sporadic CA

A
  • occur by chance or related to environmental factors
  • general population risk
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4
Q

Describe Familial CA

A
  • multiple genes & environmental factors may be involved
  • some incr CA risk
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5
Q

Describe Hereditary CA

A
  • gene mutation is inherited in family
  • significantly incr CA risk
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6
Q

Sporadic Cancer Facts

A
  • Common at older ages
  • “Common CAs”
  • only 1-2 affected in a family
  • CAs w/ a clear cause
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7
Q

What two Hereditary CA germline mutations cause CA predisposition?

A

oncogenes & tumor suppressor genes

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8
Q

Describe oncogenes.

A
  • promote cell growth & survival
    accelerator
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9
Q

Describe tumor suppressor genes

A
  • regulate cell growth, DNA repair, cell cycle
    brakes
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10
Q

What oncogenes are linked to hereditary CA syndromes?

A
  • CDK4
  • KIT
  • MET
  • RET
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11
Q

CDK4 gene incr risk of what CA?

A

cell cycle regulator malignant melanoma syndrome

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12
Q

KIT gene incr risk of what CA?

A

tyrosine kinase-familial GI stromal tumor

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13
Q

MET gene incr risk of what CA?

A

tyrosine kinase - familial papillary renal cell carcinoma

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14
Q

RET gene incr risk of what CA?

A

tyrosine kinase - multiple endocrine neoplasia

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15
Q

Which happens more somatic or germline?

A

somatic
– mechanisms activating oncogenes

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16
Q

Various functions of tumor suppressor genes?

A
  • regulation of cell cycle
  • growth inhibition through cell contact
  • repair of DNA damage/chromosome breakage
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17
Q

Tumor suppressor genes have a loss of function from one or both copies of gene?

A

BOTH

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18
Q

What is the majority cause of hereditary CA conditions?

A

tumor suppressor genes

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19
Q

Hereditary CA Factors

A
  • Young CAs
  • Rare CAs
  • Multiple CAs/tumors
  • Multiple related CAs
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20
Q

Describe Hereditary CA: Young Cancers

A
  • breast 50 or under
  • colorectal or endometrial under 50
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21
Q

Describe Hereditary CA: Rare Cancers

A
  • male breast
  • pancreatic
  • ovarian
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22
Q

Describe Hereditary CA: Multiple CAs/tumors

A
  • bilateral CAs
  • multiple primaries
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23
Q

Describe Hereditary CA: Multiple related CAs

A
  • breast, ovarian, pancreatic, prostate
  • colorectal, endometrial
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24
Q

Most hereditary CAs have what pattern of inheritance?

A

autosomal dominant & reduce penetrance

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25
List the 6 genes related to hereditary breast CA
1. HBOC - BRCA 1 & 2 2. Li - Famumeni Syndrome (TP53) 3. Cowden Synd (PTEN) 4. PALB2 5. Hereditary Diffuse Gastric CA (CDH1) 6. Peutz-Jeghers Synd (STK11)
26
High risk genes (40-60%)
- BRCA 1 & 2 - CDH1 - PALB2 - PTEN - STK11 - TP53
27
Moderate risk genes (17-40%)
- ATM - BARD1 - CHEK2 - NF1 - RAD51C/D
28
Elevated Risk Genes (<15%)
- Lynch Synd - BRIP1
29
HBOC - BRAC 1/2 gene increases breast CA risk by???
>60%
30
Management of breast cancer with BRCA genes?
- Annual breast MRI starting at **age 25-29** - mammo at age 30 RRM
31
Which BRCA gene carries a highest risk for breast, prostate, & pancreatic CAs?
BRCA 2
32
Management of male breast CA w/ BRCA genes
Annual mammo starting at age 50
33
Management of Ovarian CA in BRCA 1 gene
RRSO b/t 35 - 40yo
34
Management of Ovarian CA in BRCA 2 gene
RRSO b/t 40 - 45yo
35
Management of pancreatic CA for both BRCA genes
Screen those w/ FHx of pancreatic CA
36
Management of prostate CA for both BRCA genes
Screening starting at age 40
37
Which BRCA gene has an incr risk of melanoma?
BRCA 2
38
Management of melanoma in BRCA 2 gene
Annual full-body skin exam & minimizing UV exposure
39
PALB2 incr risk of breast CA by what %?
41 - 60%
40
Management of breast CA w/ PALB2 gene?
Annual breast MRI & mammo at **age 30** RRM
41
Li - Faumeni Syndrome (TP53) incr the risk of breast cancer by what %?
>60%
42
Managment of breast CA for Li-Fraumeni Synd
Annual breast MRI starting at **age 20-29** & mammo at **age 30**
43
Li – Fraumeni Syndrome – TP53 increases the risk of what different CAs compared to other genes
- Soft tissue sarcoma - osteosarcoma - CNS tumor - Adrenocortical carcinoma
44
Many other CAs have been assoc. w/ LFS, especially__.
melanoma, colorectal, gastric & prostate
45
Hereditary Diffuse Gastric Cancer – CDH1 incr risk for what CAs
- Lobular Breast CA - Diffuse Gastric CA
46
Hereditary Diffuse Gastric Cancer – CDH1 incr breast CA by what %?
36 - 55%
47
Management of Hereditary Diffuse Gastric Cancer – CDH1 breast CA
Annual breast MRI & mammo at **age 30**
48
Do males or females have a higher risk of gastric CA from Hereditary Diffuse Gastric CA – CDH1
Males
49
Incr risk for brain tumors cerebellar dysplastic gangliocytoma (Lhermitte-Duclos disease), may be pathognomonic, What gene is this?
Cowden Syndrome - PTEN
50
Cowden Synd (PTEN) incr risk of what CAs
- breast - thyroid - colorectal - endometrial - renal - melanoma
51
Cowden Syndrome - PTEN incr risk of breast CA by what %
40 -60%
52
Management of breast CA w/ Cowden Synd (PTEN)
Annual breast MRI & mammo starting at **age 30**
53
Management of Cowden Syndrome - PTEN thyroid CA
Annual thyroid US at **age 7**
54
Management of Cowden Syndrome - PTEN colorectal CA
Colonoscopy every 5yrs starting at **age 35**
55
Management of Cowden Syndrome - PTEN endometrial CA
- Start screening by **age 35** - Hysterectomy
56
Management of Cowden Syndrome - PTEN renal CA
- Renal US at **40**, repeated - every 1-2 yrs
57
Management of Cowden Syndrome - PTEN melanoma
annual derm exam
58
Non Cancerous Features of PTEN (5)
- Autism Spectrum d/o or developmental delay - Macrocephaly - Penile freckling (Bannayan-Riley-Ruvalcaba synd) - Derm features - Vascular features
59
Describe derm features seen w/ PTEN?
- Trichilemmomas - Papillomatous lesions - Acral keratoses - Mucosal lesions - Lipomas
60
Describe vascular features seen w/ PTEN?
- Arteriovenous malformations - hemangiomas
61
2 Diagnostic criteria for Peutz-Jeghers synd (STK11)
- 2 or more Peutz-Jeghers-type hamartomatous polyps of the GI tract - Mucocutaneous hyperpigmentation of mouth, lips, nose, eyes, genitalia, or fingers
62
Peutz-Jeghers syndrome - (STK11) NOTE
Mucocutaneous pigmentation (CAN FADE) & hyperpigmented macules
63
ATM incr risk of what CAs
- breast - contralateral breast - ovarian - pancreatic - prostate
64
BRIP1 incr the risk of what CAs
- breast - ovarian
65
RAD51/RAD51D incr risk of what CAs
- breast - contralateral breast CA (10yr cumulative risk) - ovarian
66
Familial Malignant Melanoma genes (6)
- CDKN2A - CDK4 - BRCA 2 - BAP1 - MITF - PTEN
67
Familial Malignant Melanoma Indications
- clinical & FHx - genetic counseling if 3 or more invasive cutaneous melanomas or mix of invasive melanoma, pancreatic CA &/or astrocytoma in person or family - invasive in 1st degree relative
68
Lifetime risk of developing cutaneous melanoma in women & men
- women: 1 in 34 - men--> 1 in 53
69
Genes assoc. w/ colorectal CA
- non-polyposis synd - polyposis synd
70
Criteria for the eval of lynch syndrome
- Age <50 at CRC or EC diagnosis? --> Yes - Germline MGPT eval for LS & other hereditary CA syndromes --> No - Consider germline MGPT eval for LS & other hereditary CA synd for all ppl w/ CRC or EC aged ≥50yo at dx
71
Top 3 genes linked to Lynch Synd
- **MLH1** - MSH2 - MSH6
72
Lynch Syndrome Management: Colonoscopy
every 1-2yrs starting @ **20-25yo**
73
Lynch Syndrome Management: Upper Endoscopy w/ biopsy
starting @ 30-40, repeat every 2-4 yrs
74
MLH1 (Lynch Synd) incr risk of what other CAs?
- endometrial - ovarian - brain
75
What things to consider if dx of Lynch Synd?
- Aspirin to lower colorectal CA risk - Endometrial biopsy every 1-2yrs starting @30yrs - Removal of ovaries & uterus - Annual UA @ 30-35yrs, if FHx of urothelial CA - Pancreatic imaging @ 50 (if high risk) - Annual prostate CA screening @ 40 - Skin exam every 1-2yrs - Family planning for risk of constitutional mismatch repair deficiency (CMMRD
76
6 genes assoc w/ Polyposis Synd
1. APC – Assoc. Polyposis 2. MUTYH – Assoc. Polyposis 3. Colonic Adenomatous Polyposis of Unknown Etiology 4. Peutz – Jeghers Synd 5. Juvenile Polyposis Synd 6. Serrated Polyposis Synd
77
Testing criteria for Adenomatous Polyposis
- known familial variant--> - >/= 20 cumulative adenomas--> - Multifocal/bilateral congenital hypertrophy of the retinal pigment epithelium (CHRPE)
78
Consider testing for Adenomatous Polyposis if:
- 10-19 adenomas - Desmoid tumor - Hepatoblastoma - Unilateral CHRPE - Certain variant of thyroid CA (cribriform-morular papillary)
79
Which is worse classical FAP or attenuated FAP?
classical FAP
80
What is the lifetime risk of CRC w/o tx in classical APC assoc. polyposis?
100%
81
What is the lifetime risk of CRC in attenuated APC assoc. polyposis?
- 70%
82
What is turcot synd?
the addition of CNS tumors + APC assoc. polyposis
83
Non Cancerous Features of FAP
- Congenital hypertrophy of retinal pigment epithelium (CHRPE) - Osteomas – skull, jaw - Supernumerary teeth, odontomas - Desmoids – often in abdo - Epidermoid cysts - Adrenal masses - Gastric fundic gland polyps – hamartomatous polyps
84
FAP carries a risk of what other cancers?
- SI - thyroid - pancreas - liver - CNS - stomach
85
Classical FAP Medical Management: Colonoscopy
every yr starting at 10-15* (for attenuated, late teens & every 1-2 yrs
86
Classical FAP Medical Management: Upper endoscopy
starting at age 20 - 25yo
87
Classical FAP Medical Management: thyroid US
Thyroid US every 2-5yrs starting in teens
88
Classical FAP Medical Management: Edu about S/Sx of___
- neurologic cancer, - intra-abdo desmoid tumors
89
What should be considered w/ classical FAP medial management?
- Small bowel visualization - Liver palpation, abdo US & AFP every 3-6mos 1st 5yrs of life
90
What are the other Polyposis Syndromes
- MUTYH-Assoc. Polyposis (MAP) - Juvenile Polyposis syndrome - Serrated/hyperplastic polyposis syndrome
91
Describe MUTYH-Associated Polyposis (MAP)
- Autosomal recessive inheritance - < 100 adenomas - CRC at an older age than FAP - Duodenal manifestations: cancer, adenomas
92
Describe Juvenile Polyposis synd
- polyps in colon & GI tract - BMPR1A & SMAD4* pathogenic variants - **Some ppl will have freq nosebleeds, anemia, or more bleeding than typical**
93
Describe Serrated/hyperplastic polyposis synd
- Serrated polyps in large bowel rectum - Most have no identifiable genetic cause
94
Consider surg for which gene variants?
- APC - AXIN2 - GREM1 - MSH3 (2) - MUTYH - NTHL1 (2) - POLD1 - POLE
95
Consider aspirin for which gene variants?
- EPCAM - MLH1 - MSH2 - MSH6 - PMS2
96
Consider endoscopy of rectum for which gene variants?
- APC (classic) - MUTYH
97
Recommendations w/o testing for
- Colonoscopy at **age 40** (or 10yrs before earliest dx) - Repeated every 5yrs
98
Recommendations w/o testing for
Colonoscopy at **age 45**
99
Recommendations w/o testing for FDR w/ adv adenomas or adv sessile serrated polyps
- Colonoscopy at **40** (or age of onset in relative) - Repeat every 5-10yrs
100
Reasons for genetic counseling
- Can help incr understanding by discussing poss. outcomes up front - Can help guide testing decisions - Can assist w/ insurance coverage - Can lead to changes in medical management, even w/o testing - Ethical Considerations
101
How can genetic counseling help guide testing decisions?
- Make sure right test is ordered - Make sure a pt qualifies for testing - Allows informed decision making
102
What is the cost of genetic counseling in most places?
~$250
103
List 3 Hematologic d/o
1. Chronic Myelogenous Leukemia 2. Hemoglobinopathies 3. Hemochromatosis
104
Which chromosome is assoc. w/ CML?
Philadelphia chromosome
105
Describe the Philadelphia chromosome
present in the blood cells of 90% of ppl w/ CML
106
Function of the BCR-ABL gene
tells blood cells to produce too much of a PRO called tyrosine kinase. - Tyrosine kinase promotes CA by allowing certain blood cells to grow out of control.
107
Which 2 chromosomes are assoc. w/ the Philadelphia chromosome?
chromosomes 9 & 22
108
What are the normal hgbs produced by the body?
- HgbA, HgbA2 & HgbF
109
In sickle cells, which variant causes some or all beta chains to have an abnl structure.
HBB p.Glu6Val (E6V)
110
What is the altered Hgb called associated w/ Sickle cell>
HgbS
111
How is sickle cell diagnosed?
- Hgb electrophoresis (Hgb S %) or - genetic testing (E6V)
112
1 hgbS allele (p.Glu6Val) & a 2nd pathogenic variant in the HBB gene causes...
- RBCs to distort into a sickle - AR inheritance (most homozygous) - HbAA--> Normal - HbSS--> SCA - HBSC--> sickle HgbC dz
113
Features (due to sickling of red blood cells):
- Anemia - Repeated infxs - Periodic pain episodes - Painful swelling of the hands/feet
114
Carriers--> sickle cell trait causes
- Protective against malaria (common in certain populations) - Do not see most sickling manifestations
115
Four HBA copies is causes
Standard/normal
116
3 HBA copies is causes
silent carrier
117
2 HBA copies is causes
Carrier state
118
1 HBA copies is causes
HbH Dz
119
Zero HBA copies is causes
Hb Barts Dz
120
Alpha-thalassemia: silent carrier S/Sx
Typically normal lab tests & no clinical impact
121
Alpha-thalassemia: alpha thalassemia trait
Mild anemia on lab work
122
Alpha-thalassemia: HbH Dz S/Sx
- Anemia - enlargement of liver & spleen - jaundice - specific bone changes (overgrowth of upper jaw & prominent forehead)
123
Alpha-thalassemia: Hb Bart hydrops fetalis synd/ alpha thalassemia major S/Sx
- Hydrops fetalis , severe anemia, enlarged liver/ spleen, heart defects, & GU abnl. - Can cause ppl to pass away prenatally or soon after birth
124
What does Beta Thalassemia cause
Reduces amount of hgb by impacting production of beta chains
125
Beta thalassemia inheritance pattern?
**Autosomal recessive**, pathogenic variants in HBB
126
Describe Beta thalassemia minor/trait
One working beta chain & one non-working chain
127
S/Sx of beta thalassemia minor/trait?
- no major Sxs (those AFAB may have more significant anemia when pregnant) - Lab results look like iron-deficiency anemia
128
Describe Beta thalassemia major
two non-working beta chains
129
S/Sx of beta thalassemia major
- Severe anemia in childhood Can cause - growth delay - jaundice, - enlarged liver & spleen - bone changes - recurrent infxs
130
How many types of hemochromatosis are there?
5
131
What is type 1 hemochromatosis?
the leading cause of iron overload dz
132
How is hemochromatosis commonly seen in?
northern Europeans
133
Type 2 Hemochromatosis (inheritance method & gene)
- juvenile hemochromatosis - autosomal recessive - (HAMP/HJV)
134
Type 3 Hemochromatosis (inheritance method & gene)
Autosomal recessive, (TFR2)
135
Type 4 Hemochromatosis (inheritance method & gene)
Autosomal dominant, (SLC40A1)
136
Type 5 Hemochromatosis (inheritance method & gene)
Autosomal dominant, (FTH1)
137
Hemochromatosis HFE gene controls...
hepcidin signaling
138
What is hepcidin?
a hormone that inhibits iron export from enterocytes & macrophages when iron levels are good.
139
Hemochromatosis Diagnostics
- clinical dx based on elev. serum ferritin/transferrin - elev. labs + Sx + PE or FHx--> analysis should be performed
140
S/Sx of hemochromatosis
- abdo pain - arthropathy - cardiomyopathy - cirrhosis - DM - fatigue - hepatomas - hepatomegaly - hyperpigmentation - hypogonadism - impotence - weight loss,
141
Hemochromatosis: how often do you monitor serum ferritin levels?
annually
142
Management for hemochromatosis
Phlebotomy (remove 1 unit)
143
What should be avoided if you have hemochromatosis?
- medicinal iron - mineral supplements - excess vit C - alcohol - uncooked seafood
143
How often do you get maintenance phelbotomy w/ hemochromatosis?
- every 3-4mos for men - every 6-12mos for women
144
Management of hemochromatosis for ppl w/ cirrhosis
standard screening for liver CA
145
What is hemophilia?
a bleeding d/o where blood does not clot properly
146
Severity of hemophilia depends on...?
amount of factor in the blood
147
___ the factor, the ___ the bleeding risk.
- lower - higher
148
What are the 2 types of hemophilia?
A & B
149
Hemophilia A is a deficiency in?
Factor 8 (F8 gene)
150
Hemophilia B is a deficiency in?
Factor 9 (F9 gene)
151
How is hemophilia passed?
X-linked inheritance
152
Which hemophilia is more severe?
Hemophilia B
153
Tx for hemophilia
infusion of prepared factor concentrates
154
What is the role of G6PD?
prevent cellular damage from reactive O2 species (ROS)
155
GGPD def, a defect in
enzyme causes RBCs to break down preamaturely
156
What does G6PD def show on labs?
hemolytic anemia
157
How many people are impacted by G6PD def?
400 million worldwide
158
Examples of incr ROS.
- stress - certain foods (fava beans) - certain meds (sulfa, antimalarial meds, high dose aspirin, NSAIDs, some Abx, quinidine)
159
How is G6PD gene passed?
x-linked dominant

Block 4 - Emergency Medicine (4 decks)

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