1
Q
____________ is on of the causes of genomic instability in cancer.
A
=anomalies in somatic recombination
-homologous recombination rarely occurs in somatic cells
2
Q
MSH2, MLH1, MSH6, and PMS2, and EPCAM are cause:
A
Lynch syndrome
3
Q
What are the 5 key things to know when evaluating a patient with a history of colon cancer?
A
- Family hx
- Polyps (how many, type, onset)
- Age of onset of colon cancer
- Microsatellite instability in tumor
- Immunohistochemistry for the 4 MMR proteins
4
Q
What does immunohistochemistry for the 4 MMR proteins tell you? What does it not tell you?
A
- Tells you which MMR protein is deficient
2. Does NOT tell you whether this is somatic vs germline loss
5
Q
State the inherited cancer syndrome:
- colorectal cancer
- endometrial
- ovarian
- stomach
- hepatobiliary
- urinary tract
- small bowel
- Brain (CNS)
- sebaceous neoplasm
- pancreas
A
Lynch syndrome
MSH2, MLH1, MSH6, and PMS2, and EPCAM
6
Q
A person presents with a history of 25 adenomas and colorectal cancer? What gene should you consider germline testing?
A
=APC
- consider testing if 20 or more adenomas
- fully penetrant phenotype
7
Q
A person has a history of 25 adenomas and colorectal cancer. There is no family hx of colon cancer. Should you still consider germline testing?
A
- Yes!
- 1/3 of APC germline mutations are de novo
8
Q
Define attenuated FAP
A
-20-99 adenomatous polyps
+ APC mutation
9
Q
Define classic FAP
A
- More than 100 adenomas (colon, also get in duodenum)
- +APC mutation
- usu + family hx
- 100% get colon cancer without colectomy
10
Q
What are the 2 major types of colon polyps?
A
- Adenomas
- think FAP if >20 - Hyperplastic
- can be divided into classic hyperplastic and sessile serrated (associated with increased risk of colon cancer)
11
Q
What hereditary cancer syndrome is caused by mutations in CDH1?
A
- hereditary diffuse gastric cancer
- Cancers:
1. hereditary diffuse gastric cancer at a young age
2. increased risk for lobular breast cancer
12
Q
What hereditary cancer syndrome is caused by mutations in STK11?
A
=Peutz-Jeghers
- key findings: mucocutaneous pigmentation, GI polyposis, increased cancer risk
- usually hyperpigmentation of oral mucosa, palms and soles first sign
- PJS type polyps (hamartomatous gastrointestinal polyps)-can be found anywhere in GI tract but esp in small bowel
- can get polyps outside GI tract
- can still get other types of polyps (adenomas)
13
Q
What types of cancer is a person with a germline STK11 mutation at risk for?
A
=Peutz Jeghers -Cancers 1. colon 2 small bowel 3. stomach 4. pancreas 5. breast 6. ovarian 7. testes 8. uterine 9. lung 10. kidney
14
Q
True or false: the only complication from Peutz-Jeghers type polyps is cancer
A
- false
- onset of polyps usually in 1st decade of life
- cancer risk from malignant transformation of polyps is unknown
- other risks are obstruction, bleeding, intussusception, ,rectal prolapse
15
Q
True or false: Juvenile Polyposis refers to histology of the polyps, not age of onset
A
=true
16
Q
What cancer syndrome is caused by mutations in SMAD4, BMPR1A?
A
=Juvenile polyposis
- Hamartomatous GI polyps
- considered in individuals with 5 or more juvenile polyps in colon or GI tract
- Usually some polyps appear in 1st or 2nd decade of life
- Increased risk for colon cancer, gastric and other GI cancer and pancreatic cancer
17
Q
True or false: most of the time no mutation is identified in familial pancreatic cancer cases.
A
=true
18
Q
Mutations in SMAD4 can cause an overlapping condition of what hereditary cancer and what other genetic disorder?
A
=Juvenile Polyposis/HHT
- often have some features of HHT
- also SMAD4 reported with increased risk for familial thoracic aneurysm so may also need to consider aorta screening
19
Q
EGFR missense mutations are important in what type of cancer? Why?
A
=lung cancer
- Specific missense mutations are associated with tyrosine kinase inhibitors
- the acquired T790M variant is associated with resistance to therapy with tyrosine kinase inhibitors
20
Q
JAK2 mutations are important for what type of cancer?
A
=associated with high risk ALL and ALL associated with Down syndrome
21
Q
ALK missense mutations and amplification are associated with what type of cancer?
A
Neuroblastoma
22
Q
Specific IDH1/2 gain of function mutations are implicated in what 3 types of cancer?
A
- brain cancer (astrocytomas and glioblastoma multiforme)
- AML
- sarcomas
23
Q
What is the molecular target for imatinib?
A
=BCR-ABL and C-kit
used for CML, GIST
24
Q
What is the molecular target for trastuzumab?
A
=ERBB2/HER2/neu
-breast cancer, gastric or GE junction cancer
25
What is the molecular target for crizotinib?
EML-ALK
| neuroblastoma and other ALK+ tumors
26
What is the molecular target for vermurabfinib?
BRAF V600E
| melanoma
27
The BRAF V600E gene is important in what type of cancer? Why?
Melanoma
| -important because there are specific inhibitors that are available to treat it.
28
What is the molecular target of erlotinib?
EGFR missense mutation
| -lung cancer
29
What is the molecular target of vandetanib?
RET missense mutation
| -medullary thyroid cancer
30
Everolimus can be used to treat malignancy associated with what germline disorder?
=Tuberous sclerosis (TSC1/TSC2)
| -used to tx subependymal giant cell astrocytoma
31
Olaparib (PARP inhibitor) can be used to treat cancer related with what germline mutation?
=BRCA1/2
| -used for ovarian cancer
32
Name 6 different mechanisms for cancer susceptibility
1. Common alleles associated with moderate cancer risk
- from GWAS studies
2. Numerical chromosome abnormalities
- autosomes AND sex chromosomes
3. Microdeletion/chromosomal rearrangements
4. Overgrowth syndromes
- includes imprinting disorders and mosaicism for somatic mutations
5. Autosomal dominant disorders
- loss of function mutations in tumor suppressor genes or less commonly activating mutations in proto-oncogenes
6. Autosomal recessive and X-linked recessive disorders
33
Name 6 syndromes associated with Wilms tumor and state the molecular basis for the risk for Wilms tumor.
1. Trisomy 18
- moecular basis: trisomy
2. WAGR
- molecular basis: microdeletion 11p13
3. MCYN-DDX1
- molecular basis: microduplication 2p24.3
4. Dennys-Drash
- molecular basis: point mutation in WT1 (autosomal dominant)
5. Perlman syndrome
- molecular basis- autosomal recessive disorder with mutations in DIS3L2
6. Beckwith-Wiedemann syndrome
- molecular basis: loss of imprinting, deletion, UPD, and mutation
34
What are the 2 mechanisms that can lead to cancer in Trisomy 21?
1. Transient myeloid proliferation
- somatic GATA1 mutations
- may or may not develop into AML
2. ALL
- JAK2 missense mutations and CRLF2 activation due to intrachromosomal deletion
35
Who is at increased risk for gonadoblastoma?
=mosaic Turner syndrome (due to presence of Y chromosome containing material)
36
Long-term survivors of trisomy 18 have an increased risk of what type of tumor?
=Wilms tumor
37
Denys-Drash syndrome is associated with a 90% risk of what type of tumor?
=Wilms tumor
| -due to missense and non-sense mutations in WT1
38
What does WAGR stand for? What is the locus?
=Wilms tumor, Aniridia, Genital abnormalities, mental Retardation
-contiguous gene deletion syndrome on 11p13
39
Which type of pediatric ALL is associated with a high degree of heritability and what is the gene implicated?
=hypodiploid ALL
| -associated with germline p53 mutations
40
Name 12 rare tumor types associated with a high degree of heritability? (> 10% inherited)
1. retinoblastoma
2. adrenocortical carcinoma
3. pheochromocytoma
4. paraganglionoma
5. retinal or cerebellar hemangioblastoma
6. anaplastic rhabdomyosarcoma
7. endolymphatic sac tumor
8. optic nerve tumor
9. medullary thyroid cancer
10. atypical teratoid/malignant rhabdoid tumor
11. acoustic or vestibular schwannomas
12. pulmonary pleuroblastoma
41
Multiple endocrine neoplasia type 2 is associated with mutations in what gene?
=RET (autosomal dominant)
| -oncogene
42
Hereditary papillary renal cell cancer is associated with mutations in what gene?
=MET (autosomal dominant)
| -oncogene
43
Name 6 autosomal dominant disorders associated with inherited mutations in oncogenes.
1. Multiple endocrine neoplasia type 2 (RET)
2. Hereditary papillary renal cell cancer (MET)
3. Costello syndrome (HRAS)
4. Cardio-facio-cutaneous syndrome (KRAS)
5. Hereditary neuroblastoma (ALK)
6. Familial lung cancer (EGFR)
44
Name the disorder that has the following features:
1. medullary thyroid carcinoma
2. pheochromocytomas
3. parathyroid disease
=multiple endocrine neoplasia type 2A
45
Name the disorder that has the following features:
1. mucosal ganglioneuromas of the GI tract, lips
2. early onset aggressive medullary thyroid carcinoma
3. pheochromocytomas
4. usually no clinically significant parathyroid disease
5. skeletal abnormalities (marfanoid habitus, kyphoscoliosis or lordosis, joint laxity)
=multiple endocrine neoplasia type 2B
- onsent usually in infancy
- ganglioneuromas of the GI tract can be confused with skeletal abnormalities
- associated with marfanoid habitus
autosomal dominant RET mutations
46
Prophylactic thyroidectomy is recommended for what t inherited cancer predisposition syndrome?
=multiple endocrine neoplasia type 2B
- high risk for aggressive form of medullary thyroid cancer
- depending on genotype of specific mutation, prophylactic thyroidectomy is recommended by different ages (with specific mutations by 1 year old)
47
What percentage of unilateral retinoblastoma are inherited? Bilateral?
Unilateral RB=15% inherited
| Bilateral RB= ~100% inherited
48
What percent of bilateral RB results from de novo mutations (with no family hx of Rb)?
=80%
49
True or false: retinoblastoma survivors have a high rate of second malignancies.
=True
- in childhood: bone and soft tissue sarcomas
- In adulthood: uterine leiomyosarcomas and lung cancer
- radiation exposure significantly increases risk of second malignancy, especially for sarcomas
50
What is the penetrance for lifetime tumor development with Li-Fraumeni syndrome?
=85%
| -15% have more than 1 cancer
51
Testing for which inherited cancer syndrome should be considered in all women with breast cancer diagnosed at 31 years or younger?
=TP53
52
What percent of families with Li-Fraumeni syndrome will have a detectable mutation in TP53? What percent have deletions?
=80% mutations detected (mostly missense)
-5-10% have deletions
53
Which of the following tumor types is not highly correlated with TP53 mutations?
1. analplastic embryonal rhabdomyosarcomas
2. hypodiploid ALL
3. Ewing sarcoma
4. choroid plexus carcinoma
5. adrenocortical carcinoma
6. breast cancer before age 31 yrs
=Ewing sarcoma
54
As part of the Toronto protocol, TP53 mutation carries should have all of the following performed q3-4 months EXCEPT:
a. abdominal ultrasound
b. brain MRI
c. AFP
d. UA
e. cbc
=brain MRI (perform annually)
abdominal ultrasound, UA to look for signs of adrenocortical carcinoma
55
When should adults with TP53 mutations start receiving breast MRI?
=18-21 yrs
56
What is the difference between schwannomatosis and NF2?
=schwannomatosis is characterized by multiple schwannomas but NO vestibular schwannomas that are characteristic of NF2
- autosomal dominant
- Due to mutations in INI1 (otherwise known as SMARCB1)
57
What is the ocular feature often associated with NF2?
=cataracts
58
Name 2 genes that cause colon cancer that cause lots of adenomatous polyps
1. APC
| 2. MUTYH (aka MYH)
Genetics
flashcards
Decks in class (16)
# Cards
-
Pediatric Syndromes29
-
Syndrome & Gene34
-
Syndromes Associated with ...11
-
Definitions51
-
Dysmorphology18
-
Anatomy and Dysmorphology Definitions12
-
Cytogenetics & Molecular Genetics102
-
Syndrome Pictures23
-
Connective Tissue Disorders11
-
Embryology30
-
Metabolism71
-
Prenatal49
-
Cancer58
-
ACMG Guidelines10
-
Physical Exam Findings4
-
General Clinical Genetics10
