Angela's Genetics Flashcards
What is the most common cause of a germline mutation?
Loss of heterozygosity
AW: LOH is most freq genetic alteration in human cancer.
born with one hit=heterozygous state, mitotic recomb event leads to crossover and get two of same gene locus (either 2 MT or 2 WT) in daughter cells or gene conversion of one copy so they are now identical=heterozygosity lost
What are common hereditary tumor suppressor proteins in endometrial cancer?
LYNCH
MLH1 (3p22)
MSH2 (2p21)
MSH6 (2p16)
PMS2 (7p22)
EPCAM (2p21)
COWDEN
PTEN (10q23)
(Updated from Chi table)
What are common sporadic tumor suppressor proteins in endometrial cancer?
PTEN (10q23), p53 (17p13)
AW: also ARID1A (1p36), FBXW7/CDC4 (4q31)
What is the translocation in Burkitts?
Which protein is overexpressed?
[t(8;14)]
myc protein
ovarian involvement common
translocation involve MYC gene on chr 8 and (Ig) heavy or light chain genes on chr 14, 22, or 2. Most common translocation (75%) is t(8;14)(q24;q32): MYC gene is juxtaposed to the immunoglobulin heavy chain (IgH) gene on chr 14
What is the translocation in CML?
Which protein is overexpressed?
[t(9;22)]
Abl ? BCR::ABL1 fusion protein (AW)
Philadelphia chromosome is a reciprocal translocation involving chromosomes 9 and 22 that is commonly identified in chronic myelogenous leukemia (CML). The break points of the translocation create a fusion of two genes: ABL1 on chromosome 9 and BCR on chromosome 22.
ABL1 kinase activity of BCR::ABL1 is elevated and constitutive due to fusion with a portion of BCR
Tx= Imatinib
Where is Rb gene located?
13q14
What is the chromosomal abnormality associated with etoposide-induced AML?
Rearrangements at 11q23
What are tumor suppressor genes?
Genes that normally inhibit cell proliferation
LOH of a tumor suppressor gene can act as a “second hit” that leads to the loss of the remaining functional allele.
What are common hereditary tumor suppressor proteins affected in ovarian cancer?
BRCA1 / 2, MSH2 (mutS homologue 2)
-All Lynch syndrome genes (higher risk w/MLH1 and MSH2 vs MSH6 and PMS2)
What are common sporadic tumor suppressor proteins affected in ovarian cancer?
p53 (encoded by TP53 on 17p13), p16 (encoded by CDKN2A on 9p21)
CDKN2A with homolozygous deletion in 15% of ovary ca.
What is the most common epigenetic step responsible for deactivating the second tumor-suppressor gene in the process of carcinogenesis?
Hypermethylation of CpG islands in the promoter region
Hypermethylation silences the promoter thus inhibiting transcription of the protein
What epigenetic step is critical to deactivating many tumor-suppressor genes?
Methylation of CpG islands in promoter regions
Which of the following are not associated with hereditary cancer susceptibility?
A) RB
B) P53
C) MSH
D) BRCA 1
E) Her 2 neu
E) Her 2 neu
What does the HPV protein E6 bind to?
P53
What is the most commonly inactivated gene described for human cancers?
P53
What is the gene locus of p53?
17p13
maybe remember: p53 (5x3 = 15) –> 17p13 –> 17 (15) 13
What is the most common mutation found in p53?
Single nucleotide missense mutation in the middle third (exons 5-8) of the gene affecting DNA binding domain.
If still have WT p53, the MT protein will bind it and leads to inactivation of any remaining normal P53 in the nucleus. acts in “dominant negative” fashion
OR
Mutation of one copy of the gene can be accompanied by deletion of the other copy of the gene leading the cancer cell with only mutant P53 protein.
What is the function of p53?
“Guardian of the genome”
It activates genes involved in DNA damage repair pathways at G1-S and G2-M checkpoints to prevent replication and mitosis in damaged cells by inducing apoptosis
activate proteins for cell cycle arrest (ex: p21)
activates proteins for DNA repair
induce apoptosis if damage not repaired
Where is p53 located in the cell?
Intranuclear
How does p53 stall the cell cycle?
Cellular damage –> induces p53 –> induces CIP/WAF/p21
–>p21 prevents CDK4/2 phosphorylation –> in G1 prevents Rb phosphorylation = no release of E2F –> can’t progress to S from G1/stops cell cycle –> eventually leading to apoptosis
also controls G2/M checkpt: ? via upregulation of cyclin B1
What occurs with a mutation in P53?
Mutated p53 protein accumulates in nucleus and cannot bind to DNA, interfering with wild type p53 function
“dominant negative” function
What is the most common mutation in UPSC?
p53
What is the gene defect in LiFraumeni?
p53
LiFraumeni is associated with increased risk of what cancers?
Sarcoma, breast, brain, leukemia, adrenal cortical
*important for us to know sarcoma, breast
LiFraumeni is also known as SBLA Syndrome (Sarcoma, Brain, Breast, Leukemia, Adrenal cortical)
Mnemonic: Could think of BLABS: breast, leukemia, adrenal cortical, brain, sarcoma
JS: Think of a big german woman (frau) in a sarcoma skirt and she has big brain, big boobs, big boned. Spots on her skin from working on the farm,
Aw: they had melanoma, GI= v. rare
Which diagnostic criteria must be fulfilled for Li Fraumeni?
- Proband (first affected individual) w/Sarcoma < 45yo AND
- First-degree relative with any cancer <45 AND
- Another 1 or 2 degree relative with any young cancer or any sarcoma
(JS: these are indications for when to test for Li Fraumeni)
What is the location of PTEN?
10q23
(TEN=10, 23=q if you make 2 of the curved part of q then you get a 3 )
Is PTEN a Tumor suppressor or Oncogene?
Tumor suppressor
Tumor suppressors: TGF-B, PTEN, Rb, p53, MMR, BRCA, ARID1A, p16
What does PTEN encode?
- A tyrosine phosphatase that inhibits downstream activation of FAK, ERK, MAPK
- dephosphorylates PIP3 producing PIP2, negatively regulatingthe PI3K pathway (JS)
ERKs (extracellular-signal-regulated kinases)
focal adhesion kinase (FAK)
mitogen-activated protein kinase (MAPK)
When PTEN is mutated and nonfunctional, which pathway is allowed to proceed?
PI3K/AKT pathway
What is the most common mutation in endometrial cancer?
PTEN
Incidence 30-80%
Which ovarian cancer histology exhibits higher levels of PTEN mutation?
Endometrioid OVCA
What mutations is associated with Cowden’s Syndrome?
PTEN
What cancers are associated with Cowden’s Syndrome?
Breast, endometrial, thyroid, and hamartomas
Mnemonic: “Pettin’ my cow Beth”
PTN - COWden - Breast/Endometrial/Thyroid/Hamartoma
How is Cowden’s inherited?
Autosomal dominant
What is Bannayan/Zonana?
Similar to Cowden’s
Caused by PTEN mutation
Bannayan-Zonana syndrome is a rare hamartomatous disorder, characterized by macrocephaly, multiple lipomas, and hemangiomas. Inheritance is by autosomal dominant transmission with few reported sporadic cases. Male predominance is also reported.
What are the roles of BAD BAX and BID?
All pro-apoptosis.
Proteins of the Bcl-2 family
What does downregulation of BAD, BAX or BID cause?
Decreased apoptosis, increased tumorogenesis
What are the genetic mutations associated with Lynch?
MLH1, MSH2, MSH6, PMS2
(JS: EPCAM causes lynch via silencing of MSH2, located upstream on chr 2)
MLH1 43–57%, MSH2 21–57%, MSH6 17–46%, and PMS2 0–15%
What chromosome is MLH1 located on?
3p22.2
(3-2=1? MLH1)
MLH1 3p22, MSH2 2p21-16, MSH6 2p16, PMS2 7p22
What chromosome is MSH2 located on?
2p21-16
MLH1 3p22, MSH2 2p21-16, MSH6 2p16, PMS2 7p22
What does the MSH2 protein interact with?
MSH6
What is the heritability of Lynch syndrome?
Autosomal dominant
Are MLH1, MSH2 tumor suppressor genes or a proto-oncogene?
Tumor suppressor genes
What is the mechanism of instability initiated by a mutation in MLH1 and MSH2?
Mismatch repair causes microsatellite instability
What screening is recommended for patients with Lynch?
Annual colonoscopy at age 20-25
Annual EMB at age 35
EGD q2-4 yrs
Brain, urothelial, breast, ovary, pancreatic, skin- no recommendations
Consider annual UA, MRI for pancreatic, TVUS/CA 125, derm
Where are colon cancers associated with Lynch likely to originate?
Proximal to the splenic flexure
*Lynch Syndrome is also known as hereditary non-polyposis colorectal cancer (HNPCC)
At what age is Hysterectomy recommended for patients with HNPCC (Lynch)?
NCCN: At completion of childbearing. May consider annual endometrial biopsy starting between age 30 and age 35
ASCO and ESMO say 35
SGO and ACOG say 40-45
Where in the colon do Lynch cancers occur?
Proximal colon
What gene is implicated in Colon syndrome?
What tumors is it associated with?
MLH1 (like lynch)
Colon, leukemia, Childhood colon cancer
What chromosome is affected in Turcot syndrome?
What tumors is it associated with?
Turcot’s syndrome is characterized by familial polyposis of the colon, together with malignant brain tumors. This disorder can be caused by mutations in the adenomatous polyposis coli gene (APC, on chromosome 5q21) or in the mismatch repair genes MLH1 (chromosome 3) or PMS2 (chromosome 7).
What is the MOST COMMON issue in patients with sporadic cancers that have MMR deficiency?
Hypermethylation of MLH 1 promoter
What is the mechanism of BRCA?
Homologous Recombination (repair of dsDNA Breaks)
Once phosphorylated, BRCA becomes part of several complexes that relocate to damaged DNA and coordinate cell cycle checkpoints to execute DNA repair
How does PARP work in BRCA mutated cells?
PARP is an enzyme that repairs ssDNA breaks via the base excision repair (BER) pathway. It is the salvage repair pathway in cells that have lost HR. Without either pathway cells can not live.
Where is the chromosomal abnormality in BRCA1?
17 q 21
Where is the BRCA2 gene located in the chromosome?
13 q 12
Are BRCA 1/2 tumor suppressor genes or a proto-oncogenes?
Tumor suppressor genes
What proteins does BRCA1 interact with to alter HR?
RAD51 and BARD1
What proteins does BRCA2 interact with?
RAD51 and PALB 2
In what syndrome are both BRCA2 copies mutated?
Fanconi’s anemia
When both BRCA 2 copies are mutated, how does this clinically manifest?
As Fanconi’s anemia, with Bone marrow suppression, increased leukemia and tumor risk, and short stature with skeletal anomalies
What is the most common mechanism (mutation) causing loss of heterozygosity in BRCA?
Nonsense mutation and frameshift alterations resulting in premature stop codons and protein truncation
What is the incidence of ovarian cancer in BRCA1? At what age?
What is the incidence of breast cancer?
48%, age >40yo
Breast: 55%–72%
What is the incidence of ovarian cancer in BRCA2? At what age?
What is the incidence of breast cancer?
20%, age >50
Breast: 45%–69%
***Also associated with male breast cancer
What is Peutz-Jeghers syndrome?
A syndrome caused by germline mutation of STK11
What is the heritability of Peutz-Jeghers syndrome?
Autosomal dominant
What GYN cancers are associated with Peutz-Jeghers?
Sex cord tumors with annular tubules (SCAT) (20%), adenoma malignum (10%), Granulosa-thecoma
What phenotype may a patient with Peutz-Jeghers syndrome exhibit?
Mucocutaneous melanotic pigmentation
What is ataxia telangiectasia? What gene is associated with it?
Ataxia Telangiectasia is a rare inherited childhood neurological disorder that affects the part of the brain that controls motor movement and speech.
ATM gene (same chromosome as Etoposide induced AML and Progesterone; 11q23)
What is the function of ATM?
What is the result of mutated ATM?
ATM checks cells for DNA damage during meiosis/mitosis and coordinates DNA repair by activating enzymes.
Mutations in ATM prevent cells from responding correctly to DNA damage, which allows accumulation of damaged DNA and can lead to cancer.
What is the role of ATM in Ataxia telangiectasia?
Mutations in ATM reduce or eliminate the function of ATM, causing cells to become unstable and die. Cells in the part of the brain involved in coordinating movements (the cerebellum) are particularly affected by loss of the ATM protein.
What gene is affected in Turcot syndrome?
Turcot syndrome can arise from mutations in the MMR genes (MLH1, PMS2 = type I, associated with HNPCC) or the APC genes (type II, associated with FAP). Mutations of either gene can result in colorectal cancer and brain tumors; most commonly, glioblastomas and medulloblastomas.
What tumors are associated with Turcot syndrome?
CNS tumors and colorectal cancer
What is an oncogene?
Precursor: proto-oncogene –> undergoes mutation to become an oncogene
They regulate cell proliferation, growth, and differentiation, as well as control of the cell cycle and apoptosis. The products of oncogenes include growth factors, growth factor receptors, signal transducers, transcription factors, and apoptosis regulators, as well as chromatin remodelers.
What are common oncogenes?
EGFR family, KRAS, MYC, FOS, JUN, FJS, Bcl-2
What are common oncogenes in ovarian cancer?
HER-2/NEU
K-RAS
C-MYC
PIK3CA
AKT2
“H PACK”
What are common oncogenes in endometrial cancer?
HER-2/NEU
K-RAS
C-MYC
C-FMS
β-Catenin
What is the most common mechanism of oncogene activation?
A) Amplification (HER2)
B) Chromosomal rearrangement
C) Point mutation (RAS)
D) Translocation (BCR/ABL)
E) Promoter hypermethylation
F) Increased survival of cells carrying mutated genes
Amplification (HER2)
Verified in Chi: “amplification of members of the MYC family have most often been implicated in the development of human cancers”
What are the three main ways to activate a proto-oncogene?
Mutation (RAS)
Increased expression (Her2)
Translocation (Myc)
What is RAS?
A family of G proteins with GTPase activity
Drives the growth, proliferation, and migration of cells
What does RAS activate?
MAP kinase systems
RAS -> RAF -> MEK/ERK
What does MAP kinase activation cause?
Activation of protein synthesis machinery, transcription factors, cytoskeleton
Where is the RAS protein located in the cell?
Tethered to the cell membrane
Which histologies of ovarian cancer are associated with KRAS mutations?
Mucinous OVCA
*serous borderline tumors, low grade serous carcinoma of the ovary, endometrioid ovarian cancers
Which syndrome is associated with KRAS mutation?
Noonan’s syndrome
Genetically inherited disorder with heterogeneous phenotypic manifestations. Most consistent features are wide-set eyes, low-set ears, short stature, and pulmonic stenosis. Inherited in an autosomal dominant manner.
*increased risk of developing several cancers that affect the blood (leukemia), nervous system (neuroblastoma), brain (glioma), muscle (rhabdomyosarcoma), and bones.
What is the result of a BRAF mutation?
Change a valine residue to glutamic acid, which results in an active protein that stimulates MAP kinase, deregulates genes involved in cell proliferation, differentiation, and survival
*BRAF inhibitor (vemurafenib) used in V600 mutated BRAF Positive melanoma and BRAF inhibitors in combination with a MEK inhibitor (dabrafenib and trametinib) have been used in ovarian cancer.
What are fos/jun, and myc responsible for?
DNA replication
What is the action of myc protein?
Transcription factor
Where in the cell is the myc protein found?
NUCLEUS
Which chromosome is myc on?
chromosome 8
Which translocation is common in burkitts lymphoma (myc)?
[t(8,14)]
What are the common nuclear proto-oncogene transcription factors?
FOS, JUN, MYC
*we dropped the MYC in JUNe to FOSter knowledge
What is the role of BCL-2?
Inhibits apoptosis
*part of the intrinsic apoptosis pathway along with BAX/BADD (pro-apoptotic)
What tissue is BCL-2 strongly expressed in?
Normal endometrium
*part of the intrinsic apoptosis pathway along with BAX/BADD
Does Her-2 represent a heritable cancer susceptibility?
No
What does her-2-neu encode for?
A cell-surface protein tyrosine kinase
Her-2 is encoded by which gene? On which chromosome?
ERBB2 on chromosome 17
Same chromosome as BRCA1, TP53
ERBB2 = 17q12
Which therapy is Her-2 directed? What is it’s MOA?
Herceptin (Traztuzumab), Monoclonal antibody to Her-2 receptor
What percent of breast cancers have HER-2 amplification?
20%
*Her 2 is overexpressed in 60-70% of high grade endometrial cancers
Which test should be used to confirm number of DNA gene copies of ERBB2 prior to initiating treatment?
FISH
Which is not associated with increased risk of breast cancer?
A) LiFraumeni
B) Cowden
C) Heterozygous ataxia telengectasia
D) MEN
D) MEN
What are Olliers disease and Maffucci syndrome? What GYN tumor is associated with these?
disorder that causes benign growths of cartilage in the bones (enchondromas)
Associated with juvenile granulosa cell tumors
What does c-fms encode? What is the role of MCSF?
A tyrosine kinase transmembrane receptor for MCSF
Cytokine (growth factor) that is involved in the proliferation, differentiation, and survival of monocytes, macrophages. The tumor microenvironment often produces high levels of CSF-1, creating a positive feedback loop in which the tumor stimulates survival of tumor associated macrophages (TAM) and TAMs promote tumor survival and growth. Thus, CSF1R signaling in TAMs is associated tumor survival, angiogenesis, therapy resistance, and metastasis.
c-fms = CSF1R (colony stimulating factor 1 receptor)=proto-oncogene
MCSF (macrophage colony stimulating factor) = CSF1
What is the gene for the CSF receptor?
*CSF: colony stimulating factor
c-fms
(proto-oncogene)
CSF1R gene = c-fms gene
What is FMS gene often damaged in?
High-grade endometrial cancers
Berchuck 1995
More commonly AML and MDS
Which two echondromatosis (cartlidge cysts that form in the bone) conditions are associated with juvenile granulosa cell tumors?
Olliers and Maffucci
Who has highest risk of colon CA (Lynch not included)?
A) Family h/o colon CA
B) Personal history of EMCA
C) Grandmother with BRCA postmenopausal
D) Inflammatory bowel disease
E) Familial adenomatous polyposis
E) Familial adenomatous polyposis
Which is BRCA2 least associated with?
A) Small bowel
B) Pancreatic
C) Melanoma
D) Prostate
E) Male breast cancer
Small bowel
How is the ER and PR characterized?
High affinity and low capacity
Which tumor marker may be elevated in mucinous ovarian tumors?
CEA
Which IHC markers are elevated in mucinous ovarian tumors?
P16, CK7,CK20, CDX2
PAX8 negative, WT1 negative
What oncogenes are abnormal in mucinous ovarian tumors?
KRAS occurs in 50-75% of mucinous ovarian cancer
(Also BRAF, but less common)
*NIH:
The KRAS gene (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogene that encodes a small GTPase transductor protein called KRAS.
What oncogenes are overexpressed in Borderline or low grade serous tumors?
KRAS (25-50%) and BRAF (20%)
*per NIH:
The KRAS gene (Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) is an oncogene that encodes a small GTPase transductor protein called KRAS.
What Tumor suppressor proteins are commonly altered in high grade serous tumors?
BRCA and p53
What Tumor suppressor proteins are commonly altered in endometrioid ovarian cancers?
PTEN, p53
What oncogenes are commonly activated in endometrioid ovarian cancers?
KRAS, PI3KCAr, B-catenin (grade 1)
What is the most commonly sporadically altered tumor-suppressor gene in type 2 endometrial CA?
TP53
What is the most common sporadic oncogene amplified in type 2 endometrial CA?
HER-2/neu
Which sporadic oncogenes are most commonly altered in type 1 endometrial cancer?
B-catenin, PIK3CA, KRAS (FGFR2)
Which sporadic tumor suppressor gene is most commonly altered in type I endometrial cancer?
PTEN, followed by MLH1
Which hereditary tumor suppressor genes are most commonly altered in endometrial ca?
MSH 2, MLH1, PMS1, 2, and MSH 6
Does ATM mutation increase the risk of breast cancer?
Yes - 20-30% lifetime risk of breast cancer (risk of early and bilateral)
What mutation associated with Sertoli-Leydig tumor?
DICER1 mutation (up to 70% positive)
DICER1 is an endoribonuclease in the RNase III family essential for processing microRNAs
- Germline truncating mutations have been observed in families with pleuropulmonary blastoma-family tumor and dysplasia syndrome
