LEC56: Cancer Genetics and Genomics

Question 1

what are the hallmarks of cancer?

Answer 1

1) unlimited replicative potential
2) tissue invasion and metastasis
3) sustained angiogenesis
4) evasion of apoptosis
5) insensitivity to anti-growth signals
6) self-sufficiency in growth signals

Question 2

what are emerging hallmarks of cancer?

what characteristics enable these to occur?

Answer 2

1) deregulating cellular energetics
2) avoiding immune destruction

enabled by:

1) genome instability & mutation
2) tumor-promoting inflammation

Question 3

what are the genetic points of view of cancer?

Answer 3

1) complex disease: multiple genes & environmental factors interact to produce cancer disease phenotype
2) monogenic disease: germline mutation within a single gene results in a particular cancer phenotype

Question 4

what is more common: sporadic or hereditary cancers?

Answer 4

hereditary cancers around only 10% of cancers

however there’s always a link between hereditary and sporadic forms

Question 5

what is the strongest etiological factor contributing to cancer?

Answer 5

1) genetic susceptibility, tobacco
2) diet
3) alcohol, infection, occupation
4) environmental pollution, medications, other factors

Question 6

across what populations do cancer susceptibility genes vary?

example?

Answer 6

across national populations, geographic areas

i.e. RR of skin cancer much higher in Australia than Japan

Question 7

what does it mean that “cancer is a progression of steps”?

Answer 7

transition of cells from normal differentiated state to metastatic tumor cells follows a characteristic progression

can see this at the pathology level, but note it’s occurring molecularly in germline mutations as well

Question 8

what is the progression of prostate cancer

Answer 8

normal prostate epithelial cells transition through inflammatory stage to carcinoma in situ (non-invasive) to metastatic prostate cancer to androgen-independent cancer, hormone-insensitive

Question 9

what factors contribute to genetic mutations that lead to cancer?

Answer 9

inheritance

environment

infection

Question 10

what is the schematic of how genetic mutation ends in tumor state?

Answer 10

inheritance/environment/infection -> mutation

mutation > dysfunction in growth regulating genes or products

> growth advantage

> immortalization

> autostimulation

> invasion, metastasis, angiogenesis

Question 11

what is the adenoma - carcincoma sequence?

Answer 11

colon cancer progression; shows us transition of cells from normal colonic mucosa, differentiated state, to small tubular adneomas, to larger adenomas, to those with advanced histological features, to cancer-metastatic tumor cells

sequence of events where cell goes from an adenoma, benign growth, through a carcinoma

Question 12

what is polypectomy? why important?

Answer 12

removal of polyps from colon

reduces risk of subsequent malignancy by aborting cancer progression cycle prior to point where transformed cells can metastisize

epidemiologicallky proven to nearly eradicate development of colorectal cancer

Question 13

what do tumors arise from?

why is this helpful to know re: treatment?

Answer 13

cancer tuors arise from a single progenitor monoclonal cell - 1 cell

thus if you could target the shared changes among all the cancer cells, you can get rid of the cancer

this has been used in AML

Question 14

why might a patient need several kinds of chemotherapy?

Answer 14

because tumor cells evolve and undergo different changes as they evolve

might need combination of treatments to treat these different metasteses

patient thus might need several kinds of chemotherapy

Question 15

what is chemical bottleneck?

Answer 15

can occur with treatment of cancer like AML - although can treat mutations w/ chemo, cancer cells will die, get a relapse because the cancer cells mutate, evolve in a new way from the old cells

this creates a chemical bottle neck effect

Question 16

what happens in sporadic cancers?

Answer 16

a mutation occurs in a cell line and all mitoses of that cell line will contain the mutation

Question 17

what is the molecular basis of malignancy in CML?

Answer 17

a recurrent translocation t(9;22)(q34;q11)

this philadelphia chromosome fuses Bcr and Abl genes

Question 18

what was significant finding in whole genome genotyping of glioblastoma patients?

Answer 18

12% of patients had recurrent deletion in a metabolic gene, isocitrate dehydrogenase, IDH1

example of an enzyme mutation in a sporadic cancer that causes cancer; if that particular enzyme could be treated, cancer could be stopped from development

Question 19

how can whole genome sequencing of different cancers help with therapy targetting?

Answer 19

if know a treatment works for 1 kind of cancer, and know the same mutation is in another cancer, can try out a therapy on patients with that other kind of cancer

Question 20

where do hereditary cancers manifest?

Answer 20

because mutation occurs in the germline, this means mutation is present in all cells of the body

this means increased predisposition toward developing a specific type(s) of cancer

Question 21

what are signs of a cancer being a hereditary cancer?

Answer 21

early onset

wrong gender assignment of disease (ie breast cancer in man)

multiple, bilateral, pleiotropic (syndromic)

pedigree shows autosomal dominant pattern w/ multiple affected members

Question 22

what about retinoblastoma make sit the classic hereditary cancer example?

Answer 22

it’s cancer from which knudsen developed 2 hit hypothesis of tumor suppressor genes and hereditary cancers

tumor of the nervous tissue lining of the retina

avg dx is 12-18 months

associated w/ 2ndary site tumors

directly associated w/ interstitial deletion 13q14, genetic abnormality

more likely to be bilateral than unilateral if hereditary

Question 23

what is the range of contribution of hereditary cancers to total of newly diagnosed cancers?

Answer 23

varies by tumor type

~5% in colon cancer to 10% in breast or prostate cancer

Question 24

why can’t we say that just because someone is a carrier of a gene associated w/ cancer, they will/wont get it?

Answer 24

genes have varying penetrance

risk of developing tumors at other sites varies by the gene involved

Question 25

what are management options for a person w/ a positive BRCA1 or BRCA2 test result?

Answer 25

1) surveillance: mammography, clinical breast exams
2) prophylactic surgery
3) risk avoidance
4) chemoprevention

Question 26

what syndromes are associated w/ hereditary colon cancer?

Answer 26

familial adnomatous polyposis (FAP): confers a >95% lifetime risk of developing colon cancer

hereditary non-polyposis coli (HNPCC): confers a 70-80% risk

Question 27

what is FAP caused by?

Answer 27

muations of the APC ene

confers risk of gastrointestinal - gastric, duodenum, small bowle, pancreas, liver- cancer, and non-gastrointestinal - thyroid - cancers

Question 28

what is HNPCC caused by?

Answer 28

extra-colonic tumors, most prominently endometrial cancer but also GI, urinary tract, ovarian tumors

Question 29

what is way to treat adenoma?

Answer 29

full colectomy

will protect against FAP development, as adnoma is a precancer risk

Question 30

what is treatment for HNPCC

Answer 30

colonoscopies, remove polops

Question 31

what is the diagnostic criteria used to diagnose Lynch sydndrome aka HNPCC

Answer 31

Amsterdam or Bethesda critera

Amsterdam protocol:

3 or more relatives w/ an HPNCC-related cancer, 1 of whom is a 1st degree relative of the other 2

2 or more successive generations affected

1 or more cancers daignosed before age 50

Question 32

how do macrosatellites contribute to tumors?

Answer 32

see lots of microsatellie instability b/c of replication errors leading to variable repeat lengths in DNA derived from tumor cells

occurs w/ mutations in MSH2 and MLH1 mismatch repair gene in HNPCC

Question 33

howis personalized medicine becoming applicable to cancer treatment?

Answer 33

expression and genomic sequence data tools allow discrimination now of morphologically indistinguishable tumors into distinct prognostic categories

currently working on developing personalized therapeutic approaches to maximize benefit and minimize unnecessary toxicity when treating tumors