what are the hallmarks of cancer?
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
what are emerging hallmarks of cancer?
what characteristics enable these to occur?
1) deregulating cellular energetics
2) avoiding immune destruction
1) genome instability & mutation
2) tumor-promoting inflammation
what are the genetic points of view of cancer?
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
what is more common: sporadic or hereditary cancers?
hereditary cancers around only 10% of cancers
however there's always a link between hereditary and sporadic forms
what is the strongest etiological factor contributing to cancer?
1) genetic susceptibility, tobacco
3) alcohol, infection, occupation
4) environmental pollution, medications, other factors
across what populations do cancer susceptibility genes vary?
across national populations, geographic areas
i.e. RR of skin cancer much higher in Australia than Japan
what does it mean that "cancer is a progression of steps"?
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
what is the progression of prostate cancer
normal prostate epithelial cells transition through inflammatory stage to carcinoma in situ (non-invasive) to metastatic prostate cancer to androgen-independent cancer, hormone-insensitive
what factors contribute to genetic mutations that lead to cancer?
what is the schematic of how genetic mutation ends in tumor state?
inheritance/environment/infection -> mutation
mutation > dysfunction in growth regulating genes or products
> growth advantage
> invasion, metastasis, angiogenesis
what is the adenoma - carcincoma sequence?
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
what is polypectomy? why important?
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
what do tumors arise from?
why is this helpful to know re: treatment?
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
why might a patient need several kinds of chemotherapy?
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
what is chemical bottleneck?
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
what happens in sporadic cancers?
a mutation occurs in a cell line and all mitoses of that cell line will contain the mutation
what is the molecular basis of malignancy in CML?
a recurrent translocation t(9;22)(q34;q11)
this philadelphia chromosome fuses Bcr and Abl genes
what was significant finding in whole genome genotyping of glioblastoma patients?
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
how can whole genome sequencing of different cancers help with therapy targetting?
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
where do hereditary cancers manifest?
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
what are signs of a cancer being a hereditary cancer?
wrong gender assignment of disease (ie breast cancer in man)
multiple, bilateral, pleiotropic (syndromic)
pedigree shows autosomal dominant pattern w/ multiple affected members
what about retinoblastoma make sit the classic hereditary cancer example?
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
what is the range of contribution of hereditary cancers to total of newly diagnosed cancers?
varies by tumor type
~5% in colon cancer to 10% in breast or prostate cancer
why can't we say that just because someone is a carrier of a gene associated w/ cancer, they will/wont get it?
genes have varying penetrance
risk of developing tumors at other sites varies by the gene involved
what are management options for a person w/ a positive BRCA1 or BRCA2 test result?
1) surveillance: mammography, clinical breast exams
2) prophylactic surgery
3) risk avoidance
what syndromes are associated w/ hereditary colon cancer?
familial adnomatous polyposis (FAP): confers a >95% lifetime risk of developing colon cancer
hereditary non-polyposis coli (HNPCC): confers a 70-80% risk
what is FAP caused by?
muations of the APC ene
confers risk of gastrointestinal - gastric, duodenum, small bowle, pancreas, liver- cancer, and non-gastrointestinal - thyroid - cancers
what is HNPCC caused by?
extra-colonic tumors, most prominently endometrial cancer but also GI, urinary tract, ovarian tumors
what is way to treat adenoma?
will protect against FAP development, as adnoma is a precancer risk
what is treatment for HNPCC
colonoscopies, remove polops
what is the diagnostic criteria used to diagnose Lynch sydndrome aka HNPCC
Amsterdam or Bethesda critera
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
how do macrosatellites contribute to tumors?
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
howis personalized medicine becoming applicable to cancer treatment?
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