ECON 546 Lecture Notes - Lecture 20: Chromosome, Digital Polymerase Chain Reaction, Transcription Coregulator

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BIOL 568 – Gottlieb L20: 27/3/18
L20: Cancer 2 – In the ‘New Genetics’ Age
Direction of Cancer Research – remedies:
1. Advances with specific drugs – personalised medicine
2. Advances in surgery – remove cancer and cancer cells much more effectively (micro
surgery, laser surgery)
oCancer drugs decrease QOL – not sophisticated; destroy cancer cells but other cells too.
oTreatments fail to ultimately extend life.
oInitially, 5 year survival rate. After 5 years – recovery good. After 10 years – survival rate not
so good.
oIssue: Drugs for primary tumours. However, most cancer deaths (90%) are result of
metastases – not the primary cancer. Only 7.7% of NCI-funding for metastases.
Human Genome Project – goal of mapping the whole human genome has been based on a
number of assumptions – turned out not true:
1. All of an individual’s cells posses essentially the same genetic makeup, with a few
notable exceptions such as cancer cells.
2. The human reference genome sequence exists – should be variants for different groups
e.g. ethnic; familial – cannot be done!
3. Examining genetic alterations in blood and comparing them with those in cancer tissue are
likely to reveal the genetic alterations that cause the disease.
Different (cancer) tissues have different sequences. Blood does not reflect what is
going on in every tissue.
oCompletion of the HGP in 2003 predicted to lead to major breakthroughs in:
Understanding the ontogeny of common multifactorial diseases such as cancer
Identification of the nature of all human genes by examining the complete spectrum
of human genome alterations
oDependent on gene alterations being relatively rare and on establishing a human reference
sequence – WRONG!
Human Genetic Variation:
oRealisation that each individual has their own unique genome.
o3.3m SNPs; 10,654 AA substitutions in coding regions (Watson-Venter differences)
oNow examined over 1000 complete genomes published (1000 genome project).
oEach individual has 200,000-300,000 unique SNPs – thought to decrease as no. people
studied increased (SNPs already found), but no.
oDoes a human reference sequence really exist?
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BIOL 568 – Gottlieb L20: 27/3/18
Cancer Genome Project:
oHuman Cancer Project started 2005.
oGoal to examine 1000s of individual tumours
oActual data revealed a huge number of gene alterations being identified in cancer tissues
(mainly SNPs).
oVery few gene alterations could be consistently linked to cancer – most only determined to
increase the risk of getting cancer
GWAS:
oSolution = GWAS, has become the analysis method of choice
oBased on the availability of ever more complex microarray genomic analysis tools and now
NGS technologies
oEach tumour revealed to have 100s of gene alterations
oNo. cancer-associated genes identified has increased exponentially.
Reference Sequence Dilemma:
oMeeting at European Bioinformatics Institute
oGoal to create a universally acceptable standard: a new specification for human genomic
DNA Reference Sequences that addresses the primary shortcoming of existing system:
a) The lack of universally agreed Genomic Reference Sequences for certain genes
b) DNA sequence inconsistencies between existing genomic reference sequences
(traditionally Sanger) and their NCBI RefSeqGen mRNA sequence counterparts (NGS)
c) Lack of long-term stability of reference sequences – changes over time
d) Confusion in end users’ minds concerning versioning of DNA sequences (different
ethnic, family groups)
oEnd result: a sequence has been arbitrarily designated as the Human Reference Sequence by
NCBI (present version GRC39)
oModifications include population-based sub-groups – all found to be inadequate.
Effectiveness of Genome Wide Studies:
o“Prospect of personalised medicine care based on the genetic profiles of patients has moved
closer w the discovery of millions of fresh ways in which DNA can vary from person to person.
oGWAS approach can be extremely productive, however the marker SNPs highlight regions of
the genome linked to disease, rather than the precise variation that is responsible
oLaborious & expensive “fine mapping” of these regions is required to find the causative SNP
and understand its effect” (May, 2009)
oGenes show limited value in predicting diseases (April, 2009)– cancer-associated variant
genes identified from GWAS have so far carried only a modest risk for cancer.
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BIOL 568 – Gottlieb L20: 27/3/18
Major Problems with Present Cancer Hypotheses
1. Evidence derived in humans from comparing non-cancer and cancer cells and tissues – no
actual ability to follow process – cannot predict which cell will become cancerous
2. Animal models i.e. knock-in mouse models have not lead to any big cancer breakthroughs
3. Too many gene alterations discovered in ability to distinguish between ‘driver’ and ‘passenger’
genes
4. Most cancer mortality follows metastasis – very little studied
5. Hegemony of epidemiologists? Everything now a risk factor…
Problem w understanding the role of Carcinogens
oCarcinogens: substances known to cause cancer or produces an increase in incidence of
cancer in animals or humans. However…
Cause of most cancers is unknown
Most cancers are probably multifactorial in origin
Known carcinogenic agents constitute a small % of cases
Unidentified ‘environmental’ agents probably play a role in 95% of cancers.
Relationship between carcinogens & mutagenesis:
oMany chemical carcinogens are not mutagenic agents:
Regular foods can be a significant reisk factor
Cancer-causing foods
Cancer protective foods
Suggests that perhaps mutation is not the primary force in carcinogenesis
oHormones are not mutagenic agents:
If neoplasm not caused by hormones, why do we treat them be giving hormone
antagonists or receptor disruptors?
Critical problem: almost all of these types of tumours become resistant to the anti-
hormonal treatments
E.g. prostate, breast CA.
Genetics of Cancer Recidivism
oHypothesis: new mutations occur that confer resistance to treatment regimens:
oSomatic mutations:
Non-random manner i.e. same gene or area of chromosome affected e.g. some sites
more susceptible to mutations. GpG – bias of Sanger sequencing.
Appear to occur at a v rapid rate
oOrgans and tissues selectively affected
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Document Summary

L20: cancer 2 in the new genetics" age. After 10 years survival rate not so good: issue: drugs for primary tumours. However, most cancer deaths (90%) are result of metastases not the primary cancer. Blood does not reflect what is going on in every tissue: completion of the hgp in 2003 predicted to lead to major breakthroughs in: Understanding the ontogeny of common multifactorial diseases such as cancer. Identification of the nature of all human genes by examining the complete spectrum of human genome alterations: dependent on gene alterations being relatively rare and on establishing a human reference sequence wrong! Cancer genome project: human cancer project started 2005, goal to examine 1000s of individual tumours. Gwas: solution = gwas, has become the analysis method of choice, based on the availability of ever more complex microarray genomic analysis tools and now. Ngs technologies: each tumour revealed to have 100s of gene alterations, no. cancer-associated genes identified has increased exponentially.

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