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Raunak Shrestha
Boyd et al., Genes Chromosomes Cancer. 2012
29 March 2012
BACKGROUND 2
Introduction
• Prostate – an exocrine gland of the male reproductive system in most mammals
• Plays a vital role during reproductive process
• Prostate cancer occurs when cells in the prostate start to grow uncontrollably
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http://upload.wikimedia.org/wikipedia/commons/a/a1/Prostatelead.jpg
Prostate Cancer Prevalence
• More common among men in North America than in Europe or Asia
• most common cancer among Canadian men - it will afflict 1 in 7 elderly men
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New Cases
Deathshttp://www.prostatecancer.ca/Prostate-Cancer/Prostate-Cancer/Prostate-Cancer-Facts Canadian Cancer Statistics 2011
Multifocality of Prostate Cancer• 50-75% of prostate cancer
specimens contain more than one area or focus of cancer and called multifocal prostate cancer
• generally consists of a dominant (or index) tumor and one or multiple separate smaller tumors
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Andreoiu and Cheng, Human Pathology. 2010; Squire et al., Advances in Cancer Research. 2011
Monoclonal Origin
Polyclonal Origin
Copy number alterations (CNA) disrupt normal cellular behaviour
• CNAs are segments of a chromosome ~1Kb to whole chromosomes where genetic material is lost or gained
• CNAs are a hallmark of tumour genomes
• CNAs can lead to adverse expression changes of targeted genes
• Current Focus: find CNAs for diagnostics/prognostics, gene-disease association, targets for therapeutics
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Chek (2005) Nature
Sohrab Shah, Canadian Bioinformatics Workshop. 2010
METHODS 7
Tissue Sample Selection
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• Fresh-frozen tissue from 18 males with prostate cancer
• Histopathological techniques and Immuno-histochemistrytechniques were used to find out various cancer lesions
• High-Grade Prostatic Intraepithelial Neoplasia (HGPIN) lesions were also distinguished from tumor lesions
• 48 foci from 18 samples were selected for study
Boyd et al., Genes Chromosomes Cancer. 2012
Measurement Technologies
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Resolution
FISH
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Array CGH
30-100KTech:
#:
Genotype arrays
100K-2MWGSS
Sohrab Shah, Canadian Bioinformatics Workshop. 2010
Genotyping arrays - schematic
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Sohrab Shah, Canadian Bioinformatics Workshop. 2010
• High density genotyping arrays:
• Higher resolution (more loci)
• Measurement of 2 alleles (Max. and Min. allele) at >1M loci
RESULTS 11
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• Identical genomic copy-number changes, shared by all same-case cancer foci and defined by the same breakpoints, were detected in 13 cases
Boyd et al., Genes Chromosomes Cancer. 2012
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Boyd et al., Genes Chromosomes Cancer. 2012
• copynumber changes with identical breakpoints found in separate foci from the same case always affect the same allele
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Boyd et al., Genes Chromosomes Cancer. 2012
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Boyd et al., Genes Chromosomes Cancer. 2012
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• conserved genomic alterations in majority of the cases suggesting monoclonal origin
Boyd et al., Genes Chromosomes Cancer. 2012
Conclusion
• From previous molecular studies in prostate cancer, polyclonal origin is widely believed
• But these studies assume that, for foci to be monoclonal, same case foci must share all genetic alterations
• Passenger mutations outnumber the Driver mutations
• Passenger mutations accumulate in cancer subclonesindependently and may not be common to all the subclones(or to all foci)
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Conclusion
• This paper hypothesize that,
• if foci were monoclonal in origin, all same-case foci would share some early genetic changes, with conserved breakpoints,
• individual foci from that case would harbor additional genetic changes acquired during subclonal progression.
• But does not completely rule out the polyclonal origin
• Though majority of cases exhibited monoclonal origin small fraction of cases did not fit into this model !!!
• Study recommends further study with larger sample size
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Critiques
• Analyzed only the copy-number changes to study the clonal origin of the multifocal cancers
• Sequence level variation as well as other Genomic Variation could give more insight on the topic
• Did not use the sequence information of the cancer genome to look for precise breakpoints in the genome
• DNA extraction from the micro-dissected tissue samples would be very difficult
• DNA concentration may not be well enough for sequencing
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?Questions