High-resolution genome-wide copy-number analysis suggests a monoclonal origin of multifocal prostate...

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

<10

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