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DNA copy number variation and cancer risk

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  1. DNA copy number variation and cancer risk John F Pearson Canterbury Statistics Open DayUniversity of Canterbury 2/10/2012

  2. Breast Cancer Foulkes WD. N Engl J Med 2008; 359:2143-2153

  3. Missing heritability TA Manolioet al. Nature461, 747-753 (2009) doi:10.1038/nature08494

  4. Evan E. Eichler.

  5. Copy number variation Allele 1 Allele 2 Copy number loss Copy number gain Whole gene Partial gene Contiguous genes Regulatory effects

  6. Copy number variants (CNVs) • 16,000 copy number variant loci cover >50% of the human genome • CNVs are associated with cancer risk • Rare CNVs detected in ~50% of familial cancer genes eg. BRCA1, BRCA2 • Genome-wide association studies of cancer • prostate cancer, hepatocarcinoma, nasopharyngeal carcinoma, and neuroblastoma • Increased CNV load • Li FraumeniSyndome (cancer related genes?) • breast cancer (TP53 pathway, ESR1 pathway)

  7. SNP arrays LRR = log2(Robserved/Rexpected) The B Allele Frequency (BAF) is a somewhat confusing term that actually refers to a normalized measure of relative signal intensity ratio of the B and A allelesWang et al Genome Res. 2007 November; 17(11): 1665–1674.

  8. Genomic location

  9. Copy number Copy number loss Copy neutral LOH Normal BB AB AA

  10. Copy number gain Copy number gain BBB ABB AAB AAA

  11. CNV calling Illumina bead arrays. • CNVision (workflow software) • Gnosis • PennCNV • QuantiSNP • CNV Partition CNV calling algorithms

  12. PennCNV, QuantiSNP Hidden Markov Model Estimate copy number at each SNP from • Log R ratio • B allele frequency • transition probability at previous SNP.

  13. PennCNV

  14. PennCNV ri LRR bi BAF at SNP i. ( 1 ≤ i ≤ M ) zi copy number state The likelihood of the observed data is:

  15. PennCNV ri LRR bi BAF at SNP i. ( 1 ≤ i ≤ M ) zi copy number state The likelihood of the observed data is: LRR emission probability model includes a term for chemical fluctuations and misannotation/assembly BAF emission probability complicated mixture model

  16. PennCNV ri LRR bi BAF at SNP i. ( 1 ≤ i ≤ M ) zi copy number state Transmission probabilities between 2 adjacent SNPs i -1 and i. with copy numbers zi and zi-1 at distance di. D = 100Mb for state 4, 100kb for other states. p are unknowns, estimated by the Baum-Welch algorithm.

  17. PennCNV • ri LRR • bi BAF at SNP i. ( 1 ≤ i ≤ M ) • zi copy number state • Baum-Welch used to train the model • Viterbi algorithm used to infer most likely path • CNV called whenever a stretch of states is different from normal( usually state 3 or 4)

  18. Copy number gain Copy number gain BBB ABB AAB AAA

  19. Noisy data

  20. Breast cancer A characteristic of breast tumour cells is genomic instability BRCA1, BRCA2

  21. BRCA1: known large deletions Detected Not detected • CNV prediction summary: • cnvPartition - 25% (4/16) • GNOSIS - 19% (3/16) • PennCNV- 88% (14/16) • QuantiSNP- 81% (13/16)

  22. Endometrial cancer 1343 cases ANECS, SEARCH 655 female controls Hunter Community Study Want to find: • CNVs overlapping known susceptibility genes • novel CNVs in the mismatch repair pathway • common or rare CNVs associations QC(1) – GWAS criteria 619 controls 1279 cases CNVcalling by 4 algorithms 612 controls 1210 cases Case vs. control analyses

  23. CNV frequency: all

  24. CNV frequency: rare (< 1%)

  25. CNV frequency: rare (< 1%)

  26. Association study CNV Regions

  27. Association study CNV overlapping genes

  28. Acknowledgements • University of Cambridge • Deborah Thompson • Paul Pharoah • Alison Dunning • Douglas Easton • Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) • University of Newcastle • Rodney Scott • Mark McEvoy • John Attia • Elizabeth Holliday • The Hunter Community Study • CIMBA consortium • MAYO clinic • Fergus Couch • University of Otago • Gemma Moir-Meyer • Logan Walker • Mackenzie Cancer Research Group • Queensland Institute of Medical Research • Mandy Spurdle • Felicity Lose • Yen Tan • Alex Metcalf • Australian National Endometrial Cancer Study • Bryony Thompson