class: center, middle, inverse, title-slide # HRD test ## scarHRD and sequenza ### Jun Kang ### 2021-11-08 --- # Myriad myChoice CDx - Homologous recombination deficiency (HRD) status - Presence mutations in BRCA1 and BRCA2 genes - Sensitivity to platinum-based chemotherapy - Ovarian cancer - Treatment with Zejula (niraparib) --- # Homologous recombination deficiency (HRD) - Double-strand break - Genomic scars - Large-scale loss of heterogeneity [1] - Telomere allelic imbalance [2] - Large-scale state transition [3] --- # Loss of Heterozygosity (HRD-LOH)  - Number of 15 Mb exceeding LOH regions which do not cover the whole chromosome. --- # Large Scale Transitions (LST)  - Chromosomal break between adjacent regions of at least 10 Mb, with a distance between them not larger than 3Mb --- # Telomeric Allelic Imbalances  - Number AIs that extend to the telomeric end of a chromosome. --- # HRD test as a companion diagnostics [4]  --- # Key concepts - Allele-specific copy number - Allele frequency of **heterozygous single nucleotide polymorphism (heterozygous SNP)** --- # HRD test programs - Sequenza [5] - scarHRD [6] --- class: left class: my-one-page-font ## Allele-specific copy number analysis of tumors [7] .pull-left[] .pull-right[ - B allele frequency (BAF): relative quantity of the one allele compared to the other - log R ratio (LRR): Total probe intensity of a given SNP relative to a canonical set of normal controls - Loss of heterozygosity - Allelic imbalances  ] --- ### Allele frequency[8] `\(BAF\)` `\(=\)` `\({pV+1-p} \over {pC+2(1-p)}\)` * Given copy number (C) * Variant allele count (V) * Sample purity (p) --- ### Three steps of Bayesian data analysis - Full probability model - Conditioning on observed data (posterior distribution) - Evaluating the fit of the model and the implications of the resulting posterior distribution Bayesian Data Analysis 3rd, Andrew Gelman et. al. --- class: my-one-page-font ### Full probability model $$ `\begin{aligned} r_i & \sim & N\left(log_2 \frac{pC_i+2(1-p)}{p \psi+2(1-p)}, \sigma_{ri} \right) \end{aligned}` $$ $$ `\begin{aligned} f_i & \sim & N\left(\frac{pM_i+(1-p)}{pC_i+2(1-p)}, \sigma_{fi} \right) \end{aligned}` $$ `$$\psi = \frac{\sum_{i}(l_iC_i) }{\sum_{i}(l_i)}$$` - `\(r_i\)` (log R ratio): Median-normalized log-ratio coverage of all exons within `\(S_i\)` - `\(f_i\)` (B allele frequency): MAF of SNPs within segment `\(S_i\)` - `\(p\)`: Tumor purity - `\(S_i\)`: Genomic segment - `\(l_i\)`: Length of $S_i - `\(C_i\)`: Copy number of `\(S_i\)` - `\(M_i\)`: Copy number of minor alleles in `\(S_i\)`, `\(0 \leq M_i \leq S_i\)` - `\(\psi\)`: Tumor ploidy of the sample --- ### Sequenza results <div id="htmlwidget-eb760829eda7a14a89e4" style="width:1000px;height:300px;" class="datatables html-widget"></div> <script type="application/json" 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class=\"display\">\n <thead>\n <tr>\n <th> <\/th>\n <th>chromosome<\/th>\n <th>start.pos<\/th>\n <th>end.pos<\/th>\n <th>Bf<\/th>\n <th>N.BAF<\/th>\n <th>sd.BAF<\/th>\n <th>depth.ratio<\/th>\n <th>N.ratio<\/th>\n <th>sd.ratio<\/th>\n <th>CNt<\/th>\n <th>A<\/th>\n <th>B<\/th>\n <th>LPP<\/th>\n <\/tr>\n <\/thead>\n<\/table>","options":{"autoWidth":false,"pageLength":5,"scrollX":true,"columnDefs":[{"className":"dt-right","targets":[2,3,4,5,6,7,8,9,10,11,12,13]},{"orderable":false,"targets":0}],"order":[],"orderClasses":false,"lengthMenu":[5,10,25,50,100]}},"evals":[],"jsHooks":[]}</script> --- class: center ### Sequenza results <img src="scarHRD_files/figure-html/unnamed-chunk-2-1.png" width="500" height="500" /> --- class: center ### Sequenza results <img src="scarHRD_files/figure-html/unnamed-chunk-3-1.png" width="1000" height="500" /> --- class: center ### Sequenza results <img src="scarHRD_files/figure-html/unnamed-chunk-4-1.png" width="500" height="500" /> .footer[LPP: log-posterior probability] --- ### scarHRD ```r library(scarHRD) scar_score(here::here("static/slide/scarHRD/example/example1.txt"), reference = "grch38", chr.in.names = FALSE, seqz = FALSE) ``` ``` ## Determining HRD-LOH, LST, TAI ``` ``` ## HRD Telomeric AI LST HRD-sum ## [1,] 27 27 33 87 ``` --- class: my-one-page-font # References [1] V. Abkevich, K. M. Timms, B. T. Hennessy, et al. "Patterns of Genomic Loss of Heterozygosity Predict Homologous Recombination Repair Defects in Epithelial Ovarian Cancer". En. In: _British Journal of Cancer_ 107.10 (11. 2012), pp. 1776-1782. ISSN: 1532-1827. [2] N. J. Birkbak, Z. C. Wang, J. Kim, et al. "Telomeric Allelic Imbalance Indicates Defective DNA Repair and Sensitivity to DNA-Damaging Agents". En. In: _Cancer Discov_ 2.4 (4. 2012), pp. 366-375. ISSN: 2159-8274, 2159-8290. [3] T. Popova, E. Manie, G. Rieunier, et al. "Ploidy and Large-Scale Genomic Instability Consistently Identify Basal-like Breast Carcinomas with BRCA1/2 Inactivation". En. In: _Cancer Res_ 72.21 (11. 2012), pp. 5454-5462. ISSN: 0008-5472, 1538-7445. [4] I. Ray-Coquard, P. Pautier, S. Pignata, et al. "Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer". In: _New England Journal of Medicine_ 381.25 (12. 19, 2019), pp. 2416-2428. ISSN: 0028-4793. pmid: 31851799. [5] F. Favero, T. Joshi, A. M. Marquard, et al. "Sequenza: Allele-Specific Copy Number and Mutation Profiles from Tumor Sequencing Data". In: _Annals of Oncology_ 26.1 (1. 01, 2015), pp. 64-70. ISSN: 0923-7534, 1569-8041. pmid: 25319062. [6] Z. Sztupinszki, M. Diossy, M. Krzystanek, et al. "Migrating the SNP Array-Based Homologous Recombination Deficiency Measures to next Generation Sequencing Data of Breast Cancer". In: _npj Breast Cancer_ 4.1 (1 7. 02, 2018), pp. 1-4. ISSN: 2374-4677. [7] E. F. Attiyeh, S. J. Diskin, M. A. Attiyeh, et al. "Genomic Copy Number Determination in Cancer Cells from Single Nucleotide Polymorphism Microarrays Based on Quantitative Genotyping Corrected for Aneuploidy". In: _Genome Res._ 19.2 (2. 01, 2009), pp. 276-283. ISSN: 1088-9051, 1549-5469. pmid: 19141597. [8] J. X. Sun, Y. He, E. Sanford, et al. "A Computational Approach to Distinguish Somatic vs. Germline Origin of Genomic Alterations from Deep Sequencing of Cancer Specimens without a Matched Normal". 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