HRD testscarHRD and sequenzaJun Kang2021-11-081

Myriad myChoice CDxHomologous recombination deficiency (HRD) status
Presence mutations in BRCA1 and BRCA2 genes
Sensitivity to platinum-based chemotherapy
Ovarian cancer
Treatment with Zejula (niraparib)
2

Homologous recombination deficiency (HRD)Double-strand break 
Genomic scarsLarge-scale loss of heterogeneity [1]
Telomere allelic imbalance [2]
Large-scale state transition [3]

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 conceptsAllele-specific copy numberAllele frequency of heterozygous single nucleotide polymorphism (heterozygous SNP)

8

HRD test programsSequenza [5]
scarHRD [6]
9

Allele-specific copy number analysis of tumors [7]

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]

$B A F$ $=$ $\frac{p V + 1 - p}{p C + 2 (1 - p)}$

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.

Full probability model

$\begin{aligned} r_{i} & \sim & N (l o g_{2} \frac{p C_{i} + 2 (1 - p)}{p ψ + 2 (1 - p)}, σ_{r i}) \end{aligned}$

$\begin{aligned} f_{i} & \sim & N (\frac{p M_{i} + (1 - p)}{p C_{i} + 2 (1 - p)}, σ_{f i}) \end{aligned}$

$ψ = \frac{\sum_{i} (l_{i} C_{i})}{\sum_{i} (l_{i})}$

$r_{i}$ (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 $S_{i}$ , $0 \leq M_{i} \leq S_{i}$
$ψ$ : Tumor ploidy of the sample

Sequenza results

Show entries

Search:

	chromosome	start.pos	end.pos	Bf	N.BAF	sd.BAF	depth.ratio	N.ratio	sd.ratio	CNt	A	B	LPP
1	1	881992	54694219	0.5	1636	0.1	1.1	2172	0.6	2	1	1	-6.8
2	1	54700724	60223464	0.3	73	0.1	1.5	101	1.5	3	2	1	-6.7
3	1	60381518	67890614	0	94	0	1.2	114	0.5	2	2	0	-6.8
4	1	68151686	92262955	0.5	264	0.1	2.1	338	1.6	4	2	2	-6.8
5	1	92445264	118165373	0.3	315	0.1	1.6	434	1	3	2	1	-6.7

Showing 1 to 5 of 197 entries

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Sequenza results

LPP: log-posterior probability

scarHRD

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

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". In: PLOS Computational Biology 14.2 (2018), p. e1005965. ISSN: 1553-7358.

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HRD test

scarHRD and sequenza

Jun Kang

2021-11-08

Myriad myChoice CDx

Homologous recombination deficiency (HRD)

Loss of Heterozygosity (HRD-LOH)

Large Scale Transitions (LST)

Telomeric Allelic Imbalances

HRD test as a companion diagnostics [4]

Key concepts

HRD test programs

Allele-specific copy number analysis of tumors [7]

Allele frequency[8]

Three steps of Bayesian data analysis

Full probability model

Sequenza results

Sequenza results

Sequenza results

Sequenza results

scarHRD

References

Myriad myChoice CDx

Help