DNA repair (Alberts et al. 2002)

Diseases Due to Defects in DNA Repair

Myriad myChoice CDx

• Homologous recombination deficiency (HRD) status
• Presence mutations in BRCA1 and BRCA2 genes
• Sensitivity to platinum-based chemotherapy
• Ovarian cancer
• Treatment with PARPi

Homologous recombination deficiency (HRD)

• Genomic scars based test
  • Large-scale loss of heterogeneity (Abkevich et al. 2012)
  • Telomere allelic imbalance (Birkbak et al. 2012)
  • Large-scale state transition (Popova et al. 2012)
• Signature based test

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 (Ray-Coquard et al. 2019)

Key concepts

• Allele-specific copy number
• Allele frequency of heterozygous single nucleotide polymorphism (heterozygous SNP)

scarHRD programs

• Sequenza (Favero et al. 2015)
• scarHRD (Sztupinszki et al. 2018)

Allele-specific copy number analysis of tumors (Attiyeh et al. 2009)

Allele frequency (Sun et al. 2018)

BAF = \({pV+1-p} \over {pC+2(1-p)}\)

• Given copy number (C)
• Variant allele count (V)
• Sample purity (p)

Full probability model

\[ \begin{aligned} r_i & \sim & N\left(log_2 \frac{pC_i+2(1-p)}{p \psi+2(1-p)}, \sigma \right) \end{aligned} \]

\[ \begin{aligned} f_i & \sim & N\left(\frac{pM_i+(1-p)}{pC_i+2(1-p)}, \sigma\ \right) \end{aligned} \]

Sequenza results

Sequenza results

Sequenza results

scarHRD

HRDtect (Davies et al. 2017)

Classification of structural variants in cancer genomes (Li et al. 2020)

Structural-variant signatures in human cancers

Mutational signature

Mutational signature

Mutational context (SBS)

Mutational signature (Rosenthal et al. 2016)

Mutational signature

Mutational signature