Determine LOH & HRD Status for PARP Inhibitor Treatment
Identifies Patients Who May Benefit from PARP Inhibitor Treatment
PARP inhibitors have made major breakthroughs in personalized cancer treatment over the past few years. With the recent US FDA approvals, genetic testing can now be used in patients with ovarian, breast, prostate and pancreatic cancers to identify individuals who would likely benefit from PARP inhibitor treatment.
Mutations in HRR Genes Lead to HRD
A functional homologous recombination repair (HRR) system is required for proper repair of double-strand breaks (DSBs)1,2,3, which, if left unrepaired, are detrimental to living cells. Many genes are involved in the HRR mechanism, which include the commonly known BRCA1 and BRCA2, as well as other HRR genes such as ATM, CHEK2, PALB2 and RAD51. When any of these HRR genes becomes mutated and unable to carry out its usual functions, homologous recombination deficiency (HRD) ensues. Cancer cells with HRD inevitably exhibit genome instability as a phenotype, and loss of heterozygosity (LOH) is often observed in these cells4. LOH occurs when a cancer cell that is originally heterozygous at a locus loses one of its two alleles at that locus. Therefore, LOH can be used as an indicator to assess the HRD status in cancer cells.
PARP Inhibitor Treatment
PARP inhibitors are pharmacological agents that block the activity of a family of DNA damage repair (DDR) proteins called PARPs, which are responsible for repairing single-strand breaks before DNA replication and cell division. If the single-strand breaks remain unrepaired and persist through the DNA replication process, double-strand breaks are formed as a result. PARP inhibitors cause the formation of double-strand breaks by being trapping at the sites of single-strand DNA breaks.
In tumors with homologous recombination repair (HRR) deficiency (also known as HRD, which is caused by mutations in BRCA1/2 or other HRR genes), these double-strand breaks cannot be properly repaired, which ultimately leads to cell death in a phenomenon called synthetic lethality whereby the combination of two individually non-lethal defects (i.e., PARP inhibition and HRD) leads to a unique vulnerability5.
Mutations in Non-BRCA HRR Genes and Cancer
In addition to the well-studied BRCA1 and BRCA2 genes, there is a horde of other HRR genes involved in the DNA repair process. Mutations in any of these non-BRCA HRR genes may also give rise to HRD and a dysfunctional HRR system. Therefore, genetic testing of BRCA1/2 alone is not adequate to select patients who may benefit from PARP inhibitor treatment.
2.Li X, Heyer WD. (2008) Cell Res. 18:99–113.
3.Lord CJ, Ashworth A. (2016) Nat Rev Cancer 16:110–120.
4.Watkins JA, et al. (2014) Breast Cancer Res. 16:211.
5.Hartwell LH, et al. (1997) Science. 278:1064–1068.
Hallmarks of ACTHRD™
Extensive Information on BRCA and HRR genes
Comprehensive genetic testing for BRCA1/2 and other HRR which includes coding exons and splicing regions. Uses NGS technology to detect multiple mutation types, such as single nucleotide variants (SNVs), small insertions and deletions (InDels) and large genomic rearrangements (LGRs), through the use of a proprietary algorithm (patent application in progress), copy number variants (CNVs) and LOH Status.
Up-to-date Bioinformatic Analysis based on International Databases
Bioinformatic analysis is carried out by a team of dedicated and experienced bioinformaticians with a solid clinical genetics background. Information extracted from international databases, such as gnomAD, 1000 Genome, ClinVar, COSMIC as well as ACT Genomics' in-house ethnographic database, provide relevant interpretation and useful insights on the variants identified.
Clear and Detailed Medical Reporting
The report provides recommendations in accordance with the latest ACMG Guidelines and AMP Guidelines, as well as other relevant information such as disease risk based on the currently available clinical literature.
All tests carried out by ACT Genomics are conducted in a CAP-certified laboratory, which has also earned the LDTS (Laboratory Developed Tests and Services) certification by the Taiwan FDA.
Short Turnaround Time
Provides professional solutions within 10 working days (starting from the date of receipt of approved samples at our CAP-accredited laboratory).
Next Generation Sequencing (NGS)
24 genes including BRCA1 & BRCA2
Sequencing Mean Depth
≥ 1000 x
Tumor tissue (FFPE)