I was searching RAD50 and PARPinhibitors and since i am going for a high risk genetic consult i came across this good explanation of different genetic testing.
Title of article:
Homologous Recombination Deficiency in Ovarian, Breast, Colorectal, Pancreatic, Non-Small Cell Lung and Prostate Cancers, and the Mechanisms of Resistance to PARP Inhibitors
ncbi.nlm.nih.gov/pmc/articl...
Here, we investigated the potential implications of pathogenic mutations, LOH, and promoter hypermethylation of HR-related genes using recent data in ovarian, breast, colorectal, pancreatic, non-small cell lung, and prostate cancers. Additionally, the mechanisms underlying PARPI resistance and possible strategies to overcome PARPI resistance are discussed.
besides this being a fantastic article on the following genes:
1.1 BRCA1 and BRCA2 in Homologous Recombination Repair
BRCA1 and 2 interacts with a number of other DNA repair proteins to form a complex system for DNA damage repair, including ATM, RAD51, PALB2, MRE11A, RAD50, NBN, and the Fanconi anemia proteins (30). BRCA1 and BRCA2 are potential biomarkers for HRD in ovarian and breast cancer. In the presence of DNA DSBs, BRCA1 and 2 collaborate with other HR proteins to maintain the breaks. For instance, ATM is specifically activated in response to DSBs and is essential for phosphorylating many proteins involved in controlling cell cycle checkpoints and DNA repair. Three proteins are involved in recruiting ATM to DSBs, meiotic recombination 11 (MRE11A), RAD50, and NBS1 or MRN complex. Cells deficient in ATM and NBS1 are thus sensitive to PARPIs, similar to BRCA1- and BRCA2-deficient cells (7, 31). Germline pathogenic mutations of BRCA1 and BRCA2 suppress the HR mechanism and cause hereditary breast and ovarian cancer (HBOC) syndrome (32, 33). The functions of 35 HR-related genes are described briefly in Supplementary Table S1 .
This is what i need to study to be able to advocate for what test i would like.
The use of PARPIs was recently expanded to other cancers in addition to breast and ovarian cancer, such as prostate and PC (18). Although PARPIs have shown beneficial effects in many other cancer types, the frequent development of resistance is challenging. For instance, in a phase II clinical trial, secondary resistance mutations were detected in circulating free tumor DNA in two patients with a germline BRCA2 mutation. These mutations were predicted to lead to the reversal of a somatic mutation (19). A comprehensive investigation of the underlying mechanisms is necessary to design strategies for overcoming PARPI resistance.
Another challenging issue is the development of effective biomarkers to identify patients who are more likely to respond to specific targeted therapy by using companion diagnosis (CDx). CDx is an in vitro medical device that uses biomarkers to provide information on the safe and effective use of drugs or biologicals. FDA-approved CDx includes BRACAnalysis CDx® and Myriad myChoice® CDx developed by Myriad Genetic Laboratories, and FoundationOne® CDx [F1CDx] and FoundationOne® Liquid CDx developed by Foundation medicine. The HRDetect test utilizes machine learning algorithm (20).
BRACAnalysis CDx® is an in vitro diagnostic method used for the detection and classification of DNA sequence variants in the protein-coding regions, intron or exon boundaries of the germline BRCA1 and 2 genes from whole blood sample. PCR and Sanger sequencing are used to detect small insertions and deletions (indels), and single nucleotide variants (SNVs). Large deletions and duplications are detected by multiplex PCR. The test results used as an aid to identify eligible patients for PARPIs in breast, ovarian, pancreatic and prostate cancers treatment (21). Myriad myChoice® CDx is NGS-based in vitro diagnostic test that evaluates the qualitative detection and classification of SNVs, indels and large rearrangements (LRs) in protein-coding regions and intron/exon boundaries of the BRCA1 and 2 genes, and determine Genomic Instability Score (GIS) by measuring [LOH, TAI, and LST] using DNA isolated from formalin-fixed paraffin-embedded (FFPE) tumor tissue. The test used to select eligible patients for ovarian cancer with positive HRD status for the treatment with Zejula® (niraparib) (22).
FoundationOne®CDx (F1CDx) is a qualitative NGS- and high throughput hybridization-based capture test for the detection of indels, substitutions and copy number alterations (CNAs) in 324 genes. It detects gene rearrangements, genomic signatures including microsatellite instability (MSI), tumor mutational burden (TMB) and positive HRD status (somatic BRCA-positive and/or LOH high) using DNA isolated from FFPE tumor tissue. It provides definite information for the identification of eligible patients for specific treatments of different class using specific biomarkers for many solid tumors (23).
FoundationOne® Liquid CDx is a qualitative NGS based test, which can identify indels, and substitutions in 311 genes, rearrangements in 4 genes and CNAs in 3 genes. It utilizes circulating cell-free DNA (cfDNA) isolated from plasma-driven peripheral whole blood collected in anti-coagulants. The test identifies patients that can benefit from different targeted treatments for NSCLC, breast, ovarian and prostate cancers based on specific biomarkers detected in each cancer. Negative result does not rule out the presence of an alteration in the patient’s tumor, in this case patients can opt for another tumor tissue-based CDx. The test analytical accuracy is not well demonstrated in all genes e.g., the test does not detect heterozygous deletions, and copy number losses/homozygous deletion in ATM (24).
HRDetect is a whole genome sequencing (WGS)-based classifier of HRD that can predict BRCA1 and 2 deficiency based on six mutational signatures (the HRD index [LOH + TAI + LST], microhomology-mediated indels, base-substitution signature 3 and 8, and rearrangement signature 3 and 5). It can also identify HRD in sporadic cancers (BRCAness) with and without any single detectable defect in HR genes (20, 25). HRDetect was shown highly sensitive method as compared to other HRD detection CDxs (20), but require clinical validation in independent set to avoid overfitting issue.
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