{"entity":{"id":"genome-wide-loss-of-heterozygosity","kind":"term","name":"Genome-wide loss of heterozygosity (gLOH)","aka":["gLOH","genomic LOH","LOH score","genome-wide LOH","LOH-high","genomic scar score"],"tldr":"A score for how much of a tumour's genome has lost one of its two parental copies. A high score is a scar left behind by a broken DNA repair system, and is used as a rough sign that a PARP inhibitor might work. It is a measure of damage already done, not of the fault that caused it.","summary":"Every cell carries two copies of most of its genome, one from each parent. Loss of heterozygosity is the loss of one of those copies at a locus; genome-wide loss of heterozygosity is the percentage of the interrogated genome showing it, computed from a targeted next-generation sequencing panel. It is one of the genomic scar measures of homologous recombination deficiency: a cell that cannot repair double-strand breaks accurately falls back on error-prone mechanisms, and the accumulated result is large stretches of single-copy genome. Because it measures the consequence rather than the cause, it can be raised by faults the panel does not sequence, and can be normal in a tumour that has only recently lost repair capacity.\n\nThe threshold is set by the assay, not by biology, and it is a continuous score cut into two boxes. ARIEL2 part 1 prespecified 14 percent or more as loss-of-heterozygosity high in ovarian carcinoma; that cut point was derived and validated for one assay in one disease and does not transfer unchanged. Pan-cancer work from the same platform showed that biallelic BRCA1 and BRCA2 alterations are associated with elevated genome-wide loss of heterozygosity across many tumour types while monoallelic alterations are not (Sokol 2020), and that the association extends beyond BRCA to a core set of homologous recombination repair genes including BARD1, PALB2, FANCC, RAD51C and RAD51D, particularly in breast, ovarian, pancreatic and prostate cancer, with an independent contribution from TP53 loss (Westphalen 2022).\n\nIn prostate cancer it is the number that shows the homologous recombination repair gene list is not one biomarker. Across 3,476 clinically advanced prostate tumours profiled in routine practice, BRCA1, BRCA2, ATR and FANCA alterations were associated with high genome-wide loss of heterozygosity, whereas CDK12-altered tumours, about 6 percent of the disease, were infrequently loss-of-heterozygosity high (Chung 2019). CDK12 is on the gene list that qualifies men for PARP inhibitors in several licences, and by this measure those tumours are not homologous recombination deficient in the sense a PARP inhibitor needs. That, together with TRITON3's hazard ratio of 0.95 in the ATM subgroup against 11.2 versus 6.4 months in the BRCA subgroup, is why the gene list is increasingly read gene by gene rather than as a single qualifying category.","asOf":"2026-09-25","wikipedia":"https://en.wikipedia.org/wiki/Loss_of_heterozygosity","links":[{"label":"Chung et al., JCO Precision Oncology 2019: prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","url":"https://doi.org/10.1200/po.18.00283"},{"label":"Sokol et al., JCO Precision Oncology 2020: pan-cancer analysis of BRCA1 and BRCA2 genomic alterations and their association with genomic instability as measured by genome-wide loss of heterozygosity","url":"https://doi.org/10.1200/po.19.00345"},{"label":"Westphalen et al., Clinical Cancer Research 2022: pan-cancer analysis of homologous recombination repair-associated gene alterations and genome-wide loss-of-heterozygosity score","url":"https://doi.org/10.1158/1078-0432.ccr-21-2096"},{"label":"Swisher et al., Lancet Oncology 2017 (ARIEL2 part 1): rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma","url":"https://doi.org/10.1016/s1470-2045(16)30559-9"},{"label":"Abida et al., Journal of Clinical Oncology 2020 (TRITON2): rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","url":"https://doi.org/10.1200/jco.20.01035"}],"tags":["gu","prostate-glossary"],"related":["hrd","homologous-recombination-repair","chromoplexy","paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","paper-fizazi-triton3-rucaparib-nejm-2023"],"cancers":["prostate","prostate-mcrpc","prostate-mhspc"],"sections":["diagnostics","targeted-therapy"],"technologies":["ngs","parp-inhibitor","liquid-biopsy"],"targets":["brca","atm","cdk12","tp53"],"drugs":["olaparib","rucaparib","niraparib","talazoparib"],"companies":[],"institutions":[],"pathways":["homologous-recombination-repair"],"terms":["hrd","synthetic-lethality","ngs","msi","tmb"],"trials":[],"people":[],"bottlenecks":["b-biomarker-validation","b-resistance","b-regulatory-fragmentation"],"keyPapers":["paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","paper-abida-triton2-rucaparib-brca-jco-2020","paper-fizazi-triton3-rucaparib-nejm-2023"],"journals":[],"dependsOn":[],"notes":["Scar, not cause. A genomic scar score says the repair pathway was broken for long enough to leave a mark. It does not say which gene broke, and it does not say the pathway is still broken now: a tumour that has restored BRCA function by a reversion mutation, the commonest route to PARP inhibitor resistance, keeps its high score and loses its sensitivity.","Whose threshold. There is no single agreed cut point for gLOH-high across assays or across cancers. ARIEL2 part 1's prespecified 14 percent was set for one next-generation sequencing assay in ovarian carcinoma. Any gLOH result should be read with the name of the assay attached, and a result near the threshold should be treated as what it is, a continuous number cut arbitrarily in two.","In prostate practice, tumour sequencing and germline testing answer different questions and both are needed: TRITON2 found similar objective response rates for germline and somatic BRCA alterations, which is why a normal blood test for an inherited fault does not rule out a targetable tumour."],"category":"Genomics & genetics"},"route":"/terms/genome-wide-loss-of-heterozygosity/","neighbours":{"term":[{"id":"ar-v7","kind":"term","name":"AR-V7 splice variant","route":"/terms/ar-v7/"},{"id":"chromoplexy","kind":"term","name":"Chromoplexy","route":"/terms/chromoplexy/"},{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"pathway":[{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"}],"paper":[{"id":"paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019","kind":"paper","name":"Prospective comprehensive genomic profiling of 3,476 primary and metastatic prostate tumours","route":"/key-papers/paper-chung-comprehensive-genomic-profiling-prostate-jco-po-2019/"},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","kind":"paper","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/"},{"id":"paper-fizazi-triton3-rucaparib-nejm-2023","kind":"paper","name":"TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer","route":"/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/"}],"cancer":[{"id":"prostate-mcrpc","kind":"cancer","name":"Metastatic castration-resistant prostate cancer","route":"/cancers/prostate-mcrpc/"},{"id":"prostate-mhspc","kind":"cancer","name":"Metastatic hormone-sensitive prostate cancer","route":"/cancers/prostate-mhspc/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"section":[{"id":"diagnostics","kind":"section","name":"Diagnostics & Biomarkers","route":"/fronts/diagnostics/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"cdk12","kind":"target","name":"CDK12","route":"/targets/cdk12/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"drug":[{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"rucaparib","kind":"drug","name":"Rucaparib","route":"/drugs/rucaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-biomarker-validation","kind":"bottleneck","name":"Biomarkers are not validated or standardised","route":"/bottlenecks/b-biomarker-validation/"},{"id":"b-regulatory-fragmentation","kind":"bottleneck","name":"Regulatory divergence between regions","route":"/bottlenecks/b-regulatory-fragmentation/"}],"idea":[{"id":"idea-prostate-hrr-testing-at-metastatic-diagnosis","kind":"idea","name":"Test every man for DNA repair faults on the day his prostate cancer is found to have spread, not three treatments later","route":"/ideas/idea-prostate-hrr-testing-at-metastatic-diagnosis/"}]}}