{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T20:30:07Z","timestamp":1783542607197,"version":"3.55.0"},"reference-count":33,"publisher":"American Society of Clinical Oncology (ASCO)","issue":"7","content-domain":{"domain":["ascopubs.org"],"crossmark-restriction":true},"short-container-title":["JCO Precis Oncol"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>PURPOSE<\/jats:title>\n                    <jats:p>Patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD) benefit from poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) or platinum-based chemotherapy (PlCh). Pathogenic variants in homologous recombination repair genes are used as a proxy for the phenotype. Genomic Instability Score (GIS) is a metric for the effect of HRD. This study used shallow whole-genome sequencing (sWGS), a cost-effective alternative to full-depth WGS, to calculate GIS and evaluate its predictive value for PARPi or PlCh response.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>PATIENTS AND METHODS<\/jats:title>\n                    <jats:p>We analyzed 288 tumor samples from 266 patients with mCRPC, consisting of 120 whole-genome samples from formalin-fixed paraffin-embedded material newly profiled at a sequencing depth of 2\u00d7 and 168 from fresh frozen material downsampled in silico from 106\u00d7 to 2\u00d7. The GIS was defined as the sum of large-scale transitions, telomeric-allelic imbalances, and genomic loss of heterozygosity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      The median GIS was 26 (IQR, 19-37). Samples with pathogenic variants in\n                      <jats:italic toggle=\"yes\">BRCA1<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">BRCA2<\/jats:italic>\n                      , or\n                      <jats:italic toggle=\"yes\">PALB2<\/jats:italic>\n                      (BRCA complex) had a significantly higher median GIS (38\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      26,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      &lt; .0005). The median GIS increased significantly with tumor ploidy. Patients showing \u226550% prostate-specific antigen (PSA) declines had higher GIS on both PARPi (median 40\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      28,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .0003) and PlCh (41\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      26,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .0113). Similarly, patients with a partial response by RECIST1.1 had higher GIS than those with progressive disease (PARPi: 39\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      26,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .0356; PlCh: 44\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      25,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .0046). Adding GIS to BRCA-complex status improved PSA response prediction in logistic models (AUC PARPi: 0.849\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.781,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .0308; PlCh: 0.731\n                      <jats:italic toggle=\"yes\">v<\/jats:italic>\n                      0.658,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      = .1888).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>GIS assessment by sWGS is feasible and associated with response to PARPis and PlCh. The combination of BRCA-complex status and GIS is superior to BRCA-complex status alone in predicting PSA response to PARPis but not to PlCh.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1200\/po-26-00065","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T19:59:12Z","timestamp":1783540752000},"update-policy":"https:\/\/doi.org\/10.1200\/crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Shallow Whole-Genome Sequencing to Assess Genomic Instability and Predict Treatment Response in Metastatic Castration-Resistant Prostate Cancer"],"prefix":"10.1200","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5635-919X","authenticated-orcid":true,"given":"Peter H.J.","family":"Slootbeek","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3544-3712","authenticated-orcid":true,"given":"Yarah M.","family":"Quint","sequence":"additional","affiliation":[{"name":"Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4079-062X","authenticated-orcid":true,"given":"Julian J.R.","family":"Kokke","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4511-2585","authenticated-orcid":true,"given":"Samhita","family":"Pamidimarri Naga","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0381-6246","authenticated-orcid":true,"given":"Maria Victoria","family":"Luna-Velez","sequence":"additional","affiliation":[{"name":"Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-1474","authenticated-orcid":true,"given":"Marjolijn J.L.","family":"Ligtenberg","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands"},{"name":"Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-0343","authenticated-orcid":true,"given":"Richarda M.","family":"de Voer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4794-1831","authenticated-orcid":true,"given":"Niven","family":"Mehra","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"e_1_3_8_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216367"},{"key":"e_1_3_8_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33306"},{"key":"e_1_3_8_4_2","doi-asserted-by":"publisher","unstructured":"Mota JM Barnett E Nauseef JT et al: Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol 10.1200\/PO.19.00346","DOI":"10.1200\/PO.19.00346"},{"key":"e_1_3_8_5_2","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2020.21692"},{"key":"e_1_3_8_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-024-10238-y"},{"key":"e_1_3_8_7_2","doi-asserted-by":"publisher","unstructured":"Christinat Y Ho L Cl\u00e9ment S et al: Normalized LST is an efficient biomarker for homologous recombination deficiency and olaparib response in ovarian carcinoma. JCO Precis Oncol 10.1200\/po.22.00555","DOI":"10.1200\/po.22.00555"},{"key":"e_1_3_8_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2024.05.005"},{"key":"e_1_3_8_9_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-1470"},{"key":"e_1_3_8_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexmp.2018.03.006"},{"key":"e_1_3_8_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2020.02.009"},{"key":"e_1_3_8_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djae160"},{"key":"e_1_3_8_13_2","doi-asserted-by":"publisher","unstructured":"Pamidimarri Naga S Slootbeek PHJ Tolmeijer SH et al: Assessing the detection power of genome-wide copy number variation profiles in prostate cancer using simulated shallow whole-genome sequencing data. JCO Clin Cancer Inform 10.1200\/cci-25-00240","DOI":"10.1200\/cci-25-00240"},{"key":"e_1_3_8_14_2","volume-title":"hartwigmedical\/hmftools","author":"GitHub, Inc","unstructured":"GitHub, Inc: hartwigmedical\/hmftools. https:\/\/github.com\/hartwigmedical\/hmftools"},{"key":"e_1_3_8_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_3_8_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmoldx.2016.10.002"},{"key":"e_1_3_8_17_2","doi-asserted-by":"publisher","unstructured":"Zurita AJ Graf RP Villacampa G et al: Genomic biomarkers and genome-wide loss-of-heterozygosity scores in metastatic prostate cancer following progression on androgen-targeting therapies. JCO Precis Oncol 10.1200\/po.22.00195","DOI":"10.1200\/po.22.00195"},{"key":"e_1_3_8_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-022-00976-3"},{"key":"e_1_3_8_19_2","volume-title":"The TP53 Database","unstructured":"The TP53 Database. https:\/\/tp53.isb-cgc.org"},{"key":"e_1_3_8_20_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.2702"},{"key":"e_1_3_8_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_3_8_22_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-2477"},{"key":"e_1_3_8_23_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-0034"},{"key":"e_1_3_8_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0274-8"},{"key":"e_1_3_8_25_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13050946"},{"key":"e_1_3_8_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-023-07046-3"},{"key":"e_1_3_8_27_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1911361"},{"key":"e_1_3_8_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-015-3435-y"},{"key":"e_1_3_8_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdy460"},{"key":"e_1_3_8_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19406-4"},{"key":"e_1_3_8_31_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-015-0033-4"},{"key":"e_1_3_8_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0268-6"},{"key":"e_1_3_8_33_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00339"},{"key":"e_1_3_8_34_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI132031"}],"container-title":["JCO Precision Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascopubs.org\/doi\/pdfdirect\/10.1200\/PO-26-00065","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T19:59:14Z","timestamp":1783540754000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascopubs.org\/doi\/10.1200\/PO-26-00065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":33,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1200\/PO-26-00065"],"URL":"https:\/\/doi.org\/10.1200\/po-26-00065","relation":{},"ISSN":["2473-4284"],"issn-type":[{"value":"2473-4284","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]},"assertion":[{"value":"2026-01-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-26","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-02","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-08","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2600065"}}