Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival
To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC. We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/3...
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| creator | Kahn, Ryan M. Selenica, Pier Boerner, Thomas Roche, Kara Long Xiao, Yonghong Sia, Tiffany Y. Maio, Anna Kemel, Yelena Sheehan, Margaret Salo-Mullen, Erin Breen, Kelsey E. Zhou, Qin Iasonos, Alexia Grisham, Rachel N. O’Cearbhaill, Roisin E. Chi, Dennis S. Berger, Michael F. Kundra, Ritika Schultz, Nikolaus Ellenson, Lora H. Stadler, Zsofia K. Offit, Kenneth Mandelker, Diana Aghajanian, Carol Zamarin, Dmitriy Sabbatini, Paul Weigelt, Britta Liu, Ying L. |
| description | To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1–6.0] vs. 1.2 mut/Mb [0.6–2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p |
| doi_str_mv | 10.1016/j.ygyno.2023.11.019 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2896811440</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0090825823015639</els_id><sourcerecordid>2896811440</sourcerecordid><originalsourceid>FETCH-LOGICAL-c359t-2a05d6456d8b9673cc1ad6c9d7e1b72f696c4d9961c62e8379ac246de81246213</originalsourceid><addsrcrecordid>eNp9kc1uEzEUhS0EoqHwBEjISzYz9fXMODYSizTiT6rUCsHacuybxNGMHeyZSPMCPDduU7rs6my-c4_uOYS8B1YDA3F1qOfdHGLNGW9qgJqBekEWwFRXCdmpl2TBmGKV5J28IG9yPjDGGgb8NbloJGtBMViQv3dm3McdBm_pDtPQ-4D0ZJI3YczUBxpiqK5_rldwxek-DrGPuzhlmtDGYeODGX0MxRnwgY5nK7UmWEyf6CqYfs4-07il4zTERI97DHGcj0hNcDRP6eRPpn9LXm1Nn_Hdo16S31-__Fp_r25uv_1Yr24q23RqrLhhnRNtJ5zcKLFsrAXjhFVuibBZ8q1QwrZOKQFWcJTNUhnLW-FQQhEOzSX5eL57TPHPhHnUg88W-94ELG9pLpWQAG3LCtqcUZtizgm3-pj8YNKsgen7AfRBPwyg7wfQALoMUFwfHgOmzYDuyfO_8QJ8PgNY3jx5TDpbj6Ut50uno3bRPxvwDyIcmdI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2896811440</pqid></control><display><type>article</type><title>Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Kahn, Ryan M. ; Selenica, Pier ; Boerner, Thomas ; Roche, Kara Long ; Xiao, Yonghong ; Sia, Tiffany Y. ; Maio, Anna ; Kemel, Yelena ; Sheehan, Margaret ; Salo-Mullen, Erin ; Breen, Kelsey E. ; Zhou, Qin ; Iasonos, Alexia ; Grisham, Rachel N. ; O’Cearbhaill, Roisin E. ; Chi, Dennis S. ; Berger, Michael F. ; Kundra, Ritika ; Schultz, Nikolaus ; Ellenson, Lora H. ; Stadler, Zsofia K. ; Offit, Kenneth ; Mandelker, Diana ; Aghajanian, Carol ; Zamarin, Dmitriy ; Sabbatini, Paul ; Weigelt, Britta ; Liu, Ying L.</creator><creatorcontrib>Kahn, Ryan M. ; Selenica, Pier ; Boerner, Thomas ; Roche, Kara Long ; Xiao, Yonghong ; Sia, Tiffany Y. ; Maio, Anna ; Kemel, Yelena ; Sheehan, Margaret ; Salo-Mullen, Erin ; Breen, Kelsey E. ; Zhou, Qin ; Iasonos, Alexia ; Grisham, Rachel N. ; O’Cearbhaill, Roisin E. ; Chi, Dennis S. ; Berger, Michael F. ; Kundra, Ritika ; Schultz, Nikolaus ; Ellenson, Lora H. ; Stadler, Zsofia K. ; Offit, Kenneth ; Mandelker, Diana ; Aghajanian, Carol ; Zamarin, Dmitriy ; Sabbatini, Paul ; Weigelt, Britta ; Liu, Ying L.</creatorcontrib><description>To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1–6.0] vs. 1.2 mut/Mb [0.6–2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01).
OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.
•Those with germline pathogenic variants (PV) in non-BRCA1/2 homologous recombination (HR) genes were a heterogeneous group.•There was enrichment of HR-deficient (HRD) phenotype in those with germline PVs in PALB2 and RAD51B/C/D compared to BRIP1.•Patients with BRCA1/2-associated ovarian cancer (OC) had improved survival compared to those with wildtype OC.•Survival was variable among those with germline PVs in other HR genes.•OC associated with germline PVs in PALB2 and RAD51B/C/D may have similar features to BRCA1/2-associated OC.</description><identifier>ISSN: 0090-8258</identifier><identifier>ISSN: 1095-6859</identifier><identifier>EISSN: 1095-6859</identifier><identifier>DOI: 10.1016/j.ygyno.2023.11.019</identifier><identifier>PMID: 38041901</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>BRCA1 Protein - genetics ; BRCA1/2 ; BRCA2 Protein - genetics ; Female ; Genetic Predisposition to Disease ; Genetics ; Germ Cells - pathology ; Germ-Line Mutation ; Homologous Recombination ; Humans ; Ovarian cancer ; Ovarian Neoplasms - pathology ; Phenotype ; Poly (ADP-ribose) polymerase ; Survival</subject><ispartof>Gynecologic oncology, 2024-01, Vol.180, p.35-43</ispartof><rights>2023 Elsevier Inc.</rights><rights>Copyright © 2023 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c359t-2a05d6456d8b9673cc1ad6c9d7e1b72f696c4d9961c62e8379ac246de81246213</citedby><cites>FETCH-LOGICAL-c359t-2a05d6456d8b9673cc1ad6c9d7e1b72f696c4d9961c62e8379ac246de81246213</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0090825823015639$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38041901$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kahn, Ryan M.</creatorcontrib><creatorcontrib>Selenica, Pier</creatorcontrib><creatorcontrib>Boerner, Thomas</creatorcontrib><creatorcontrib>Roche, Kara Long</creatorcontrib><creatorcontrib>Xiao, Yonghong</creatorcontrib><creatorcontrib>Sia, Tiffany Y.</creatorcontrib><creatorcontrib>Maio, Anna</creatorcontrib><creatorcontrib>Kemel, Yelena</creatorcontrib><creatorcontrib>Sheehan, Margaret</creatorcontrib><creatorcontrib>Salo-Mullen, Erin</creatorcontrib><creatorcontrib>Breen, Kelsey E.</creatorcontrib><creatorcontrib>Zhou, Qin</creatorcontrib><creatorcontrib>Iasonos, Alexia</creatorcontrib><creatorcontrib>Grisham, Rachel N.</creatorcontrib><creatorcontrib>O’Cearbhaill, Roisin E.</creatorcontrib><creatorcontrib>Chi, Dennis S.</creatorcontrib><creatorcontrib>Berger, Michael F.</creatorcontrib><creatorcontrib>Kundra, Ritika</creatorcontrib><creatorcontrib>Schultz, Nikolaus</creatorcontrib><creatorcontrib>Ellenson, Lora H.</creatorcontrib><creatorcontrib>Stadler, Zsofia K.</creatorcontrib><creatorcontrib>Offit, Kenneth</creatorcontrib><creatorcontrib>Mandelker, Diana</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Zamarin, Dmitriy</creatorcontrib><creatorcontrib>Sabbatini, Paul</creatorcontrib><creatorcontrib>Weigelt, Britta</creatorcontrib><creatorcontrib>Liu, Ying L.</creatorcontrib><title>Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival</title><title>Gynecologic oncology</title><addtitle>Gynecol Oncol</addtitle><description>To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1–6.0] vs. 1.2 mut/Mb [0.6–2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01).
OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.
•Those with germline pathogenic variants (PV) in non-BRCA1/2 homologous recombination (HR) genes were a heterogeneous group.•There was enrichment of HR-deficient (HRD) phenotype in those with germline PVs in PALB2 and RAD51B/C/D compared to BRIP1.•Patients with BRCA1/2-associated ovarian cancer (OC) had improved survival compared to those with wildtype OC.•Survival was variable among those with germline PVs in other HR genes.•OC associated with germline PVs in PALB2 and RAD51B/C/D may have similar features to BRCA1/2-associated OC.</description><subject>BRCA1 Protein - genetics</subject><subject>BRCA1/2</subject><subject>BRCA2 Protein - genetics</subject><subject>Female</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetics</subject><subject>Germ Cells - pathology</subject><subject>Germ-Line Mutation</subject><subject>Homologous Recombination</subject><subject>Humans</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Phenotype</subject><subject>Poly (ADP-ribose) polymerase</subject><subject>Survival</subject><issn>0090-8258</issn><issn>1095-6859</issn><issn>1095-6859</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1uEzEUhS0EoqHwBEjISzYz9fXMODYSizTiT6rUCsHacuybxNGMHeyZSPMCPDduU7rs6my-c4_uOYS8B1YDA3F1qOfdHGLNGW9qgJqBekEWwFRXCdmpl2TBmGKV5J28IG9yPjDGGgb8NbloJGtBMViQv3dm3McdBm_pDtPQ-4D0ZJI3YczUBxpiqK5_rldwxek-DrGPuzhlmtDGYeODGX0MxRnwgY5nK7UmWEyf6CqYfs4-07il4zTERI97DHGcj0hNcDRP6eRPpn9LXm1Nn_Hdo16S31-__Fp_r25uv_1Yr24q23RqrLhhnRNtJ5zcKLFsrAXjhFVuibBZ8q1QwrZOKQFWcJTNUhnLW-FQQhEOzSX5eL57TPHPhHnUg88W-94ELG9pLpWQAG3LCtqcUZtizgm3-pj8YNKsgen7AfRBPwyg7wfQALoMUFwfHgOmzYDuyfO_8QJ8PgNY3jx5TDpbj6Ut50uno3bRPxvwDyIcmdI</recordid><startdate>202401</startdate><enddate>202401</enddate><creator>Kahn, Ryan M.</creator><creator>Selenica, Pier</creator><creator>Boerner, Thomas</creator><creator>Roche, Kara Long</creator><creator>Xiao, Yonghong</creator><creator>Sia, Tiffany Y.</creator><creator>Maio, Anna</creator><creator>Kemel, Yelena</creator><creator>Sheehan, Margaret</creator><creator>Salo-Mullen, Erin</creator><creator>Breen, Kelsey E.</creator><creator>Zhou, Qin</creator><creator>Iasonos, Alexia</creator><creator>Grisham, Rachel N.</creator><creator>O’Cearbhaill, Roisin E.</creator><creator>Chi, Dennis S.</creator><creator>Berger, Michael F.</creator><creator>Kundra, Ritika</creator><creator>Schultz, Nikolaus</creator><creator>Ellenson, Lora H.</creator><creator>Stadler, Zsofia K.</creator><creator>Offit, Kenneth</creator><creator>Mandelker, Diana</creator><creator>Aghajanian, Carol</creator><creator>Zamarin, Dmitriy</creator><creator>Sabbatini, Paul</creator><creator>Weigelt, Britta</creator><creator>Liu, Ying L.</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202401</creationdate><title>Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival</title><author>Kahn, Ryan M. ; Selenica, Pier ; Boerner, Thomas ; Roche, Kara Long ; Xiao, Yonghong ; Sia, Tiffany Y. ; Maio, Anna ; Kemel, Yelena ; Sheehan, Margaret ; Salo-Mullen, Erin ; Breen, Kelsey E. ; Zhou, Qin ; Iasonos, Alexia ; Grisham, Rachel N. ; O’Cearbhaill, Roisin E. ; Chi, Dennis S. ; Berger, Michael F. ; Kundra, Ritika ; Schultz, Nikolaus ; Ellenson, Lora H. ; Stadler, Zsofia K. ; Offit, Kenneth ; Mandelker, Diana ; Aghajanian, Carol ; Zamarin, Dmitriy ; Sabbatini, Paul ; Weigelt, Britta ; Liu, Ying L.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c359t-2a05d6456d8b9673cc1ad6c9d7e1b72f696c4d9961c62e8379ac246de81246213</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>BRCA1 Protein - genetics</topic><topic>BRCA1/2</topic><topic>BRCA2 Protein - genetics</topic><topic>Female</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetics</topic><topic>Germ Cells - pathology</topic><topic>Germ-Line Mutation</topic><topic>Homologous Recombination</topic><topic>Humans</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Phenotype</topic><topic>Poly (ADP-ribose) polymerase</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kahn, Ryan M.</creatorcontrib><creatorcontrib>Selenica, Pier</creatorcontrib><creatorcontrib>Boerner, Thomas</creatorcontrib><creatorcontrib>Roche, Kara Long</creatorcontrib><creatorcontrib>Xiao, Yonghong</creatorcontrib><creatorcontrib>Sia, Tiffany Y.</creatorcontrib><creatorcontrib>Maio, Anna</creatorcontrib><creatorcontrib>Kemel, Yelena</creatorcontrib><creatorcontrib>Sheehan, Margaret</creatorcontrib><creatorcontrib>Salo-Mullen, Erin</creatorcontrib><creatorcontrib>Breen, Kelsey E.</creatorcontrib><creatorcontrib>Zhou, Qin</creatorcontrib><creatorcontrib>Iasonos, Alexia</creatorcontrib><creatorcontrib>Grisham, Rachel N.</creatorcontrib><creatorcontrib>O’Cearbhaill, Roisin E.</creatorcontrib><creatorcontrib>Chi, Dennis S.</creatorcontrib><creatorcontrib>Berger, Michael F.</creatorcontrib><creatorcontrib>Kundra, Ritika</creatorcontrib><creatorcontrib>Schultz, Nikolaus</creatorcontrib><creatorcontrib>Ellenson, Lora H.</creatorcontrib><creatorcontrib>Stadler, Zsofia K.</creatorcontrib><creatorcontrib>Offit, Kenneth</creatorcontrib><creatorcontrib>Mandelker, Diana</creatorcontrib><creatorcontrib>Aghajanian, Carol</creatorcontrib><creatorcontrib>Zamarin, Dmitriy</creatorcontrib><creatorcontrib>Sabbatini, Paul</creatorcontrib><creatorcontrib>Weigelt, Britta</creatorcontrib><creatorcontrib>Liu, Ying L.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Gynecologic oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kahn, Ryan M.</au><au>Selenica, Pier</au><au>Boerner, Thomas</au><au>Roche, Kara Long</au><au>Xiao, Yonghong</au><au>Sia, Tiffany Y.</au><au>Maio, Anna</au><au>Kemel, Yelena</au><au>Sheehan, Margaret</au><au>Salo-Mullen, Erin</au><au>Breen, Kelsey E.</au><au>Zhou, Qin</au><au>Iasonos, Alexia</au><au>Grisham, Rachel N.</au><au>O’Cearbhaill, Roisin E.</au><au>Chi, Dennis S.</au><au>Berger, Michael F.</au><au>Kundra, Ritika</au><au>Schultz, Nikolaus</au><au>Ellenson, Lora H.</au><au>Stadler, Zsofia K.</au><au>Offit, Kenneth</au><au>Mandelker, Diana</au><au>Aghajanian, Carol</au><au>Zamarin, Dmitriy</au><au>Sabbatini, Paul</au><au>Weigelt, Britta</au><au>Liu, Ying L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival</atitle><jtitle>Gynecologic oncology</jtitle><addtitle>Gynecol Oncol</addtitle><date>2024-01</date><risdate>2024</risdate><volume>180</volume><spage>35</spage><epage>43</epage><pages>35-43</pages><issn>0090-8258</issn><issn>1095-6859</issn><eissn>1095-6859</eissn><abstract>To define molecular features of ovarian cancer (OC) with germline pathogenic variants (PVs) in non-BRCA homologous recombination (HR) genes and analyze survival compared to BRCA1/2 and wildtype (WT) OC.
We included patients with OC undergoing tumor-normal sequencing (MSK-IMPACT) from 07/01/2015–12/31/2020, including germline assessment of BRCA1/2 and other HR genes ATM, BARD1, BRIP1, FANCA, FANCC, NBN, PALB2, RAD50, RAD51B, RAD51C, and RAD51D. Biallelic inactivation was assessed within tumors. Progression-free (PFS) and overall survival (OS) were calculated from pathologic diagnosis using the Kaplan-Meier method with left truncation. Whole-exome sequencing (WES) was performed in a subset.
Of 882 patients with OC, 56 (6.3%) had germline PVs in non-BRCA HR genes; 95 (11%) had BRCA1-associated OC (58 germline, 37 somatic); and 59 (6.7%) had BRCA2-associated OC (40 germline, 19 somatic). High rates of biallelic alterations were observed among germline PVs in BRIP1 (11/13), PALB2 (3/4), RAD51B (3/4), RAD51C (3/4), and RAD51D (8/10). In cases with WES (27/35), there was higher tumor mutational burden (TMB; median 2.5 [1.1–6.0] vs. 1.2 mut/Mb [0.6–2.6]) and enrichment of HR-deficient (HRD) mutational signatures in tumors associated with germline PALB2 and RAD51B/C/D compared with BRIP1 PVs (p < 0.01). Other features of HRD, including telomeric-allelic imbalance (TAI) and large-scale state transitions (LSTs), were similar. Although there was heterogeneity in PFS/OS by gene group, only BRCA1/2-associated OC had improved survival compared to WT OC (p < 0.01).
OCs associated with germline PVs in non-BRCA HR genes represent a heterogenous group, with PALB2 and RAD51B/C/D associated with an HRD phenotype.
•Those with germline pathogenic variants (PV) in non-BRCA1/2 homologous recombination (HR) genes were a heterogeneous group.•There was enrichment of HR-deficient (HRD) phenotype in those with germline PVs in PALB2 and RAD51B/C/D compared to BRIP1.•Patients with BRCA1/2-associated ovarian cancer (OC) had improved survival compared to those with wildtype OC.•Survival was variable among those with germline PVs in other HR genes.•OC associated with germline PVs in PALB2 and RAD51B/C/D may have similar features to BRCA1/2-associated OC.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>38041901</pmid><doi>10.1016/j.ygyno.2023.11.019</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0090-8258 |
| ispartof | Gynecologic oncology, 2024-01, Vol.180, p.35-43 |
| issn | 0090-8258 1095-6859 1095-6859 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2896811440 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | BRCA1 Protein - genetics BRCA1/2 BRCA2 Protein - genetics Female Genetic Predisposition to Disease Genetics Germ Cells - pathology Germ-Line Mutation Homologous Recombination Humans Ovarian cancer Ovarian Neoplasms - pathology Phenotype Poly (ADP-ribose) polymerase Survival |
| title | Pathogenic germline variants in non-BRCA1/2 homologous recombination genes in ovarian cancer: Analysis of tumor phenotype and survival |
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