Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma
Copyright © 2023 American Association for the Study of Liver Diseases..
BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts.
APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors.
CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed.
| Errataetall: |
CommentIn: Hepatology. 2023 Aug 1;78(2):375-377. - PMID 36626621 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:78 |
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| Enthalten in: |
Hepatology (Baltimore, Md.) - 78(2023), 2 vom: 01. Aug., Seite 452-467 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
An, Jihyun [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 19.07.2023 Date Revised 02.09.2023 published: Print-Electronic CommentIn: Hepatology. 2023 Aug 1;78(2):375-377. - PMID 36626621 Citation Status MEDLINE |
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| doi: |
10.1002/hep.32812 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM346932351 |
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| 245 | 1 | 0 | |a Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma |
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| 500 | |a Date Revised 02.09.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Hepatology. 2023 Aug 1;78(2):375-377. - PMID 36626621 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 American Association for the Study of Liver Diseases. | ||
| 520 | |a BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts | ||
| 520 | |a APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors | ||
| 520 | |a CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 700 | 1 | |a Oh, Ji-Hye |e verfasserin |4 aut | |
| 700 | 1 | |a Oh, Bora |e verfasserin |4 aut | |
| 700 | 1 | |a Oh, Yoo-Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Ju, Jin-Sung |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Wonkyung |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Hyo Jung |e verfasserin |4 aut | |
| 700 | 1 | |a Sung, Chang Ohk |e verfasserin |4 aut | |
| 700 | 1 | |a Shim, Ju Hyun |e verfasserin |4 aut | |
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