Alterations in homologous recombination repair genes in prostate cancer brain metastases

被引：17

作者：

Rodriguez-Calero, Antonio ^{[1
,2
]}

Gallon, John ^{[3
]}

Akhoundova, Dilara ^{[1
,4
]}

Maletti, Sina ^{[1
,5
]}

Ferguson, Alison ^{[6
]}

Cyrta, Joanna ^{[7
]}

Amstutz, Ursula ^{[8
]}

Garofoli, Andrea ^{[8
]}

Paradiso, Viola ^{[9
,10
]}

Tomlins, Scott A. ^{[2
,24
,25
]}

Hewer, Ekkehard ^{[2
]}

Genitsch, Vera ^{[2
]}

Fleischmann, Achim ^{[2
,11
]}

Vassella, Erik ^{[2
]}

Rushing, Elisabeth J. ^{[12
]}

Grobholz, Rainer ^{[13
]}

Fischer, Ingeborg ^{[13
]}

Jochum, Wolfram ^{[14
]}

Cathomas, Gieri ^{[15
]}

Osunkoya, Adeboye O. ^{[16
,17
]}

Bubendorf, Lukas ^{[8
]}

Moch, Holger ^{[18
]}

Thalmann, George ^{[19
]}

Ng, Charlotte K. Y. ^{[1
]}

Gillessen, Silke ^{[20
,21
,22
]}

Piscuoglio, Salvatore ^{[3
,8
]}

Rubin, Mark A. ^{[1
,23
]}

机构：

[1] Univ Bern, Dept BioMed Res, Bern, Switzerland

[2] Univ Bern, Inst Pathol, Bern, Switzerland

[3] Univ Basel, Dept Biomed, Visceral Surg & Precis Med Res Lab, Basel, Switzerland

[4] Univ Hosp Zurich, Dept Med Oncol & Hematol, Zurich, Switzerland

[5] Univ Lausanne, Ludwig Canc Ctr, Dept Oncol, Lausanne, Switzerland

[6] Univ Paris Sci & Lettres, Inst Curie, Dept Pathol, Paris, France

[7] Univ Bern, Bern Univ Hosp, Dept Clin Chem, Inselspital, Bern, Switzerland

[8] Univ Basel, Univ Hosp Basel, Inst Med Genet & Pathol, Basel, Switzerland

[9] Univ Michigan, Med Sch, Dept Pathol, Ann Arbor, MI 48109 USA

[10] Univ Michigan, Med Sch, Dept Urol, Ann Arbor, MI 48109 USA

[11] Cantonal Hosp Thurgau, Inst Pathol, Munsterlingen, Switzerland

[12] Univ Hosp Zurich, Inst Neuropathol, Zurich, Switzerland

[13] Cantonal Hosp Aarau, Inst Pathol, Aarau, Switzerland

[14] Cantonal Hosp St Gallen, Inst Pathol, St Gallen, Switzerland

[15] Cantonal Hosp Baselland, Inst Pathol, Liestal, Switzerland

[16] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA

[17] Emory Univ, Sch Med, Dept Urol, Atlanta, GA 30322 USA

[18] Univ Hosp Zurich, Dept Pathol & Mol Pathol, Zurich, Switzerland

[19] Bern Univ Hosp, Dept Urol, Inselspital, Bern, Switzerland

[20] USI, Fac Biomed Sci, Lugano, Switzerland

[21] Cantonal Hosp St Gallen, Dept Oncol, St Gallen, Switzerland

[22] Univ Manchester, Div Canc Sci, Manchester, Lancs, England

[23] Univ Bern, Bern Univ Hosp, Bern Ctr Precis Med, Inselspital, Bern, Switzerland

[24] Lausanne Univ Hosp, Inst Pathol, Lausanne, Switzerland

[25] Univ Lausanne, Lausanne, Switzerland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

关键词：

MUTATIONAL SIGNATURES; BREAST-CANCER; INSTABILITY; DEFICIENCY; CARCINOMAS; DISCOVERY; GENOMICS; SURVIVAL; EZH2;

D O I：

10.1038/s41467-022-30003-5

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Improved survival rates for prostate cancer through more effective therapies have also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. Here we investigate the repertoire of somatic genetic alterations present in brain metastases from 51 patients with prostate cancer brain metastases (PCBM). We highlight the clonal evolution occurring in PCBM and demonstrate an increased mutational burden, concomitant with an enrichment of the homologous recombination deficiency mutational signature in PCBM compared to non-brain metastases. Focusing on known pathogenic alterations within homologous recombination repair genes, we find 10 patients (19.6%) fulfilling the inclusion criteria used in the PROfound clinical trial, which assessed the efficacy of PARP inhibitors (PARPi) in homologous recombination deficient prostate cancer. Eight (15.7%) patients show biallelic loss of one of the 15 genes included in the trial, while 5 patients (9.8%) harbor pathogenic alterations in BRCA1/2 specifically. Uncovering these molecular features of PCBM may have therapeutic implications, suggesting the need of clinical trial enrollment of PCBM patients when evaluating potential benefit from PARPi. The diagnosis of prostate cancer brain metastasis (PCBM) has increased. Here, the authors investigate the landscape of somatic genetic alterations in brain metastases in a PCBM cohort of 51 patients with non-synchronous matched primary samples available for 20 patients.

引用

页数：10

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