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Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability

  • Preclinical study
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Abstract

Purpose

Germline mutations in CHEK2 gene represent the second most frequent cause of hereditary breast cancer (BC) after BRCA1/2 lesions. This study aimed to identify the molecular characteristics of CHEK2-driven BCs.

Methods

Loss of heterozygosity (LOH) for the remaining CHEK2 allele was examined in 50 CHEK2-driven BCs using allele-specific PCR assays for the germline mutations and analysis of surrounding single-nucleotide polymorphisms (SNPs). Paired tumor and normal DNA samples from 25 cases were subjected to next-generation sequencing analysis.

Results

CHEK2 LOH was detected in 28/50 (56%) BCs. LOH involved the wild-type allele in 24 BCs, mutant CHEK2 copy was deleted in 3 carcinomas, while in one case the origin of the deleted allele could not be identified. Somatic PIK3CA and TP53 mutations were present in 13/25 (52%) and 4/25 (16%) tumors, respectively. Genomic features of homologous recombination deficiency (HRD), including the HRD score ≥ 42, the predominance of BRCA-related mutational signature 3, and the high proportion of long (≥ 5 bp) indels, were observed only in 1/20 (5%) BC analyzed for chromosomal instability. Tumors with the deleted wild-type CHEK2 allele differed from LOH-negative cases by elevated HRD scores (median 23 vs. 7, p = 0.010) and higher numbers of chromosomal segments affected by copy number aberrations (p = 0.008).

Conclusion

Somatic loss of the wild-type CHEK2 allele is observed in approximately half of CHEK2-driven BCs. Tumors without CHEK2 LOH are chromosomally stable. BCs with LOH demonstrate some signs of chromosomal instability; however, its degree is significantly lower as compared to BRCA1/2-associated cancers.

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Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

References

  1. Sokolenko AP, Bogdanova N, Kluzniak W, Preobrazhenskaya EV, Kuligina ES, Iyevleva AG, Aleksakhina SN, Mitiushkina NV, Gorodnova TV, Bessonov AA, Togo AV, Lubiński J, Cybulski C, Jakubowska A, Dörk T, Imyanitov EN (2014) Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations. Breast Cancer Res Treat 145(2):553–562. https://doi.org/10.1007/s10549-014-2971-1

    Article  CAS  PubMed  Google Scholar 

  2. Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, Evans DG, Eccles D, Meijers C, Lohman F, Klijn J, van den Ouweland A, Futreal PA, Nathanson KL, Weber BL, Easton DF, Stratton MR, Rahman N, Breast Cancer Linkage Consortium (2003) Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J Hum Genet 72(4):1023–1028. https://doi.org/10.1086/373965

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Weischer M, Bojesen SE, Ellervik C, Tybjaerg-Hansen A, Nordestgaard BG (2008) CHEK2*1100delC genotyping for clinical assessment of breast cancer risk: meta-analyses of 26,000 patient cases and 27,000 controls. J Clin Oncol 26(4):542–548. https://doi.org/10.1200/JCO.2007.12.5922

    Article  PubMed  Google Scholar 

  4. Cybulski C, Huzarski T, Górski B, Masojć B, Mierzejewski M, Debniak T, Gliniewicz B, Matyjasik J, Złowocka E, Kurzawski G, Sikorski A, Posmyk M, Szwiec M, Czajka R, Narod SA, Lubiński J (2004) A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res 64(8):2677–2679. https://doi.org/10.1158/0008-5472.can-04-0341

    Article  CAS  PubMed  Google Scholar 

  5. Cybulski C, Wokołorczyk D, Huzarski T, Byrski T, Gronwald J, Górski B, Debniak T, Masojć B, Jakubowska A, Gliniewicz B, Sikorski A, Stawicka M, Godlewski D, Kwias Z, Antczak A, Krajka K, Lauer W, Sosnowski M, Sikorska-Radek P, Bar K, Klijer R, Zdrojowy R, Małkiewicz B, Borkowski A, Borkowski T, Szwiec M, Narod SA, Lubiński J (2006) A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet 43(11):863–866. https://doi.org/10.1136/jmg.2006.044974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cybulski C, Wokołorczyk D, Huzarski T, Byrski T, Gronwald J, Górski B, Debniak T, Masojć B, Jakubowska A, van de Wetering T, Narod SA, Lubiński J (2007) A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland. Breast Cancer Res Treat 102(1):119–122. https://doi.org/10.1007/s10549-006-9320-y

    Article  CAS  PubMed  Google Scholar 

  7. Domagala P, Wokolorczyk D, Cybulski C, Huzarski T, Lubinski J, Domagala W (2012) Different CHEK2 germline mutations are associated with distinct immunophenotypic molecular subtypes of breast cancer. Breast Cancer Res Treat 132(3):937–945. https://doi.org/10.1007/s10549-011-1635-7

    Article  CAS  PubMed  Google Scholar 

  8. Cybulski C, Huzarski T, Byrski T, Gronwald J, Debniak T, Jakubowska A, Górski B, Wokołorczyk D, Masojć B, Narod SA, Lubiński J (2009) Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention. Clin Genet 75(1):72–78. https://doi.org/10.1111/j.1399-0004.2008.01111.x

    Article  CAS  PubMed  Google Scholar 

  9. Schmidt MK, Hogervorst F, van Hien R et al (2016) Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol 34:2750–2760. https://doi.org/10.1200/JCO.2016.66.5844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nagel JH, Peeters JK, Smid M, Sieuwerts AM, Wasielewski M, de Weerd V, Trapman-Jansen AM, van den Ouweland A, Brüggenwirth H, van I Jcken WF, Klijn JG, van der Spek PJ, Foekens JA, Martens JW, Schutte M, Meijers-Heijboer H (2012) Gene expression profiling assigns CHEK2 1100delC breast cancers to the luminal intrinsic subtypes. Breast Cancer Res Treat 132(2):439–448. https://doi.org/10.1007/s10549-011-1588-x

    Article  CAS  PubMed  Google Scholar 

  11. Huszno J, Budryk M, Kołosza Z, Tęcza K, Pamuła Piłat J, Nowara E, Grzybowska E (2016) A comparison between CHEK2*1100delC/I157T mutation carrier and noncarrier breast cancer patients: a clinicopathological analysis. Oncology 90(4):193–198. https://doi.org/10.1159/000444326

    Article  CAS  PubMed  Google Scholar 

  12. Schmidt MK, Tollenaar RA, de Kemp SR, Broeks A, Cornelisse CJ, Smit VT, Peterse JL, van Leeuwen FE, Van’t Veer LJ (2007) Breast cancer survival and tumor characteristics in premenopausal women carrying the CHEK2*1100delC germline mutation. J Clin Oncol 25(1):64–69. https://doi.org/10.1200/JCO.2006.06.3024

    Article  CAS  PubMed  Google Scholar 

  13. Weischer M, Nordestgaard BG, Pharoah P et al (2012) CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. J Clin Oncol 30:4308–4316. https://doi.org/10.1200/JCO.2012.42.7336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang S, Phelan CM, Zhang P, Rousseau F, Ghadirian P, Robidoux A, Foulkes W, Hamel N, McCready D, Trudeau M, Lynch H, Horsman D, De Matsuda ML, Aziz Z, Gomes M, Costa MM, Liede A, Poll A, Sun P, Narod SA (2008) Frequency of the CHEK2 1100delC mutation among women with breast cancer: an international study. Cancer Res 68(7):2154–2157. https://doi.org/10.1158/0008-5472.CAN-07-5187

    Article  CAS  PubMed  Google Scholar 

  15. de Bock GH, Schutte M, Krol-Warmerdam EM, Seynaeve C, Blom J, Brekelmans CT, Meijers-Heijboer H, van Asperen CJ, Cornelisse CJ, Devilee P, Tollenaar RA, Klijn JG (2004) Tumour characteristics and prognosis of breast cancer patients carrying the germline CHEK2*1100delC variant. J Med Genet 41(10):731–735. https://doi.org/10.1136/jmg.2004.019737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kilpivaara O, Bartkova J, Eerola H, Syrjäkoski K, Vahteristo P, Lukas J, Blomqvist C, Holli K, Heikkilä P, Sauter G, Kallioniemi OP, Bartek J, Nevanlinna H (2005) Correlation of CHEK2 protein expression and c.1100delC mutation status with tumor characteristics among unselected breast cancer patients. Int J Cancer 113(4):575–580. https://doi.org/10.1002/ijc.20638

    Article  CAS  PubMed  Google Scholar 

  17. Fletcher O, Johnson N, Dos Santos SI, Kilpivaara O, Aittomäki K, Blomqvist C, Nevanlinna H, Wasielewski M, Meijers-Heijerboer H, Broeks A, Schmidt MK, Van’t Veer LJ, Bremer M, Dörk T, Chekmariova EV, Sokolenko AP, Imyanitov EN, Hamann U, Rashid MU, Brauch H, Justenhoven C, Ashworth A, Peto J (2009) Family history, genetic testing, and clinical risk prediction: pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls. Cancer Epidemiol Biomark Prev 18(1):230–234. https://doi.org/10.1158/1055-9965.EPI-08-0416

    Article  CAS  Google Scholar 

  18. Vahteristo P, Bartkova J, Eerola H, Syrjäkoski K, Ojala S, Kilpivaara O, Tamminen A, Kononen J, Aittomäki K, Heikkilä P, Holli K, Blomqvist C, Bartek J, Kallioniemi OP, Nevanlinna H (2002) A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet 71(2):432–438. https://doi.org/10.1086/341943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Muranen TA, Greco D, Fagerholm R, Kilpivaara O, Kämpjärvi K, Aittomäki K, Blomqvist C, Heikkilä P, Borg A, Nevanlinna H (2011) Breast tumors from CHEK2 1100delC-mutation carriers: genomic landscape and clinical implications. Breast Cancer Res 13(5):R90. https://doi.org/10.1186/bcr3015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Massink MP, Kooi IE, Martens JW, Waisfisz Q, Meijers-Heijboer H (2015) Genomic profiling of CHEK2*1100delC-mutated breast carcinomas. BMC Cancer 15:877. https://doi.org/10.1186/s12885-015-1880-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Maxwell KN, Wubbenhorst B, Wenz BM, De Sloover D, Pluta J, Emery L, Barrett A, Kraya AA, Anastopoulos IN, Yu S, Jiang Y, Chen H, Zhang NR, Hackman N, D’Andrea K, Daber R, Morrissette JJD, Mitra N, Feldman M, Domchek SM, Nathanson KL (2017) BRCA locus-specific loss of heterozygosity in germline BRCA1 and BRCA2 carriers. Nat Commun 8(1):319. https://doi.org/10.1038/s41467-017-00388-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lord CJ, Ashworth A (2016) BRCAness revisited. Nat Rev Cancer 16(2):110–120. https://doi.org/10.1038/nrc.2015.21

    Article  CAS  PubMed  Google Scholar 

  23. Davies H, Morganella S, Purdie CA, Jang SJ, Borgen E, Russnes H, Glodzik D, Zou X, Viari A, Richardson AL, Børresen-Dale AL, Thompson A, Eyfjord JE, Kong G, Stratton MR, Nik-Zainal S (2017) Whole-genome sequencing reveals breast cancers with mismatch repair deficiency. Cancer Res 77(18):4755–4762. https://doi.org/10.1158/0008-5472.CAN-17-1083

    Article  CAS  PubMed  Google Scholar 

  24. Sodha N, Bullock S, Taylor R, Mitchell G, Guertl-Lackner B, Williams RD, Bevan S, Bishop K, McGuire S, Houlston RS, Eeles RA (2002) CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours. Br J Cancer 87(12):1445–1448. https://doi.org/10.1038/sj.bjc.6600637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Oldenburg RA, Kroeze-Jansema K, Kraan J, Morreau H, Klijn JG, Hoogerbrugge N, Ligtenberg MJ, van Asperen CJ, Vasen HF, Meijers C, Meijers-Heijboer H, de Bock TH, Cornelisse CJ, Devilee P (2003) The CHEK2*1100delC variant acts as a breast cancer risk modifier in non-BRCA1/BRCA2 multiple-case families. Cancer Res 63(23):8153–8157

    CAS  PubMed  Google Scholar 

  26. Jekimovs CR, Chen X, Arnold J, Gatei M, Richard DJ, Spurdle AB, Khanna KK, Chenevix-Trench G, kConFab Investigators (2005) Low frequency of CHEK2 1100delC allele in Australian multiple-case breast cancer families: functional analysis in heterozygous individuals. Br J Cancer 92(4):784–790. https://doi.org/10.1038/sj.bjc.6602381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mandelker D, Kumar R, Pei X, Selenica P, Setton J, Arunachalam S, Ceyhan-Birsoy O, Brown DN, Norton L, Robson ME, Wen HY, Powell S, Riaz N, Weigelt B, Reis-Filho JS (2019) The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers. JNCI Cancer Spectr 3(2):pkz027. https://doi.org/10.1093/jncics/pkz027

    Article  PubMed  PubMed Central  Google Scholar 

  28. Suspitsin EN, Yanus GA, Sokolenko AP, Yatsuk OS, Zaitseva OA, Bessonov AA, Ivantsov AO, Heinstein VA, Klimashevskiy VF, Togo AV, Imyanitov EN (2014) Development of breast tumors in CHEK2, NBN/NBS1 and BLM mutation carriers does not commonly involve somatic inactivation of the wild-type allele. Med Oncol 31(2):828. https://doi.org/10.1007/s12032-013-0828-9

    Article  CAS  PubMed  Google Scholar 

  29. Sodha N, Williams R, Mangion J, Bullock SL, Yuille MR, Eeles RA (2000) Screening hCHK2 for mutations. Science 289(5478):359. https://doi.org/10.1126/science.289.5478.359a

    Article  CAS  PubMed  Google Scholar 

  30. Sokolenko AP, Bizin IV, Preobrazhenskaya EV, Gorodnova TV, Ivantsov AO, Iyevleva AG, Savonevich EL, Kotiv KB, Kuligina ES, Imyanitov EN (2020) Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: analysis of primary, residual and relapsed tumors. Int J Cancer 146(7):1879–1888. https://doi.org/10.1002/ijc.32776

    Article  CAS  PubMed  Google Scholar 

  31. Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, Banks E, Garimella KV, Altshuler D, Gabriel S, De Pristo MA (2013) From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinform. https://doi.org/10.1002/0471250953.bi1110s43

    Article  Google Scholar 

  32. Chevalier A, Lichtenstein L, Smirnov A, Lee SK, Babidi M, Benjamin DI, Ruano-Rubio V (2017) GATK ACNV: allelic copy-number variation discovery from SNPs and coverage data. Cancer Res 77(Suppl 13):3581. https://doi.org/10.1158/1538-7445.AM2017-3581

    Article  Google Scholar 

  33. Sokolenko AP, Gorodnova TV, Bizin IV, Kuligina ES, Kotiv KB, Romanko AA, Ermachenkova TI, Ivantsov AO, Preobrazhenskaya EV, Sokolova TN, Broyde RV, Imyanitov EN (2021) Molecular predictors of the outcome of paclitaxel plus carboplatin neoadjuvant therapy in high-grade serous ovarian cancer patients. Cancer Chemother Pharmacol 88(3):439–450. https://doi.org/10.1007/s00280-021-04301-6

    Article  CAS  PubMed  Google Scholar 

  34. Shooter S, Czarnecki J, Nik-Zainal S (2019) Signal: the home page of mutational signatures. Ann Oncol 30(Suppl 7):VII33. https://doi.org/10.1093/annonc/mdz413.118

    Article  Google Scholar 

  35. Telli ML, Timms KM, Reid J, Hennessy B, Mills GB, Jensen KC, Szallasi Z, Barry WT, Winer EP, Tung NM, Isakoff SJ, Ryan PD, Greene-Colozzi A, Gutin A, Sangale Z, Iliev D, Neff C, Abkevich V, Jones JT, Lanchbury JS, Hartman AR, Garber JE, Ford JM, Silver DP, Richardson AL (2016) Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22(15):3764–3773. https://doi.org/10.1158/1078-0432.CCR-15-2477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chin K, DeVries S, Fridlyand J, Spellman PT, Roydasgupta R, Kuo WL, Lapuk A, Neve RM, Qian Z, Ryder T, Chen F, Feiler H, Tokuyasu T, Kingsley C, Dairkee S, Meng Z, Chew K, Pinkel D, Jain A, Ljung BM, Esserman L, Albertson DG, Waldman FM, Gray JW (2006) Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10(6):529–541. https://doi.org/10.1016/j.ccr.2006.10.009

    Article  CAS  PubMed  Google Scholar 

  37. Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, Vassal G, Delaloge S, Hortobagyi GN, Symmans WF, Lazar V, Pusztai L (2009) Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res 15(2):441–451. https://doi.org/10.1158/1078-0432.CCR-08-1791

    Article  CAS  PubMed  Google Scholar 

  38. Kwei KA, Kung Y, Salari K, Holcomb IN, Pollack JR (2010) Genomic instability in breast cancer: pathogenesis and clinical implications. Mol Oncol 4(3):255–266. https://doi.org/10.1016/j.molonc.2010.04.00138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Polak P, Kim J, Braunstein LZ, Karlic R, Haradhavala NJ, Tiao G, Rosebrock D, Livitz D, Kübler K, Mouw KW, Kamburov A, Maruvka YE, Leshchiner I, Lander ES, Golub TR, Zick A, Orthwein A, Lawrence MS, Batra RN, Caldas C, Haber DA, Laird PW, Shen H, Ellisen LW, D’Andrea AD, Chanock SJ, Foulkes WD, Getz G (2017) A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat Genet 49(10):1476–1486. https://doi.org/10.1038/ng.3934

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Stolarova L, Kleiblova P, Janatova M, Soukupova J, Zemankova P, Macurek L, Kleibl Z (2020) CHEK2 germline variants in cancer predisposition: stalemate rather than checkmate. Cells 9(12):2675. https://doi.org/10.3390/cells9122675

    Article  CAS  PubMed Central  Google Scholar 

  41. Sutcliffe EG, Stettner AR, Miller SA, Solomon SR, Marshall ML, Roberts ME, Susswein LR, Arvai KJ, Klein RT, Murphy PD, Hruska KS (2020) Differences in cancer prevalence among CHEK2 carriers identified via multi-gene panel testing. Cancer Genet 246–247:12–17. https://doi.org/10.1016/j.cancergen.2020.07.001

    Article  CAS  PubMed  Google Scholar 

  42. Rainville I, Hatcher S, Rosenthal E, Larson K, Bernhisel R, Meek S, Gorringe H, Mundt E, Manley S (2020) High risk of breast cancer in women with biallelic pathogenic variants in CHEK2. Breast Cancer Res Treat 180(2):503–509. https://doi.org/10.1007/s10549-020-05543-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Póti Á, Gyergyák H, Németh E, Rusz O, Tóth S, Kovácsházi C, Chen D, Szikriszt B, Spisák S, Takeda S, Szakács G, Szallasi Z, Richardson AL, Szüts D (2019) Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents. Genome Biol 20(1):240. https://doi.org/10.1186/s13059-019-1867-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Golan T, O’Kane GM, Denroche RE, Raitses-Gurevich M, Grant RC, Holter S, Wang Y, Zhang A, Jang GH, Stossel C, Atias D, Halperin S, Berger R, Glick Y, Park JP, Cuggia A, Williamson L, Wong HL, Schaeffer DF, Renouf DJ, Borgida A, Dodd A, Wilson JM, Fischer SE, Notta F, Knox JJ, Zogopoulos G, Gallinger S (2021) Genomic features and classification of homologous recombination deficient pancreatic ductal adenocarcinoma. Gastroenterology 160(6):2119-2132.e9. https://doi.org/10.1053/j.gastro.2021.01.220

    Article  CAS  PubMed  Google Scholar 

  45. Lotan TL, Kaur HB, Salles DC, Murali S, Schaeffer EM, Lanchbury JS, Isaacs WB, Brown R, Richardson AL, Cussenot O, Cancel-Tassin G, Timms KM, Antonarakis ES (2021) Homologous recombination deficiency (HRD) score in germline BRCA2- versus ATM-altered prostate cancer. Mod Pathol 34(6):1185–1193. https://doi.org/10.1038/s41379-020-00731-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, Shah PD, Ballinger TJ, Yang ES, Vinayak S, Melisko M, Brufsky A, DeMeo M, Jenkins C, Domchek S, D’Andrea A, Lin NU, Hughes ME, Carey LA, Wagle N, Wulf GM, Krop IE, Wolff AC, Winer EP, Garber JE (2020) TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol 38(36):4274–4282. https://doi.org/10.1200/JCO.20.02151

    Article  CAS  PubMed  Google Scholar 

  47. Abida W, Campbell D, Patnaik A, Shapiro JD, Sautois B, Vogelzang NJ, Voog EG, Bryce AH, McDermott R, Ricci F, Rowe J, Zhang J, Piulats JM, Fizazi K, Merseburger AS, Higano CS, Krieger LE, Ryan CJ, Feng FY, Simmons AD, Loehr A, Despain D, Dowson M, Green F, Watkins SP, Golsorkhi T, Chowdhury S (2020) Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: analysis from the phase II TRITON2 study. Clin Cancer Res 26(11):2487–2496. https://doi.org/10.1158/1078-0432.CCR-20-0394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, Syndikus I, Ralph C, Jain S, Varughese M, Parikh O, Crabb S, Robinson A, McLaren D, Birtle A, Tanguay J, Miranda S, Figueiredo I, Seed G, Bertan C, Flohr P, Ebbs B, Rescigno P, Fowler G, Ferreira A, Riisnaes R, Pereira R, Curcean A, Chandler R, Clarke M, Gurel B, Crespo M, Nava Rodrigues D, Sandhu S, Espinasse A, Chatfield P, Tunariu N, Yuan W, Hall E, Carreira S, de Bono JS (2020) Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 21(1):162–174. https://doi.org/10.1016/S1470-2045(19)30684-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Stopsack KH (2021) Efficacy of PARP inhibition in metastatic castration-resistant prostate cancer is very different with non-BRCA DNA repair alterations: reconstructing prespecified endpoints for cohort B from the phase 3 PROfound trial of olaparib. Eur Urol 79(4):442–445. https://doi.org/10.1016/j.eururo.2020.09.024

    Article  CAS  PubMed  Google Scholar 

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Funding

The study has been supported by the Russian Science Foundation (Grant Number 21-75-30015).

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Authors and Affiliations

  1. N.N. Petrov Institute of Oncology, Leningradskaya str. 68, Pesochny, Saint Petersburg, Russia, 197758

    Aglaya G. Iyevleva, Svetlana N. Aleksakhina, Anna P. Sokolenko, Sofia V. Baskina, Aigul R. Venina, Ilya V. Bizin, Alexandr O. Ivantsov, Yana V. Belysheva, Alexandra P. Chernyakova, Alexandr V. Togo & Evgeny N. Imyanitov

  2. Mariinskaya City Hospital, Saint Petersburg, Russia, 191014

    Elena I. Anisimova

  3. St.-Petersburg State Pediatric Medical University, Saint Petersburg, Russia, 194100

    Evgeny N. Imyanitov

  4. I.I. Mechnikov North-Western Medical University, Saint Petersburg, Russia, 191015

    Evgeny N. Imyanitov

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  1. Aglaya G. Iyevleva
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  2. Svetlana N. Aleksakhina
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AGI, SNA, and ENI involved in conceptualization. APS, IVB, AOI, and AVT participated in methodology. SVB, ARV, EIA, YVB, APC, and AVT did formal analysis and investigation. AGI took part in writing—original draft preparation. All authors involved in writing—review and editing, and ENI performed supervision.

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Correspondence to Aglaya G. Iyevleva.

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All other authors have no relevant financial or non-financial interests to disclose.

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The study was approved by the local Ethics Committee. The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

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Informed consent was obtained from all individual participants included in the study.

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Iyevleva, A.G., Aleksakhina, S.N., Sokolenko, A.P. et al. Somatic loss of the remaining allele occurs approximately in half of CHEK2-driven breast cancers and is accompanied by a border-line increase of chromosomal instability. Breast Cancer Res Treat 192, 283–291 (2022). https://doi.org/10.1007/s10549-022-06517-3

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