Skip to main content
SpringerLink
Log in

Genomic scar signatures associated with homologous recombination deficiency predict adverse clinical outcomes in patients with ovarian clear cell carcinoma

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

We investigated whether genomic scar signatures associated with homologous recombination deficiency (HRD), which include telomeric allelic imbalance (TAI), large-scale transition (LST), and loss of heterozygosity (LOH), can predict clinical outcomes in patients with ovarian clear cell carcinoma (OCCC). We enrolled patients with OCCC (n = 80) and high-grade serous carcinoma (HGSC; n = 92) subjected to primary cytoreductive surgery, most of whom received platinum-based adjuvant chemotherapy. Genomic scar signatures based on genome-wide copy number data were determined in all participants and investigated in relation to prognosis. OCCC had significantly lower genomic scar signature scores than HGSC (p < 0.001). Near-triploid OCCC specimens showed higher TAI and LST scores compared with diploid tumors (p < 0.001). While high scores of these genomic scar signatures were significantly associated with better clinical outcomes in patients with HGSC, the opposite was evident for OCCC. Multivariate survival analysis in patients with OCCC identified high LOH scores as the main independent adverse predictor for both cancer-specific (hazard ratio [HR] = 3.22, p = 0.005) and progression-free survival (HR = 2.54, p = 0.01). In conclusion, genomic scar signatures associated with HRD predict adverse clinical outcomes in patients with OCCC. The LOH score was identified as the strongest prognostic indicator in this patient group.

Key messages

  • Genomic scar signatures associated with HRD are less frequent in OCCC than in HGSC.

  • Genomic scar signatures associated with HRD have an adverse prognostic impact in patients with OCCC.

  • LOH score is the strongest adverse prognostic factor in patients with OCCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. del Carmen MG, Birrer M, Schorge JO (2012) Clear cell carcinoma of the ovary: a review of the literature. Gynecol Oncol 126:481–490

    Article  PubMed  Google Scholar 

  2. Ku FC, Wu RC, Yang LY, Tang YH, Chang WY, Yang JE, Wang CC, Jung SM, Lin CT, Chang TC, et al (2017) Clear cell carcinomas of the ovary have poorer outcomes compared with serous carcinomas: results from a single-center Taiwanese study. J Formos Med Assoc 117:117–125

  3. Fujiwara K, Shintani D, Nishikawa T (2016) Clear-cell carcinoma of the ovary. Ann Oncol 27(Suppl 1):i50–i52

    Article  PubMed  Google Scholar 

  4. Chan JK, Teoh D, Hu JM, Shin JY, Osann K, Kapp DS (2008) Do clear cell ovarian carcinomas have poorer prognosis compared to other epithelial cell types? A study of 1411 clear cell ovarian cancers. Gynecol Oncol 109:370–376

    Article  PubMed  Google Scholar 

  5. Sugiyama T, Kamura T, Kigawa J, Terakawa N, Kikuchi Y, Kita T, Suzuki M, Sato I, Taguchi K (2000) Clinical characteristics of clear cell carcinoma of the ovary: a distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy. Cancer 88:2584–2589

    Article  PubMed  CAS  Google Scholar 

  6. Jekimovs C, Bolderson E, Suraweera A, Adams M, O’Byrne KJ, Richard DJ (2014) Chemotherapeutic compounds targeting the DNA double-strand break repair pathways: the good, the bad, and the promising. Front Oncol 4:86

    Article  PubMed  PubMed Central  Google Scholar 

  7. 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 22:3764–3773

    Article  PubMed  CAS  Google Scholar 

  8. Roy R, Chun J, Powell SN (2011) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12:68–78

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD (2015) Homologous recombination deficiency: exploiting the fundamental vulnerability of ovarian cancer. Cancer Discov 5:1137–1154

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, Konecny GE, Coleman RL, Tinker AV, O'Malley DM, Kristeleit RS, Ma L, Bell-McGuinn KM, Brenton JD, Cragun JM, Oaknin A, Ray-Coquard I, Harrell MI, Mann E, Kaufmann SH, Floquet A, Leary A, Harding TC, Goble S, Maloney L, Isaacson J, Allen AR, Rolfe L, Yelensky R, Raponi M, McNeish IA (2017) Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 18:75–87

    Article  PubMed  CAS  Google Scholar 

  11. Lheureux S, Lai Z, Dougherty BA, Runswick S, Hodgson DR, Timms KM, Lanchbury JS, Kaye S, Gourley C, Bowtell D, Kohn EC, Scott C, Matulonis U, Panzarella T, Karakasis K, Burnier JV, Gilks CB, O'Connor MJ, Robertson JD, Ledermann J, Barrett JC, Ho TW, Oza AM (2017) Long-term responders on olaparib maintenance in high-grade serous ovarian cancer: clinical and molecular characterization. Clin Cancer Res 23:4086–4094

    Article  PubMed  CAS  Google Scholar 

  12. Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, Ramakrishna M, Martin S, Boyault S, Sieuwerts AM, Simpson PT, King TA, Raine K, Eyfjord JE, Kong G, Borg Å, Birney E, Stunnenberg HG, van de Vijver MJ, Børresen-Dale AL, Martens JWM, Span PN, Lakhani SR, Vincent-Salomon A, Sotiriou C, Tutt A, Thompson AM, van Laere S, Richardson AL, Viari A, Campbell PJ, Stratton MR, Nik-Zainal S (2017) HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517–525

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, Bowman-Colin C, Li Y, Greene-Colozzi A, Iglehart JD, Tung N, Ryan PD, Garber JE, Silver DP, Szallasi Z, Richardson AL (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366–375

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, Delattre O, Sigal-Zafrani B, Bollet M, Longy M, Houdayer C, Sastre-Garau X, Vincent-Salomon A, Stoppa-Lyonnet D, Stern MH (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462

    Article  PubMed  CAS  Google Scholar 

  15. Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, Smith-McCune K, Broaddus R, Lu KH, Chen J, Tran TV, Williams D, Iliev D, Jammulapati S, FitzGerald LM, Krivak T, DeLoia JA, Gutin A, Mills GB, Lanchbury JS (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Telli ML, Jensen KC, Vinayak S, Kurian AW, Lipson JA, Flaherty PJ, Timms K, Abkevich V, Schackmann EA, Wapnir IL, Carlson RW, Chang PJ, Sparano JA, Head B, Goldstein LJ, Haley B, Dakhil SR, Reid JE, Hartman AR, Manola J, Ford JM (2015) Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol 33:1895–1901

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Marquard AM, Eklund AC, Joshi T, Krzystanek M, Favero F, Wang ZC, Richardson AL, Silver DP, Szallasi Z, Birkbak NJ (2015) Pan-cancer analysis of genomic scar signatures associated with homologous recombination deficiency suggests novel indications for existing cancer drugs. Biomark Res 3:9

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chao A, Wu RC, Jung SM, Lee YS, Chen SJ, Lu YL, Tsai CL, Lin CY, Tang YH, Chen MY, Huang HJ, Chou HH, Huang KG, Chang TC, Wang TH, Lai CH (2016) Implication of genomic characterization in synchronous endometrial and ovarian cancers of endometrioid histology. Gynecol Oncol 143:60–67

    Article  PubMed  CAS  Google Scholar 

  19. Van Loo P, Nordgard SH, Lingjaerde OC, Russnes HG, Rye IH, Sun W, Weigman VJ, Marynen P, Zetterberg A, Naume B et al (2010) Allele-specific copy number analysis of tumors. Proc Natl Acad Sci U S A 107:16910–16915

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bakhoum SF, Landau DA (2017) Chromosomal instability as a driver of tumor heterogeneity and evolution. Cold Spring Harb Perspect Med 7

  21. Sansregret L, Swanton C (2017) The role of aneuploidy in cancer evolution. Cold Spring Harb Perspect Med 7

  22. Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mądry R, Christensen RD, Berek JS, Dørum A, Tinker AV, du Bois A, González-Martín A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA, ENGOT-OV16/NOVA Investigators (2016) Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med 375:2154–2164

    Article  PubMed  CAS  Google Scholar 

  23. Chao A, Chang TC, Lapke N, Jung SM, Chi P, Chen CH, Yang LY, Lin CT, Huang HJ, Chou HH, Liou JD, Chen SJ, Wang TH, Lai CH (2016) Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget 7:85529–85541

    PubMed  PubMed Central  Google Scholar 

  24. Sakamoto I, Hirotsu Y, Nakagomi H, Ouchi H, Ikegami A, Teramoto K, Amemiya K, Mochizuki H, Omata M (2016) BRCA1 and BRCA2 mutations in Japanese patients with ovarian, fallopian tube, and primary peritoneal cancer. Cancer 122:84–90

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to Ms. Jung-Erh Yang for her excellent technical assistance. Clinical data were supported by the Cancer Center and formalin-fixed paraffin-embedded specimens were kindly provided by the Tumor Bank of Chang Gung Memorial Hospital.

Funding

This study was financially supported by grants from the Chang Gung Foundation (CMRPG3C0931/2/3 and CMRPG3H0351 to AC, CMRPG3E2021/2/3 and CMRPG3F0041/2 to RCW), Ministry of Science and Technology (106-2314-B-182-053-MY2 to AC and 106-2320-B-182-037-MY2 to RCW), and the Taiwanese Ministry of Health and Welfare (grant MOHW106-TDU-B-212-113005).

Author information

Author notes

  1. Angel Chao, Chyong-Huey Lai, and Tzu-Hao Wang are contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, Taoyuan, Taiwan

    Angel Chao, Chyong-Huey Lai, Tzu-Hao Wang, Fei-Chun Ku, Huei-Jean Huang, An-Shine Chao, Chin-Jung Wang & Ting-Chang Chang

  2. Gynecologic Cancer Research Center, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan

    Angel Chao, Chyong-Huey Lai, Tzu-Hao Wang, Fei-Chun Ku, Huei-Jean Huang & Ting-Chang Chang

  3. Department of Anatomic Pathology, Chang Gung Memorial Hospital Linkou Medical Center, Chang Gung University, 5 Fushing Street, Guishan, Taoyuan, 333, Taiwan

    Shih-Ming Jung & Ren-Chin Wu

  4. Department of Biotechnology, Ming-Chuan University, Taoyuan, Taiwan

    Yun-Shien Lee

  5. Biostatistics Unit, Clinical Trial Center, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan, Taiwan

    Wei-Yang Chang & Lan-Yang Yang

Authors
  1. Angel Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chyong-Huey Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tzu-Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shih-Ming Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yun-Shien Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wei-Yang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lan-Yang Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fei-Chun Ku
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Huei-Jean Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. An-Shine Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Chin-Jung Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ting-Chang Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ren-Chin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ren-Chin Wu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Details of ethics approval

Ethical approval was granted by the Institutional Review Board of the Chang Gung Memorial Hospital, Taiwan (IRB number: 105-2338C) on December 19, 2011.

Electronic supplementary material

ESM 1

(DOC 400 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chao, A., Lai, CH., Wang, TH. et al. Genomic scar signatures associated with homologous recombination deficiency predict adverse clinical outcomes in patients with ovarian clear cell carcinoma. J Mol Med 96, 527–536 (2018). https://doi.org/10.1007/s00109-018-1643-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-018-1643-8

Keywords

Search

Navigation