Abstract

PIN1-mediated substrate isomerization plays a role in the repair of DNA double-strand breaks. We hypothesized that genetic polymorphisms in PIN1-related pathways may affect tumor sensitivity to oxaliplatin or irinotecan in metastatic colorectal cancer (mCRC) patients. We analyzed genomic DNA from five cohorts of mCRC patients (total 950) treated with different first-line treatments: oxaliplatin cohorts 1 (n = 146) and 2 (n = 70); irinotecan cohorts 1 (n = 228), and 2 (n = 276); and combination cohort (n = 230). Single nucleotide polymorphisms of candidate genes were analyzed by PCR-based direct sequencing. In the oxaliplatin cohort 1, patients carrying any PIN1 rs2233678 C allele had shorter progression-free survival (PFS) and overall survival (OS) than the G/G variant (PFS, 7.4 vs. 15.0 months, hazard ratio [HR] 3.24, P < 0.001; OS, 16.9 vs. 31.5 months, HR: 2.38, P = 0.003). In contrast, patients with C allele had longer median PFS than patients with G/G (11.9 vs. 9.4 months, HR: 0.64, 95%CI: 0.45–0.91, P = 0.009) in the irinotecan cohort 1. No significant differences were observed in the combination cohort. In comparison between the irinotecan cohort 1 and combination cohort, the patients carrying the G/G variant benefit greatly from the combination compared with irinotecan-based regimen (PFS, 11.6 vs. 9.4 months, HR 0.61, 95%CI: 0.47–0.78, P < 0.001; OS, 30.6 vs. 24.0 months, HR 0.79, 95%CI: 0.62–1.02, P = 0.060), while no significant difference was shown in any C allele. Germline PIN1 polymorphisms may predict clinical outcomes in mCRC patients receiving oxaliplatin-based or irinotecan-based therapy, and identify specific populations favorable to oxaliplatin plus irinotecan combination therapy.

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Acknowledgements

The National Institutes of Health (P30CA014089-27S1), the Gloria Borges Wunderglo Project, the Dhont Family Foundation, the Dave Butler Research Fund, and the Call to Cure Research Fund partially supported this work. Mitsukuni Suenaga received a grant from the Takashi Tsuruo Memorial Fund. Martin D. Berger received a grant from the Swiss Cancer League (BIL KLS-3334-02-2014) and the Werner and Hedy Berger-Janser Foundation for Cancer Research. Yuji Miyamoto received a grant from the Japan Society for the Promotion of Science (S2606).

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Affiliations

  1. Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA

    • Mitsukuni Suenaga
    • , Marta Schirripa
    • , Wu Zhang
    • , Yang Ning
    • , Satoshi Okazaki
    • , Martin D. Berger
    • , Yuji Miyamoto
    • , Roel Gopez Jr.
    • , Afsaneh Barzi
    •  & Heinz-Josef Lenz
  2. Gastroenterology Center, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    • Mitsukuni Suenaga
    •  & Toshiharu Yamaguchi
  3. Medical Oncology 1, Veneto Institute of Oncology, Institute for Research and Health Care (IRCCS), Padova, Italy

    • Marta Schirripa
    • , Sara Lonardi
    • , Francesca Bergamo
    •  & Fotios Loupakis
  4. Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    • Shu Cao
    •  & Dongyun Yang
  5. Medical Oncology Unit 2, Pisa University Hospital, Tuscan Tumor Institute, Pisa, Italy

    • Chiara Cremolini
    •  & Alfredo Falcone
  6. Departments of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    • Noriko Yamamoto
  7. Department of Hematology and Oncology, University of Munich (LMU), Munich, Germany

    • Sebastian Stintzing
    •  & Volker Heinemann

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Correspondence to Heinz-Josef Lenz.

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https://doi.org/10.1038/s41397-018-0030-8