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The Frequencies and Clinical Implications of Mutations in 33 Kinase-Related Genes in Locally Advanced Rectal Cancer: A Pilot Study

  • Colorectal Cancer
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes.

Methods

We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway–related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform. DNA samples were extracted from pretreatment LARC biopsy samples taken from 201 patients who were then treated with long-course neoadjuvant CRT followed by surgical resection.

Results

Sixty-two mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (47 %), PIK3CA (14 %), STK11 (6.5 %), and CTNNB1 (6 %). Mutations were detected in BRAF, NRAS, AKT1, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK, and TNK2, but at frequencies of <5 %. As expected, a pathologic complete response (pCR) was associated with improved 5-year recurrence-free survival (RFS; hazard ratio, 0.074; 95 % CI 0.01–0.54; p = 0.001). Mutations in PI3K pathway–related genes (odds ratio, 5.146; 95 % CI 1.17–22.58; p = 0.030), but not MAPK pathway–related genes (p = 0.911), were associated with absence of pCR after neoadjuvant CRT. In contrast, in patients who did not achieve pCR, mutations in PI3K pathway–related genes were not associated with recurrence-free survival (p = 0.987). However, in these patients, codon 12 (G12D/G12 V/G12S) and 13 mutations in KRAS were associated with poor recurrence-free survival (hazard ratio, 1.579; 95 % confidence ratio, 1.00–2.48; p = 0.048).

Conclusions

Mutations in kinase signaling pathways modulate treatment responsiveness and clinical outcomes in LARC and may constitute rational targets for novel therapies.

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Acknowledgment

This work was supported by Grant funding from SLICR (St. Lukes Institute of Cancer Research), NECRET (North East Cancer Research and Education Trust), NESERT (North East Surgical Education Research Trust), and Science Foundation Ireland under Grant No. 08/SRC/B1410.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Beaumont Hospital, Dublin, Ireland

    Khairun I. Abdul-Jalil MRCSI, Sinead Toomey PhD, Oscar Breathnach FRCPI, Liam Grogan FRCPI & Bryan T. Hennessy MD

  2. Department of Surgery, Our Lady of Lourdes Hospital Drogheda, Co. Louth, Ireland

    Khairun I. Abdul-Jalil MRCSI, Sherif El-Masry FRCSI & Peter Gillen FRCSI

  3. Department of Histopathology, Beaumont Hospital and Royal College of Surgeons in Ireland, Dublin, Ireland

    Katherine M. Sheehan FRCPath, Anthony O’Grady PhD, Robert Cummins BSc & Elaine W. Kay FRCPath

  4. Department of Physiology and Medical Physics, Centre for Systems Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland

    Jasmin Schmid MSc & Jochen Prehn PhD

  5. Department of Radiation Oncology, Beaumont Hospital and St. Luke’s Hospital, Dublin, Ireland

    Brian O’Neill FFRRCSI & Joseph Deasy FRCSI

  6. Department of Colorectal Surgery, Beaumont Hospital, Dublin, Ireland

    Deborah A. McNamara FRCSI

  7. Centre for Colorectal Disease, St. Vincent’s University Hospital, Dublin, Ireland

    Ailin Rogers MRCSI, Glen Doherty FRCPI, Des Winter FRCSI, David Gibbons FCAP & Kieran Sheahan FRCPath

  8. Department of Histopathology, Our Lady of Lourdes Hospital Drogheda, Co. Louth, Ireland

    John Ryan FRCPath

  9. Department of Molecular Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland

    Bryan T. Hennessy MD

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  1. Khairun I. Abdul-Jalil MRCSI
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  2. Katherine M. Sheehan FRCPath
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  8. Brian O’Neill FFRRCSI
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Corresponding author

Correspondence to Bryan T. Hennessy MD.

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Abdul-Jalil, K.I., Sheehan, K.M., Toomey, S. et al. The Frequencies and Clinical Implications of Mutations in 33 Kinase-Related Genes in Locally Advanced Rectal Cancer: A Pilot Study. Ann Surg Oncol 21, 2642–2649 (2014). https://doi.org/10.1245/s10434-014-3658-x

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  • DOI: https://doi.org/10.1245/s10434-014-3658-x

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