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Annals of Surgical Oncology

, Volume 21, Issue 8, pp 2642–2649 | Cite as

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

  • Khairun I. Abdul-Jalil
  • Katherine M. Sheehan
  • Sinead Toomey
  • Jasmin Schmid
  • Jochen Prehn
  • Anthony O’Grady
  • Robert Cummins
  • Brian O’Neill
  • Deborah A. McNamara
  • Joseph Deasy
  • Oscar Breathnach
  • Liam Grogan
  • Ailin Rogers
  • Glen Doherty
  • Des Winter
  • John Ryan
  • Sherif El-Masry
  • David Gibbons
  • Kieran Sheahan
  • Peter Gillen
  • Elaine W. Kay
  • Bryan T. Hennessy
Colorectal Cancer

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.

Keywords

Rectal Cancer KRAS Mutation PI3K Pathway PIK3CA Mutation Rectal Adenocarcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Supplementary material

10434_2014_3658_MOESM1_ESM.doc (89 kb)
Supplementary material 1 (DOC 89 kb)

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Copyright information

© Society of Surgical Oncology 2014

Authors and Affiliations

  • Khairun I. Abdul-Jalil
    • 1
    • 2
  • Katherine M. Sheehan
    • 3
  • Sinead Toomey
    • 1
  • Jasmin Schmid
    • 4
  • Jochen Prehn
    • 4
  • Anthony O’Grady
    • 3
  • Robert Cummins
    • 3
  • Brian O’Neill
    • 5
  • Deborah A. McNamara
    • 6
  • Joseph Deasy
    • 5
  • Oscar Breathnach
    • 1
  • Liam Grogan
    • 1
  • Ailin Rogers
    • 7
  • Glen Doherty
    • 7
  • Des Winter
    • 7
  • John Ryan
    • 8
  • Sherif El-Masry
    • 2
  • David Gibbons
    • 7
  • Kieran Sheahan
    • 7
  • Peter Gillen
    • 2
  • Elaine W. Kay
    • 3
  • Bryan T. Hennessy
    • 1
    • 9
  1. 1.Department of Medical OncologyBeaumont HospitalDublinIreland
  2. 2.Department of SurgeryOur Lady of Lourdes Hospital DroghedaCo. LouthIreland
  3. 3.Department of HistopathologyBeaumont Hospital and Royal College of Surgeons in IrelandDublinIreland
  4. 4.Department of Physiology and Medical Physics, Centre for Systems MedicineRoyal College of Surgeons in IrelandDublinIreland
  5. 5.Department of Radiation OncologyBeaumont Hospital and St. Luke’s HospitalDublinIreland
  6. 6.Department of Colorectal SurgeryBeaumont HospitalDublinIreland
  7. 7.Centre for Colorectal DiseaseSt. Vincent’s University HospitalDublinIreland
  8. 8.Department of HistopathologyOur Lady of Lourdes Hospital DroghedaCo. LouthIreland
  9. 9.Department of Molecular MedicineRoyal College of Surgeons in IrelandDublinIreland

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