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Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing

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Abstract

Mutation frequencies of common genetic alterations in colorectal cancer have been in the spotlight for many years. This study highlights few rare somatic mutations, which possess the attributes of a potential CRC biomarker yet are often neglected. Next-generation sequencing was performed over 112 tumor samples to detect genetic alterations in 31 rare genes in colorectal cancer. Mutations were detected in 26/31 (83.9 %) uncommon genes, which together contributed toward 149 gene mutations in 67/112 (59.8 %) colorectal cancer patients. The most frequent mutations include KDR (19.6 %), PTEN (17 %), FBXW7 (10.7 %), SMAD4 (10.7 %), VHL (8 %), KIT (8 %), MET (7.1 %), ATM (6.3 %), CTNNB1 (4.5 %) and CDKN2A (4.5 %). RB1, ERBB4 and ERBB2 mutations were persistent in 3.6 % patients. GNAS, FGFR2 and FGFR3 mutations were persistent in 1.8 % patients. Ten genes (EGFR, NOTCH1, SMARCB1, ABL1, STK11, SMO, RET, GNAQ, CSF1R and FLT3) were found mutated in 0.9 % patients. Lastly, no mutations were observed in AKT, HRAS, MAP2K1, PDGFR and JAK2. Significant associations were observed between VHL with tumor site, ERBB4 and SMARCB1 with tumor invasion, CTNNB1 with lack of lymph node involvement and CTNNB1, FGFR2 and FGFR3 with TNM stage. Significantly coinciding mutation pairs include PTEN and SMAD4, PTEN and KDR, EGFR and RET, EGFR and RB1, FBXW7 and CTNNB1, KDR and FGFR2, FLT3 and CTNNB1, RET and RB1, ATM and SMAD4, ATM and CDKN2A, ERBB4 and SMARCB1. This study elucidates few potential colorectal cancer biomarkers, specifically KDR, PTEN, FBXW7 and SMAD4, which are found mutated in more than 10 % patients.

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Acknowledgments

We thank the Department of Research at Sir Ganga Ram Hospital, Delhi, India, and Strand Life Sciences, Bangalore, India, and Mrs. Parul Takkar for their support. This study has been funded by Merck Serono, India.

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Authors and Affiliations

  1. Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, 110060, India

    Mayank Jauhri, Yogender Shokeen, Sachin Minhas & Shyam Aggarwal

  2. Amity Institute of Biotechnology, Amity University, Noida, 201313, India

    Akanksha Bhatnagar

  3. Strand Life Sciences, Bangalore, 560024, India

    Satish Gupta

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  1. Mayank Jauhri
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Correspondence to Mayank Jauhri.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Jauhri, M., Bhatnagar, A., Gupta, S. et al. Targeted molecular profiling of rare genetic alterations in colorectal cancer using next-generation sequencing. Med Oncol 33, 106 (2016). https://doi.org/10.1007/s12032-016-0820-2

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  • DOI: https://doi.org/10.1007/s12032-016-0820-2

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