Pyrosequencing-based methods reveal marked inter-individual differences in oncogene mutation burden in human colorectal tumours

TY - JOUR

T1 - Pyrosequencing-based methods reveal marked inter-individual differences in oncogene mutation burden in human colorectal tumours

A1 - Weidlich,S.

A1 - Walsh,K.

A1 - Crowther,D.

A1 - Burczynski,M. E.

A1 - Feuerstein,G.

A1 - Carey,Francis

A1 - Steele,R. J. C.

A1 - Wolf,C. R.

A1 - Miele,G.

A1 - Smith,G.

AU - Weidlich,S.

AU - Walsh,K.

AU - Crowther,D.

AU - Burczynski,M. E.

AU - Feuerstein,G.

AU - Carey,Francis

AU - Steele,R. J. C.

AU - Wolf,C. R.

AU - Miele,G.

AU - Smith,G.

PY - 2011/7/12

Y1 - 2011/7/12

N2 - <p>BACKGROUND: The epidermal growth factor receptor-targeted monoclonal antibody cetuximab (Erbitux) was recently introduced for the treatment of metastatic colorectal cancer. Treatment response is dependent on Kirsten-Ras (K-Ras) mutation status, in which the majority of patients with tumour-specific K-Ras mutations fail to respond to treatment. Mutations in the oncogenes B-Raf and PIK3CA (phosphoinositide-3-kinase) may also influence cetuximab response, highlighting the need for a sensitive, accurate and quantitative assessment of tumour mutation burden.</p><p>METHODS: Mutations in K-Ras, B-Raf and PIK3CA were identified by both dideoxy and quantitative pyrosequencing-based methods in a cohort of unselected colorectal tumours (n = 102), and pyrosequencing-based mutation calls correlated with various clinicopathological parameters.</p><p>RESULTS: The use of quantitative pyrosequencing-based methods allowed us to report a 13.7% increase in mutation burden, and to identify low-frequency (&lt;30% mutation burden) mutations not routinely detected by dideoxy sequencing. K-Ras and B-Raf mutations were mutually exclusive and independently associated with a more advanced tumour phenotype.</p><p>CONCLUSION: Pyrosequencing-based methods facilitate the identification of low-frequency tumour mutations and allow more accurate assessment of tumour mutation burden. Quantitative assessment of mutation burden may permit a more detailed evaluation of the role of specific tumour mutations in the pathogenesis and progression of colorectal cancer and may improve future patient selection for targeted drug therapies. British Journal of Cancer (2011) 105, 246-254. doi: 10.1038/bjc.2011.197 www.bjcancer.com Published online 28 June 2011 (C) 2011 Cancer Research UK</p>

AB - <p>BACKGROUND: The epidermal growth factor receptor-targeted monoclonal antibody cetuximab (Erbitux) was recently introduced for the treatment of metastatic colorectal cancer. Treatment response is dependent on Kirsten-Ras (K-Ras) mutation status, in which the majority of patients with tumour-specific K-Ras mutations fail to respond to treatment. Mutations in the oncogenes B-Raf and PIK3CA (phosphoinositide-3-kinase) may also influence cetuximab response, highlighting the need for a sensitive, accurate and quantitative assessment of tumour mutation burden.</p><p>METHODS: Mutations in K-Ras, B-Raf and PIK3CA were identified by both dideoxy and quantitative pyrosequencing-based methods in a cohort of unselected colorectal tumours (n = 102), and pyrosequencing-based mutation calls correlated with various clinicopathological parameters.</p><p>RESULTS: The use of quantitative pyrosequencing-based methods allowed us to report a 13.7% increase in mutation burden, and to identify low-frequency (&lt;30% mutation burden) mutations not routinely detected by dideoxy sequencing. K-Ras and B-Raf mutations were mutually exclusive and independently associated with a more advanced tumour phenotype.</p><p>CONCLUSION: Pyrosequencing-based methods facilitate the identification of low-frequency tumour mutations and allow more accurate assessment of tumour mutation burden. Quantitative assessment of mutation burden may permit a more detailed evaluation of the role of specific tumour mutations in the pathogenesis and progression of colorectal cancer and may improve future patient selection for targeted drug therapies. British Journal of Cancer (2011) 105, 246-254. doi: 10.1038/bjc.2011.197 www.bjcancer.com Published online 28 June 2011 (C) 2011 Cancer Research UK</p>

KW - K-Ras

KW - Mutation

KW - Dideoxy sequencing

KW - Pyrosequencing

KW - Colorectal tumour

KW - Personalised medicine

KW - Growth factor receptor

KW - Kirsten Ras mutations

KW - PIK3CA mutations

KW - Prognostic significance

KW - Gene mutation

KW - Colon cancer

KW - CETUXIMAB

KW - BRAF

U2 - 10.1038/bjc.2011.197

DO - 10.1038/bjc.2011.197

M1 - Article

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 2

VL - 105

SP - 246

EP - 254

ER -