Over the last 12 years, the Wales Cancer Biobank (WCB) has consented to more than 2000 patients with colorectal cancer (CRC). From these patients, clinical data has been collected and patients have been followed through their cancer journey. Clinical data from these patients have been analyzed to identify any correlation between disease grade and outcome. In a small cohort, consisting of 407 patients, WCB has performed genetic analysis on patient primary tumor samples, identifying and characterizing mutations in the KRAS , NRAS , BRAF , PIK3CA and TP53 genes. The majority of patients with CRC who were consented to WCB were male with a mean age of 69 years and received surgery as the primary treatment for their disease. Pathology and disease-free survival data confirmed worse prognos e s associated with more advanced disease. Heterogeneity within the primary tumor was explored in a subgroup of patients. Analysis of the KRAS and TP53 genes confirmed that more than 40% of CRC patients who were tested, harbored a genetic mutation within these genes in their primary tumor. Due to the limited sample size tested, most mutations did not show significant differences in disease - free survival , however, mutation of the BRAF gene did show a decrease in the disease specific survival, in keeping with the published data. Analysis of the patients diagnosed with CRC within the Biobank has provided us with valuable information on the status of CRC disease and treatment within the Welsh p opulation. Over 12 years of consenting , we have witnessed significant changes in the information that researchers are interested in when sourcing s amples for translational research. The development of new drugs that are tailored to the genetics of a cancer is emerging and at WCB we are focusing our collections on samples and data that meet the needs of this ever-evolvin g field.
Verma, M. (2012) Personalized Medicine and Cancer. Journal of Personalized Medicine, 2, 1-14. https://doi.org/10.3390/jpm2010001
Patel, S.B., Gill, D. and Garrido-Laguna, I. (2016) Profile of Panitumumab as First-Line Treatment in Patients with Wild-Type KRAS Metastatic Colorectal Cancer. OncoTargets and Therapy, 9, 75-86. https://doi.org/10.2147/OTT.S68558
Reck, M., Rodríguez-Abreu, D., Robinson, A.G., Hui, R., Csőszi, T., Fülöp, A., et al. (2016) Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. The New England Journal of Medicine, 375, 1823-1833. https://doi.org/10.1056/NEJMoa1606774
Cho, S.H., Jeon, J. and Kim, S.I. (2012) Personalized Medicine in Breast Cancer: A Systematic Review. Journal of Breast Cancer, 15, 265-272. https://doi.org/10.4048/jbc.2012.15.3.265
Torre, L.A., Bray, F., Siegel, R.L., Ferlay, J., Lortet-Tieulent, J. and Jemal, A. (2015) Global Cancer Statistics, 2012. CA, 65, 87-108. https://doi.org/10.3322/caac.21262
Bogaert, J. and Prenen, H. (2014) Molecular Genetics of Colorectal Cancer. Annals of Gastroenterology, 27, 9-14.
Network, C.G.A. (2012) Comprehensive Molecular Characterization of Human Colon and Rectal Cancer. Nature, 487, 330-337. https://doi.org/10.1038/nature11252
Fang, J.Y. and Richardson, B.C. (2005) The MAPK Signalling Pathways and Colorectal Cancer. The Lancet Oncology, 6, 322-327. https://doi.org/10.1016/S1470-2045(05)70168-6
Vale, C.L., Tierney, J.F., Fisher, D., Adams, R.A., Kaplan, R., Maughan, T.S., et al. (2012) Does Anti-EGFR Therapy Improve Outcome in Advanced Colorectal Cancer? A Systematic Review and meta-Analysis. Cancer Treatment Reviews, 38, 618-625. https://doi.org/10.1016/j.ctrv.2011.11.002
Spindler, K.L., Pallisgaard, N., Lindebjerg, J., Frifeldt, S.K. and Jakobsen, A. (2011) EGFR Related Mutational Status and Association to Clinical Outcome of Third-Line Cetuximab-Irinotecan in Metastatic Colorectal Cancer. BMC Cancer, 11, Article No. 107. https://doi.org/10.1186/1471-2407-11-107
Barras, D. (2015) BRAF Mutation in Colorectal Cancer: An Update. Biomarkers in Cancer, 7, BIC.S25248. https://doi.org/10.4137/BIC.S25248
Kalady, M.F., Dejulius, K.L., Sanchez, J.A., Jarrar, A., Liu, X., Manilich, E., et al. (2012) BRAF Mutations in Colorectal Cancer Are Associated with Distinct Clinical Characteristics and Worse Prognosis. Diseases of the Colon & Rectum, 55, 128-133. https://doi.org/10.1097/DCR.0b013e31823c08b3
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., et al. (2012) Unresponsiveness of Colon Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR. Nature, 483, 100-103. https://doi.org/10.1038/nature10868
Parry-Jones, A. and Spary, L.K. (2018) The Wales Cancer Bank (WCB). Open Journal of Bioresources, 5, 10. https://doi.org/10.5334/ojb.46
Welsh Cancer Intelligence and Surveillance Unit (2022) Cancer Incidence in Wales, 2002-2019. https://phw.nhs.wales/services-and-teams/welsh-cancer-intelligence-and-surveillance-unit-wcisu/cancer-incidence-in-wales-2002-2019/
Welsh Cancer Intelligence and Surveillance Unit (2022) PHW Latest Available Cancer Mortality Official Statistics for Wales for Years 2002 to 2021 by Cancer Type, Sex, Age at Death and Area Disadvantage. WCISU. https://phw.nhs.wales/services-and-teams/welsh-cancer-intelligence-and-surveillance-unit-wcisu/cancer-mortality-in-wales-2002-2021/
Kaur, J. and Poole, J. (2017) Cancer Registration Statistics, England: 2015. Office for National Statistics.
Scotland, I.S.D. (2017) Cancer Incidence in Scotland (2015). NHS.
Siegel, R.L., Miller, K.D., Fedewa, S.A., Ahnen, D.J., Meester, R.G.S., Barzi, A., et al. (2017) Colorectal Cancer Statistics, 2017. A Cancer Journal for Clinicians, 67, 177-193. https://doi.org/10.3322/caac.21395
Cancer Research UK (2018) Bowel cancer Incidence Statistics. Cancer Research UK. http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bowel-cancer/incidence#ref-10
Overman, M.J., Lonardi, S., Wong, K.Y.M., Lenz, H.-J., Gelsomino, F., Aglietta, M., et al. (2018) Durable Clinical Benefit with Nivolumab Plus Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. Journal of Clinical Oncology, 36, 773-779. https://doi.org/10.1200/JCO.2017.76.9901
Barras, D., Missiaglia, E., Wirapati, P., Sieber, O.M., Jorissen, R.N., Love, C., et al. (2017) BRAF V600E Mutant Colorectal Cancer Subtypes Based on Gene Expression. Clinical Cancer Research, 23, 104-115. https://doi.org/10.1158/1078-0432.CCR-16-0140
Patel, D.K. (2008) Clinical Use of Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies in Metastatic Colorectal Cancer. Pharmacotherapy, 28, 31S-41S. https://doi.org/10.1592/phco.28.11-supp.31S
Corcoran, R.B., Ebi, H., Turke, A.B., Coffee, E.M., Nishino, M., Cogdill, A.P., et al. (2012) EGFR-Mediated Re-Activation of MAPK Signaling Contributes to Insensitivity of BRAF Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib. Cancer Discovery, 2, 227-235. https://doi.org/10.1158/2159-8290.CD-11-0341
Therkildsen, C., Bergmann, T.K., Henrichsen-Schnack, T., Ladelund, S. and Nilbert, M. (2014) The Predictive Value of KRAS, NRAS, BRAF, PIK3CA and PTEN for Anti-EGFR Treatment in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. Acta Oncologica, 53, 852-864. https://doi.org/10.3109/0284186X.2014.895036
Chapman, A.M., Sun, K.Y., Ruestow, P., Cowan, D.M. and Madl, A.K. (2016) Lung Cancer Mutation Profile of EGFR, ALK and KRAS: Meta-Analysis and Comparison of never and ever Smokers. Lung Cancer, 102, 122-134. https://doi.org/10.1016/j.lungcan.2016.10.010
Agarwal, A. and Saif, M.W. (2014) KRAS in Pancreatic Cancer. Journal of the Pancreas, 15, 303-305.
Schubbert, S., Shannon, K. and Bollag, G. (2007) Hyperactive Ras in Developmental Disorders and Cancer. Nature Reviews Cancer, 7, 295-308. https://doi.org/10.1038/nrc2109
Fernández-Medarde, A. and Santos, E. (2011) Ras in Cancer and Developmental Diseases. Genes & Cancer, 2, 344-358. https://doi.org/10.1177/1947601911411084
Irahara, N., Baba, Y., Nosho, K., Shima, K., Yan, L., Dias-Santagata, D., et al. (2010) NRAS Mutations Are Rare in Colorectal Cancer. Diagnostic Molecular Pathology, 19, 157-163. https://doi.org/10.1097/PDM.0b013e3181c93fd1
Amado, R.G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D.J., et al. (2008) Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients with Metastatic Colorectal Cancer. Journal of Clinical Oncology, 26, 1626-1634. https://doi.org/10.1200/JCO.2007.14.7116
Edkins, S., O’Meara, S., Parker, A., Stevens, C., Reis, M., Jones, S., et al. (2006) Recurrent KRAS Codon 146 Mutations in Human Colorectal Cancer. Cancer Biology & Therapy, 5, 928-932.
Vaughn, C.P., Zobell, S.D., Furtado, L.V., Baker, C.L. and Samowitz, W.S. (2011) Frequency of KRAS, BRAF and NRAS Mutations in Colorectal Cancer. Genes, Chromosomes and Cancer, 50, 307-312. https://doi.org/10.1002/gcc.20854
Phipps, A.I., Buchanan, D.D., Makar, K.W., Win, A.K., Baron, J.A., Lindor, N.M., et al. (2013) KRAS-Mutation Status in Relation to Colorectal Cancer Survival: The Joint Impact of Correlated Tumour Markers. British Journal of Cancer, 108, 1757-1764. https://doi.org/10.1038/bjc.2013.118
Phipps, A.I., Limburg, P.J., Baron, J.A., Burnett-Hartman, A.N., Weisenberger, D.J., Laird, P.W., et al. (2015) Association between Molecular Subtypes of Colorectal Cancer and Patient Survival. Gastroenterology, 148, 77-87. https://doi.org/10.1053/j.gastro.2014.09.038
Samuels, Y., Wang, Z., Bardelli, A., Silliman, N., Ptak, J., Szabo, S., et al. (2004) High Frequency of Mutations of the PIK3CA Gene in Human Cancers. Science, 304, 554. https://doi.org/10.1126/science.1096502
Karakas, B., Bachman, K.E. and Park, B.H. (2006) Mutation of the PIK3CA Oncogene in Human Cancers. British Journal of Cancer, 94, 455-459. https://doi.org/10.1038/sj.bjc.6602970
Mei, Z.B., Duan, C.Y., Li, C.B., Cui, L. and Ogino, S. (2016) Prognostic Role of Tumor PIK3CA Mutation in Colorectal Cancer: A Systematic Review and Meta-Analysis. Annals of Oncology, 27, 1836-1848. https://doi.org/10.1093/annonc/mdw264
De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G., et al. (2010) Effects of KRAS, BRAF, NRAS and PIK3CA Mutations on the Efficacy of Cetuximab Plus Chemotherapy in Chemotherapy-Refractory Metastatic Colorectal Cancer: A Retrospective Consortium Analysis. Lancet Oncology, 11, 753-762.
Lai, Y.L., Mau, B.L., Cheng, W.H., Chen, H.M., Chiu, H.H. and Tzen, C.Y. (2008) PIK3CA Exon 20 Mutation Is Independently Associated with a Poor Prognosis in Breast Cancer Patients. Annals of Surgical Oncology, 15, 1064-1069. https://doi.org/10.1245/s10434-007-9751-7
Cathomas, G. (2014) PIK3CA in Colorectal Cancer. Frontiers in Oncology, 4, Article 35. https://doi.org/10.3389/fonc.2014.00035
Olivier, M., Hollstein, M. and Hainaut, P. (2010) TP53 Mutations in Human Cancers: Origins, Consequences and Clinical Use. Cold Spring Harbor Perspectives in Biology, 2, a001008. https://doi.org/10.1101/cshperspect.a001008
Naccarati, A., Polakova, V., Pardini, B., Vodickova, L., Hemminki, K., Kumar, R., et al. (2012) Mutations and Polymorphisms in TP53 Gene—An Overview on the Role in Colorectal Cancer. Mutagenesis, 27, 211-218. https://doi.org/10.1093/mutage/ger067
Li, X.L., Zhou, J., Chen, Z.R. and Chng, W.J. (2015) P53 Mutations in Colorectal Cancer—Molecular Pathogenesis and Pharmacological Reactivation. World Journal of Gastroenterology, 21, 84-93. https://doi.org/10.3748/wjg.v21.i1.84
Cho, Y., Gorina, S., Jeffrey, P.D. and Pavletich, N.P. (1994) Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations. Science, 265, 346-355. https://doi.org/10.1126/science.8023157
Rivlin, N., Brosh, R., Oren, M. and Rotter, V. (2011) Mutations in the p53 Tumor Suppressor Gene: Important Milestones at the Various Steps of Tumorigenesis. Genes Cancer, 2, 466-474. https://doi.org/10.1177/1947601911408889
Grugan, K.D., Vega, M.E., Wong, G.S., Diehl, J.A., Bass, A.J., Wong, K.K., et al. (2013) A Common p53 Mutation (R175H) Activates c-Met Receptor Tyrosine Kinase to Enhance Tumor Cell Invasion. Cancer Biology & Therapy, 14, 853-859. https://doi.org/10.4161/cbt.25406
Dong, P., Xu, Z., Jia, N., Li, D. and Feng, Y. (2009) Elevated Expression of p53 Gain-of-Function Mutation R175H in Endometrial Cancer Cells Can Increase the Invasive Phenotypes by Activation of the EGFR/PI3K/AKT Pathway. Molecular Cancer, 8, Article No. 103. https://doi.org/10.1186/1476-4598-8-103
Schlomm, T., Iwers, L., Kirstein, P., Jessen, B., Köllermann, J., Minner, S., et al. (2008) Clinical Significance of p53 Alterations in Surgically Treated Prostate Cancers. Modern Pathology, 21, 1371-1378. https://doi.org/10.1038/modpathol.2008.104
Olivier, M., Langerød, A., Carrieri, P., Bergh, J., Klaar, S., Eyfjord, J., et al. (2006) The Clinical Value of Somatic TP53 Gene Mutations in 1,794 Patients with Breast Cancer. Clinical Cancer Research, 12, 1157-1167. https://doi.org/10.1158/1078-0432.CCR-05-1029
Robles, A.I. and Harris, C.C. (2010) Clinical Outcomes and Correlates of TP53 Mutations and Cancer. Cold Spring Harbor Perspectives in Biology, 2, a001016. https://doi.org/10.1101/cshperspect.a001016