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Published in: World Journal of Surgery 5/2017

Open Access 01-05-2017 | Original Scientific Report

Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer

Authors: Huw Geraint Jones, Gareth Jenkins, Namor Williams, Paul Griffiths, Phil Chambers, John Beynon, Dean Harris

Published in: World Journal of Surgery | Issue 5/2017

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Abstract

Introduction

Colorectal cancer (CRC) is a highly heterogeneous disease, with pathologically similar cancers having completely different responses to treatment and patient survival. Intra-tumour heterogeneity (defined as distinct morphological and phenotypic differences) has recently been demonstrated to be an important factor in the development and behaviour of cancer cells and can be used to determine response to anticancer therapy.

Method

Patients with resected CRC had DNA extracted from eight defined tumour areas which were analysed for two genetic mutations (BRAF and KRAS) and one epigenetic trait (CpG island methylator phenotype/CIMP). Normal adjacent tissue was studied as control.

Results

Twelve patients with CRC were included. Intra-tumoural heterogeneity for KRAS mutation was seen in 2 patients (17%). There was no statistical evidence of CIMP status heterogeneity (p = 0.85), but 6 of the 12 patients (50%) demonstrated at least one heterogeneous area within the tumour.

Discussion

Intra-tumoural heterogeneity for both genetic and epigenetic factors in CRC is more prevalent than previously thought in Stage II and Stage III CRC. This study provides new insight into epigenetic heterogeneity of CRC and supports the development of a more targeted biopsy strategy to support expansion of personalised treatment.
Literature
1.
go back to reference Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805(1):105–117PubMed Marusyk A, Polyak K (2010) Tumor heterogeneity: causes and consequences. Biochim Biophys Acta 1805(1):105–117PubMed
2.
go back to reference Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892CrossRefPubMedPubMedCentral Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366(10):883–892CrossRefPubMedPubMedCentral
3.
go back to reference Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323–334CrossRefPubMed Marusyk A, Almendro V, Polyak K (2012) Intra-tumour heterogeneity: a looking glass for cancer? Nat Rev Cancer 12(5):323–334CrossRefPubMed
4.
go back to reference Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M (2011) Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469(7330):356–361CrossRefPubMed Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M (2011) Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469(7330):356–361CrossRefPubMed
5.
go back to reference Shackleton M, Quintana E, Fearon ER, Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829CrossRefPubMed Shackleton M, Quintana E, Fearon ER, Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829CrossRefPubMed
6.
go back to reference Baisse B, Bouzourene H, Saraga EP, Bosman FT, Benhattar J (2001) Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma. Int J Cancer 93(3):346–352CrossRefPubMed Baisse B, Bouzourene H, Saraga EP, Bosman FT, Benhattar J (2001) Intratumor genetic heterogeneity in advanced human colorectal adenocarcinoma. Int J Cancer 93(3):346–352CrossRefPubMed
7.
go back to reference Yagi K, Akagi K, Hayashi H, Nagae G, Tsuji S, Isagawa T, Midorikawa Y, Nishimura Y, Sakamoto H, Seto Y, Aburatani H, Kaneda A (2010) Three DNA methylation epigenotypes in human colorectal cancer. Clin Cancer Res 16(1):21–33CrossRefPubMed Yagi K, Akagi K, Hayashi H, Nagae G, Tsuji S, Isagawa T, Midorikawa Y, Nishimura Y, Sakamoto H, Seto Y, Aburatani H, Kaneda A (2010) Three DNA methylation epigenotypes in human colorectal cancer. Clin Cancer Res 16(1):21–33CrossRefPubMed
8.
go back to reference Kaneda A, Yagi K (2011) Two groups of DNA methylation markers to classify colorectal cancer into three epigenotypes. Cancer Sci 102(1):18–24CrossRefPubMed Kaneda A, Yagi K (2011) Two groups of DNA methylation markers to classify colorectal cancer into three epigenotypes. Cancer Sci 102(1):18–24CrossRefPubMed
9.
go back to reference Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27(35):5931–5937CrossRefPubMed Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, Taylor G, Barrett JH, Quirke P (2009) KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol 27(35):5931–5937CrossRefPubMed
10.
11.
12.
go back to reference Turner NC, Reis-Filho JS (2012) Genetic heterogeneity and cancer drug resistance. Lancet Oncol 13(4):e178–e185CrossRefPubMed Turner NC, Reis-Filho JS (2012) Genetic heterogeneity and cancer drug resistance. Lancet Oncol 13(4):e178–e185CrossRefPubMed
13.
go back to reference Sieber OM, Heinimann K, Tomlinson IP (2003) Genomic instability–the engine of tumorigenesis? Nat Rev Cancer 3(9):701–708CrossRefPubMed Sieber OM, Heinimann K, Tomlinson IP (2003) Genomic instability–the engine of tumorigenesis? Nat Rev Cancer 3(9):701–708CrossRefPubMed
14.
go back to reference Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7(1):21–33CrossRefPubMed Feinberg AP, Ohlsson R, Henikoff S (2006) The epigenetic progenitor origin of human cancer. Nat Rev Genet 7(1):21–33CrossRefPubMed
15.
16.
go back to reference Leith JT, Michelson S, Faulkner LE, Bliven SF (1987) Growth properties of artificial heterogeneous human colon tumors. Cancer Res 47(4):1045–1051PubMed Leith JT, Michelson S, Faulkner LE, Bliven SF (1987) Growth properties of artificial heterogeneous human colon tumors. Cancer Res 47(4):1045–1051PubMed
18.
go back to reference Richman SD, Chambers P, Seymour MT, Daly C, Grant S, Hemmings G, Quirke P (2011) Intra-tumoral heterogeneity of KRAS and BRAF mutation status in patients with advanced colorectal cancer (aCRC) and cost-effectiveness of multiple sample testing. Anal Cell Pathol (Amst) 34(1–2):61–66CrossRef Richman SD, Chambers P, Seymour MT, Daly C, Grant S, Hemmings G, Quirke P (2011) Intra-tumoral heterogeneity of KRAS and BRAF mutation status in patients with advanced colorectal cancer (aCRC) and cost-effectiveness of multiple sample testing. Anal Cell Pathol (Amst) 34(1–2):61–66CrossRef
19.
go back to reference Farber L, Efrati E, Elkin H, Peerless Y, Sabo E, Ben-Izhak O, Hershkovitz D (2011) Molecular morphometric analysis shows relative intra-tumoural homogeneity for KRAS mutations in colorectal cancer. Virchows Arch 459(5):487–493CrossRefPubMed Farber L, Efrati E, Elkin H, Peerless Y, Sabo E, Ben-Izhak O, Hershkovitz D (2011) Molecular morphometric analysis shows relative intra-tumoural homogeneity for KRAS mutations in colorectal cancer. Virchows Arch 459(5):487–493CrossRefPubMed
20.
go back to reference Molinari F, Martin V, Saletti P, De Dosso S, Spitale A, Camponovo A, Bordoni A, Crippa S, Mazzucchelli L, Frattini M (2009) Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer 100(7):1087–1094CrossRefPubMedPubMedCentral Molinari F, Martin V, Saletti P, De Dosso S, Spitale A, Camponovo A, Bordoni A, Crippa S, Mazzucchelli L, Frattini M (2009) Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. Br J Cancer 100(7):1087–1094CrossRefPubMedPubMedCentral
21.
go back to reference Fadhil W, Ibrahem S, Seth R, AbuAli G, Ragunath K, Kaye P, Ilyas M (2012) The utility of diagnostic biopsy specimens for predictive molecular testing in colorectal cancer. Histopathology 61(6):1117–1124CrossRefPubMed Fadhil W, Ibrahem S, Seth R, AbuAli G, Ragunath K, Kaye P, Ilyas M (2012) The utility of diagnostic biopsy specimens for predictive molecular testing in colorectal cancer. Histopathology 61(6):1117–1124CrossRefPubMed
22.
go back to reference Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50(1):113–130CrossRefPubMed Jass JR (2007) Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50(1):113–130CrossRefPubMed
23.
go back to reference NICE (2014) CG131: Colorectal cancer: the diagnosis and management of colorectal cancer NICE (2014) CG131: Colorectal cancer: the diagnosis and management of colorectal cancer
24.
go back to reference Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, Andrews SR, Stegle O, Reik W, Kelsey G (2014) Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods 11(8):817–820CrossRefPubMedPubMedCentral Smallwood SA, Lee HJ, Angermueller C, Krueger F, Saadeh H, Peat J, Andrews SR, Stegle O, Reik W, Kelsey G (2014) Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods 11(8):817–820CrossRefPubMedPubMedCentral
25.
go back to reference Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, Mourtzoukou D, Kontogeorgos G, Zografos G, Pintzas A (2014) Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat 35(3):329–340CrossRefPubMed Kosmidou V, Oikonomou E, Vlassi M, Avlonitis S, Katseli A, Tsipras I, Mourtzoukou D, Kontogeorgos G, Zografos G, Pintzas A (2014) Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumor mutation profile differences and their therapeutic implications. Hum Mutat 35(3):329–340CrossRefPubMed
26.
go back to reference Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648CrossRefPubMed Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, Zanon C, Moroni M, Veronese S, Siena S, Bardelli A (2007) Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti-epidermal growth factor receptor antibody therapies. Cancer Res 67(6):2643–2648CrossRefPubMed
27.
go back to reference De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603CrossRefPubMed De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar S (2011) KRAS, BRAF, PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol 12(6):594–603CrossRefPubMed
Metadata
Title
Genetic and Epigenetic Intra-tumour Heterogeneity in Colorectal Cancer
Authors
Huw Geraint Jones
Gareth Jenkins
Namor Williams
Paul Griffiths
Phil Chambers
John Beynon
Dean Harris
Publication date
01-05-2017
Publisher
Springer International Publishing
Published in
World Journal of Surgery / Issue 5/2017
Print ISSN: 0364-2313
Electronic ISSN: 1432-2323
DOI
https://doi.org/10.1007/s00268-016-3860-z

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