Molecular Testing for Gastrointestinal Cancer

다국어 초록 (Multilingual Abstract)

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

참고문헌 (Reference)

1 Di Nicolantonio F, "Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer" 26 : 5705-5712, 2008

2 Bosman FT, "WHO classification of tumours of the digestive system" IARC Press 13-177, 2010

3 Hyman DM, "Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations" 373 : 726-736, 2015

4 Kamel-Reid S, "Validation of KRAS testing for anti-EGFR therapeutic decisions for patients with metastatic colorectal carcinoma" 136 : 26-32, 2012

5 Yarden Y, "Untangling the ErbB signalling network" 2 : 127-137, 2001

6 Ionov Y, "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis" 363 : 558-561, 1993

7 Bang YJ, "Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial" 376 : 687-697, 2010

8 Bettington M, "The serrated pathway to colorectal carcinoma : current concepts and challenges" 62 : 367-386, 2013

9 Watson P, "The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome" 123 : 444-449, 2008

10 Huth C, "The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors" 25 : 911-916, 2012

11 Xiao Y, "The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy" 5 : 16-18, 2015

12 Cerami E, "The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data" 2 : 401-404, 2012

13 Schmoll HJ, "Targeting HER2: precision oncology for colorectal cancer" 17 : 685-686, 2016

14 Hurwitz H, "Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors" 34 (34): 653-, 2016

15 Sartore-Bianchi A, "Sensitivity to entrectinib associated with a novel LMNA-NTRK1 gene fusion in metastatic colorectal cancer" 108 : djv306-, 2016

16 Ogino S, "Sensitive sequencing method for KRAS mutation detection by pyrosequencing" 7 : 413-421, 2005

17 Peltomaki P, "Role of DNA mismatch repair defects in the pathogenesis of human cancer" 21 : 1174-1179, 2003

18 Wolff AC, "Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update" 31 : 3997-4013, 2013

19 Magliacane G, "Rapid targeted somatic mutation analysis of solid tumors in routine clinical diagnostics" 6 : 30592-30603, 2015

20 Buhard O, "Quasimonomorphic mononucleotide repeats for high-level microsatellite instability analysis" 20 : 251-257, 2004

21 Ahmadian A, "Pyrosequencing: history, biochemistry and future" 363 : 83-94, 2006

22 Ali SM, "Prospective comprehensive genomic profiling of advanced gastric carcinoma cases reveals frequent clinically relevant genomic alterations and new routes for targeted therapies" 20 : 499-507, 2015

23 Ma C, "Programmed death-ligand 1 expression is common in gastric cancer associated with Epstein-Barr virus or microsatellite instability" 40 : 1496-1506, 2016

24 Mei ZB, "Prognostic role of tumor PIK3CA mutation in colorectal cancer: a systematic review and meta-analysis" 27 : 1836-1848, 2016

25 Roth AD, "Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial" 28 : 466-474, 2010

26 Kim JH, "Prognostic implications of CpG island hypermethylator phenotype in colorectal cancers" 455 : 485-494, 2009

27 Sinicrope FA, "Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients" 131 : 729-737, 2006

28 Jung KW, "Prediction of cancer incidence and mortality in Korea, 2016" 48 : 451-457, 2016

29 Hampel H, "Point: justification for Lynch syndrome screening among all patients with newly diagnosed colorectal cancer" 8 : 597-601, 2010

30 Kopetz S, "Phase II pilot study of vemurafenib in patients with metastatic BRAF-mutated colorectal cancer" 33 : 4032-4038, 2015

31 Douillard JY, "Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer" 369 : 1023-1034, 2013

32 Prenen H, "PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer" 15 : 3184-3188, 2009

33 Janku F, "PIK3CA mutation H1047R is associated with response to PI3K/AKT/mTOR signaling pathway inhibitors in early-phase clinical trials" 73 : 276-284, 2013

34 Perrone F, "PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients" 20 : 84-90, 2009

35 Boger C, "PD-L1 is an independent prognostic predictor in gastric cancer of Western patients" 7 : 24269-24283, 2016

36 Rosenbaum MW, "PD-L1 expression in colorectal cancer is associated with microsatellite instability, BRAF mutation, medullary morphology and cytotoxic tumor-infiltrating lymphocytes" 29 : 1104-1112, 2016

37 Le DT, "PD-1 blockade in tumors with mismatch-repair deficiency" 372 : 2509-2520, 2015

38 Yu J, "Novel recurrently mutated genes and a prognostic mutation signature in colorectal cancer" 64 : 636-645, 2015

39 Chevrier S, "Next-generation sequencing analysis of lung and colon carcinomas reveals a variety of genetic alterations" 45 : 1167-1174, 2014

40 Amatu A, "NTRK gene fusions as novel targets of cancer therapy across multiple tumour types" 1 : e000023-, 2016

41 Lin EI, "Mutational profiling of colorectal cancers with microsatellite instability" 6 : 42334-42344, 2015

42 Miglio U, "Mutation analysis of KRAS in primary colorectal cancer and matched metastases by means of highly sensitivity molecular assay" 209 : 233-236, 2013

43 Marrone M, "Multi-marker solid tumor panels using next-generation sequencing to direct molecularly targeted therapies" 6 : 2014

44 Davies KD, "Molecular pathways : ROS1 fusion proteins in cancer" 19 : 4040-4045, 2013

45 Sinicrope FA, "Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes" 148 : 88-99, 2015

46 Gulley ML, "Molecular diagnosis of Epstein-Barr virus-related diseases" 3 : 1-10, 2001

47 Chia NY, "Molecular classification of gastric cancer" 27 : 763-769, 2016

48 Cristescu R, "Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes" 21 : 449-456, 2015

49 Oh JR, "Microsatellite instability testing in Korean patients with colorectal cancer" 11 : 459-466, 2012

50 Thibodeau SN, "Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1" 58 : 1713-1718, 1998

51 김주연, "Microsatellite Instability Status in Gastric Cancer: A Reappraisal of Its Clinical Significance and Relationship with Mucin Phenotypes" 대한병리학회 47 (47): 28-35, 2013

52 Peeters M, "Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer" 19 : 1902-1912, 2013

53 Pietrantonio F, "MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer" 6 : 963-971, 2016

54 Ramanathan RK, "Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy: a phase II trial" 22 : 858-865, 2004

55 Malapelle U, "Less frequently mutated genes in colorectal cancer: evidences from next-generation sequencing of 653 routine cases" 69 : 767-771, 2016

56 Phipps AI, "KRAS-mutation status in relation to colorectal cancer survival : the joint impact of correlated tumour markers" 108 : 1757-1764, 2013

57 Herreros-Villanueva M, "KRAS mutations: analytical considerations" 431 : 211-220, 2014

58 Lievre A, "KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab" 26 : 374-379, 2008

59 Richman SD, "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" 27 : 5931-5937, 2009

60 van Grieken NC, "KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study" 108 : 1495-1501, 2013

61 Sundstrom M, "KRAS analysis in colorectal carcinoma: analytical aspects of pyrosequencing and allele-specific PCR in clinical practice" 10 : 660-, 2010

62 Karapetis CS, "K-ras mutations and benefit from cetuximab in advanced colorectal cancer" 359 : 1757-1765, 2008

63 Choi YY, "Is microsatellite instability a prognostic marker in gastric cancer? A systematic review with meta-analysis" 110 : 129-135, 2014

64 Lindor NM, "Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors" 20 : 1043-1048, 2002

65 Lee J, "Identification of ROS1 rearrangement in gastric adenocarcinoma" 119 : 1627-1635, 2013

66 Moreira L, "Identification of Lynch syndrome among patients with colorectal cancer" 308 : 1555-1565, 2012

67 Kim KM, "Human epidermal growth factor receptor 2 testing in gastric cancer: recommendations of an Asia-Pacific task force." 10 : 297-307, 2014

68 Pearson A, "High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial" 6 : 838-851, 2016

69 Ruschoff J, "HER2 testing in gastric cancer: a practical approach" 25 : 637-650, 2012

70 Seo AN, "HER2 status in colorectal cancer: its clinical significance and the relationship between HER2 gene amplification and expression" 9 : e98528-, 2014

71 Jemal A, "Global patterns of cancer incidence and mortality rates and trends" 19 : 1893-1907, 2010

72 Lee YS, "Genomic profile analysis of diffusetype gastric cancers" 15 : R55-, 2014

73 Wong SS, "Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing" 5 : 5477-, 2014

74 Carethers JM, "Genetics and genetic biomarkers in sporadic colorectal cancer" 149 : 1177-1190.e3, 2015

75 Lin Y, "Gene mutations in gastric cancer: a review of recent next-generation sequencing studies" 36 : 7385-7394, 2015

76 Lee J, "Gastrointestinal malignancies harbor actionable MET exon 14 deletions" 6 : 28211-28222, 2015

77 Chetty R, "Gastrointestinal cancers accompanied by a dense lymphoid component: an overview with special reference to gastric and colonic medullary and lymphoepithelioma-like carcinomas" 65 : 1062-1065, 2012

78 Fox SB, "Gastric HER2 Testing Study (GaTHER): an evaluation of gastric/gastroesophageal junction cancer testing accuracy in Australia" 36 : 577-582, 2012

79 Vaughn CP, "Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer" 50 : 307-312, 2011

80 Conradi LC, "Frequency of HER-2 positivity in rectal cancer and prognosis" 37 : 522-531, 2013

81 Longnecker RM, "Fields virology" Lippincott-Williams and Wilkins 1898-1959, 2013

82 Turner N, "Fibroblast growth factor signalling : from development to cancer" 10 : 116-129, 2010

83 Dieci MV, "Fibroblast growth factor receptor inhibitors as a cancer treatment : from a biologic rationale to medical perspectives" 3 : 264-279, 2013

84 Heinemann V, "FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial" 15 : 1065-1075, 2014

85 Sakai K, "Extended RAS and BRAF mutation snalysis using next-generation sequencing" 10 : e0121891-, 2015

86 Wang K, "Exome sequencing identifies frequent mutation of ARID1A in molecular subtypes of gastric cancer" 43 : 1219-1223, 2011

87 Boland CR, "Evolution of the nomenclature for the hereditary colorectal cancer syndromes" 4 : 211-218, 2005

88 Koudelakova V, "Evaluation of HER2 gene status in breast cancer samples with indeterminate fluorescence in situ hybridization by quantitative real-time PCR" 17 : 446-455, 2015

89 Lee HS, "Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma" 10 : 1698-1705, 2004

90 Ambinder RF, "Epstein-Barr-encoded RNA in situ hybridization: diagnostic applications" 25 : 602-605, 1994

91 Spano JP, "Epidermal growth factor receptor signaling in colorectal cancer: preclinical data and therapeutic perspectives" 16 : 189-194, 2005

92 Nam SK, "Effects of fixation and storage of human tissue samples on nucleic Acid preservation" 48 : 36-42, 2014

93 De Roock W, "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" 11 : 753-762, 2010

94 Srinivasan M, "Effect of fixatives and tissue processing on the content and integrity of nucleic acids" 161 : 1961-1971, 2002

95 Palomaki GE, "EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome" 11 : 42-65, 2009

96 Sartore-Bianchi A, "Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial" 17 : 738-746, 2016

97 Li X, "Distinct subtypes of gastric cancer defined by molecular characterization include novel mutational signatures with prognostic capability" 76 : 1724-1732, 2016

98 Lee HS, "Distinct clinical features and outcomes of gastric cancers with microsatellite instability" 15 : 632-640, 2002

99 Ogino S, "Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker : power and promise of molecular pathological epidemiology" 33 : 2949-2955, 2014

100 Kim MJ, "Different metastatic pattern according to the KRAS mutational status and site-specific discordance of KRAS status in patients with colorectal cancer" 12 : 347-, 2012

101 Oh JE, "Detection of low-level KRAS mutations using PNA-mediated asymmetric PCR clamping and melting curve analysis with unlabeled probes" 12 : 418-424, 2010

102 Sargent DJ, "Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer" 28 : 3219-3226, 2010

103 Shaw AT, "Crizotinib in ROS1-rearranged non-small-cell lung cancer" 371 : 1963-1971, 2014

104 Bria E, "Comprehensive molecular portrait using next generation sequencing of resected intestinal-type gastric cancer patients dichotomized according to prognosis" 6 : 22982-, 2016

105 Cancer Genome Atlas Research Network, "Comprehensive molecular characterization of human colon and rectal cancer" 487 : 330-337, 2012

106 Cancer Genome Atlas Research Network, "Comprehensive molecular characterization of gastric adenocarcinoma" 513 : 202-209, 2014

107 Kuboki Y, "Comprehensive analyses using next-generation sequencing and immunohistochemistry enable precise treatment in advanced gastric cancer" 27 : 127-133, 2016

108 Corcoran RB, "Combined BRAF and MEK inhibition with dabrafenib and trametinib in BRAF V600-mutant colorectal cancer" 33 : 4023-4031, 2015

109 Akihito Kawazoe, "Clinicopathological features of programmed death ligand 1 expression with tumor-infiltrating lymphocyte, mismatch repair, and Epstein–Barr virus status in a large cohort of gastric cancer patients" Springer Nature 20 (20): 407-415, 2017

110 Jun SY, "Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma" 29 : 402-415, 2016

111 D’Haene N, "Clinical validation of targeted next generation sequencing for colon and lung cancers" 10 : e0138245-, 2015

112 Lee HE, "Clinical significance of intratumoral HER2 heterogeneity in gastric cancer" 49 : 1448-1457, 2013

113 Dallol A, "Clinical significance of frequent somatic mutations detected by high-throughput targeted sequencing in archived colorectal cancer samples" 14 : 118-, 2016

114 de la Chapelle A, "Clinical relevance of microsatellite instability in colorectal cancer" 28 : 3380-3387, 2010

115 Mukherjee S, "Chromosomal microarray provides enhanced targetable gene aberration detection when paired with next generation sequencing panel in profiling lung and colorectal tumors" 209 : 119-129, 2016

116 Van Cutsem E, "Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer" 360 : 1408-1417, 2009

117 Oh CM, "Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2013" 48 : 436-450, 2016

118 Nam SK, "BRAF, PIK3CA, and HER2 oncogenic alterations according to KRAS mutation status in advanced colorectal cancers with distant metastasis" 11 : e0151865-, 2016

119 Lee SH, "BRAF and KRAS mutations in stomach cancer" 22 : 6942-6945, 2003

120 Liao X, "Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival" 367 : 1596-1606, 2012

121 Kloor M, "Analysis of EPCAM protein expression in diagnostics of Lynch syndrome" 29 : 223-227, 2011

122 Bardelli A, "Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer" 3 : 658-673, 2013

123 Smith G, "Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours : implications for personalised cancer medicine" 102 : 693-703, 2010

124 Edge SB, "AJCC cancer staging manual" Springer 241-249, 2010

125 Amin MB, "AJCC cancer staging manual" Spinger 203-274, 2017

126 Franca LT, "A review of DNA sequencing techniques" 35 : 169-200, 2002

127 Bang YJ, "A randomized, open-label phase II study of AZD4547 (AZD) versus Paclitaxel (P) in previously treated patients with advanced gastric cancer (AGC) with fibroblast growth factor receptor 2 (FGFR2) polysomy or gene amplification (amp): SHINE study" 33 (33): 4014-, 2015

128 Bertotti A, "A molecularly annotated platform of patient-derived xenografts (“xenopatients”) identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer" 1 : 508-523, 2011

129 Gonzalez de Castro D, "A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens" 107 : 345-351, 2012

130 Boland CR, "A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition : development of international criteria for the determination of microsatellite instability in colorectal cancer" 58 : 5248-5257, 1998

131 Altimari A, "454 next generation-sequencing outperforms allele-specific PCR, Sanger sequencing, and pyrosequencing for routine KRAS mutation analysis of formalinfixed, paraffin-embedded samples" 6 : 1057-1064, 2013