- Email: [email protected]
Landscape of Genetic Aberrations Detected in Human Colorectal Cancers
686
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 145, No. 3
been useful in determining if this observation was related to anatomic location. Finally, regarding the overall findings, the average proximal serrated polyp detection rate in the current study (12%; range, 6%–22%) is similar to the detection rate in the study by Kahi et al (average 13%; range, 1%–18%). However, the average ADR is slightly lower in the current study (29%) compared with the Indiana study (38%). As stated, this could be owing to one endoscopist’s data “skewing the results.” Overall, the results are well within the suggested proximal serrated polyp detection rate of 5% for a corresponding ADR of 20%. Of note, all of the endoscopists have a median withdrawal time of 8 minutes, which is longer than current minimum recommendation for average withdrawal time (Am J Gastroenterol 2009;104:739–750). These withdrawal times along with the overall high ADR and proximal serrated polyp detection rate provide the reader with important reassurance that the colonoscopies in this study were performed with great care. In conclusion, the current study demonstrates that proximal serrated polyp detection rate, like ADR, varies among endoscopists. Furthermore, proximal serrated polyp detection rate, like ADR, is strongly correlated with the withdrawal time. A major strength of this study is that these investigators demonstrated this correlation after controlling for important patient factors including age and gender, as well as procedure factors such as bowel preparation. Clearly, spending more time looking in the colon increases the yield of polyp detection, either adenomatous or serrated. However, there are still unanswered questions. Unlike the 20% recommendation for ADR, there is no current “standard” for proximal serrated polyp detection rate that has been validated longitudinally. Another unknown is the optimal withdrawal time that endoscopists should “shoot for” to achieve this desired proximal serrated polyp detection rate. A minimum 6 minutes average withdrawal time is recommended for achieving an acceptable ADR, but does this recommendation need to be increased to achieve the “standard” proximal serrated polyp detection rate? Data from this study suggest that a withdrawal time of 8 minutes would be more than adequate to achieve the standard proximal serrated polyp detection rate of 5% in screening colonoscopy as recommended by Kahi et al. However, more studies are needed to determine the standard for proximal serrated polyp detection rate as well as the optimal minimum withdrawal time. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
LANDSCAPE OF GENETIC ABERRATIONS DETECTED IN HUMAN COLORECTAL CANCERS The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337. The Cancer Genome Atlas Project aimed to comprehensively profile genomic changes in many human cancer types. The project first targeted glioblastoma multiforme, lung cancer, and ovarian cancer, and in 2009 expanded to >20 different types of cancer. The results for glioblastoma multiforme and ovarian cancer have been so far published. To reveal the genetic aberrations accumulated in colorectal cancers, in their recently published paper in the Nature, researchers of the Cancer Genome Atlas Network conducted comprehensive multidimensional analyses, including exome sequence, DNA copy number, promoter methylation, and messenger RNA and microRNA expression in 276 samples of human colorectal carcinomas (CRC) as well as low-depth-of-coverage whole-genome sequencing in 97 CRC samples. Through extensive screening and subsequent validation experiments, they demonstrated that approximately 16% of the human CRC possesses a mutation rate of >12/106 bases, which they designated hypermutated CRC. Interestingly, three quarters of hypermutated CRC had high levels of microsatellite instability (MSI), and many hypermutated CRCs also showed CpG island methylator phenotype and/or mismatch-repair genes MLH1 methylation. The remaining one fourth of hypermutated CRC had somatic mutations in one or more mismatch repair genes or polymerase ε aberrations, and the mutation rate was >100/ 106 bases. On the other hand, non-hypermutated CRC had mutations not only in the well-known tumor-related genes, such as APC, TP53, KRAS, PIK3CA, SMAD4, but also in several other genes, including SMAD2, CTNNB1, FAM123B, SOX9, and ARID1A. Interestingly, TP53 and APC were significantly less mutated in hypermutated CRC than in non-hypermutated CRC. By contrast, BRAF (V600E), which was rarely mutated in non-hypermutated CRC, had a high mutation rate in hypermutated CRC. They deduced that these findings indicated different sequences of genetic events between hypermutated and non-hypermutated tumors. One thing to be noted is that although colon cancers differ from rectal cancers anatomically, they have very similar genomic alteration patterns, especially in nonhypermutated cancer. As for the biologic functions of the identified mutated genes, FAM123B, also known as WTX, is an X-linked negative regulator of WNT signaling, and SOX9 is related to differentiation in the intestinal stem cell niche. ARID1A is involved in chromatin remodeling, and mutations of ARID1A were recently reported in various types of gastrointestinal tumors, including gastric and liver cancers. This analysis also showed that IGF2 is among the most frequently overexpressed or amplified genes. IGF2
September 2013
overexpression activates the PI3K signaling pathway through IFG1R-IRS2-PIK3CA. They also demonstrated mutations and focal amplifications in ERBB2 (HER2). ERBB2 is associated with proliferation in normal cells, and ERBB2 mutations are found not only in CRC, but also in breast and gastric cancers. This comprehensive, integrative analysis of CRC revealed that samples could be grouped by hypermutation status. Moreover, the study identified recurrent alterations in 5 signaling pathways: The WNT signaling pathway (including APC, CTNNB1, ARID1A, SOX9, and FAM123B); the PI3K signaling pathway (including IGF2, IRS2, PTEN, and PIK3CA); the RTK-RAS signaling pathway (KRAS, BRAF, and ERBB family); the transforming growth factorb signaling pathway (SMAD2 and SMAD4); and the p53 signaling pathway (TP53). Finally, they clearly demonstrated that almost all CRC have changes in MYC transcriptional signal targets, indicating a critical role for MYC in the development of both hypermutated and nonhypermutated CRCs. Comment. CRCs arise through multiple genetic and
epigenetic events in a sequential order. To date, 2 distinct, major pathways are known to be involved in the development of CRC: The chromosomal instability (CIN) and MSI pathways (Nature 1998;396:643–649). CIN phenotypes exhibit aberration at the chromosomal level, such as losses and/or gains of whole chromosomes or large portions thereof, typically characterized by frequent lossof-heterozygosity, at tumor suppressor gene loci and/or numerical abnormalities of chromosomes, so-called aneuploidy. CRCs with the CIN feature typically develop via stepwise genomic events initiated by APC mutation, followed by the activation of KRAS and loss of function of p53 (N Engl J Med 1988;319:525–532). On the other hand, MSI is characterized by instability in stretches of DNA microsatellites caused by a loss of the DNA mismatch repair function. MSI is frequently associated with epigenetic instability characterized by the CpG island methylation phenotype, in which widespread CpG island hypermethylation at the promoter region of tumor suppressor genes and BRAF mutations are related to development of MSI tumors (Gastroenterology 2005;129:837–845). Clinically, CIN accounts for approximately 60%–70% of sporadic CRCs and CIN pathway is usually associated with a traditional “adenoma to carcinoma sequence,” whereas MSI is observed in 15%–20% of CRCs and is frequently related to the “serrated pathway,” describing the progression of sessile serrated adenomas to CRCs. In the present study, the authors conducted genome-wide analyses of >200 CRC samples. They found that 84% of the CRCs had a low mutation rate (mutation rates of <8.24/106 bases, defined as non-hypermutated), whereas the remaining 16% of CRCs had a high mutation rate (mutation rates of >12/106 bases, defined as hypermutated). Accordingly, the mutation frequency of well-known tumor-related genes, APC, KRAS, BRAF, TP53 was 81%, 43%, 3%, and 59% in non-hypermutated CRCs and 53%, 30%, 47%, and 17%
SELECTED SUMMARIES 687
in hypermutated CRCs, respectively. Around the same time, Seshagiri et al applied deep-sequencing to >70 pairs of primary CRCs and characterized their exomes, transcriptomes, and copy number alterations (Nature 2012;488:660–664). They observed that the mean nonsynonymous mutation frequency in MSI and microsatellitestable (mainly corresponding with non-hypermutated type in the current paper) tumors was 47 and 2.8 mutations per 106 bases, respectively. Consistent with the results shown in the current paper, the several well-known CRC-related tumor-related genes, such as APC, KRAS, TP53, and SMAD4, were frequently mutated in CRC samples, but they also reported several new genes recurrently mutated in CRCs (eg, the chromatin-remodeling genes TET1, TET2, and TET3, and receptor tyrosine kinase ERBB3). Because the tissue samples used in these studies were collected randomly from newly diagnosed patients with CRCs undergoing operative resection, we cannot fully evaluate the clinical background of these patients with CRCs. The mutational profiles, however, suggested that the hypermutated and non-hypermutated tumors determined in these studies basically correspond with the CIN and MSI phenotypes, respectively. Comprehensive integrative analysis using recently advanced technology has provided detailed information about the deregulated pathways in human CRCs. The present study demonstrated that >90% of CRCs had a deregulated WNT signaling pathway caused by biallelic inactivation of APC, activating mutations of CTNNB1, or mutations in SOX9, TCF7L2, DKK family members, AXIN2, FBXW7, FAM123B, and ARID1A (AT-rich interactive domain-containing protein 1A). Seshagiri et al revealed a critical role of WNT dysregulation in CRC tumorigenesis by showing multiple transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 (Nature 2012;488:660–664). They showed that RSPO fusions were mutually exclusive with APC mutations, indicating that RSPO fusion expression was capable of leading to activation of the WNT pathway. Both studies also identified ARID1A as one of the most frequently mutated genes in CRC. ARID1A is a member of the SWI/SNF family and is also involved in the regulation of WNT signaling. Recently, mutations in ARID1A were reported in a variety of human cancers, such as 83% of MSI gastric cancer, 73% of Epstein-Barr virus–associated gastric cancers, and 11% of microsatellite-stable gastric cancers showed ARID1A inactivation or protein loss alteration (Nat Genet 2011;43:1219–1223). In breast cancer, Mamo et al identified ARID1A as a candidate tumor suppressor gene, and showed that ARID1A is intimately related to prognosis (Oncogene 2012;31:2090–2100). The finding that ARID1A mutation rates were higher in hypermutated CRC than in non-hypermutated CRC (37% vs 5%, respectively) was consistent with the mutational profile observed in gastric cancers showing the ARID1A mutation is frequently detectable in MSI tumors. Because ARID1A is also involved in chromatin remodeling and thus dysfunction of ARID1A has the potential to cause
688
SELECTED SUMMARIES
epigenetic instability (Nat Rev Cancer 2011;11:481–492), these findings may suggest a close correlation between genetic and epigenetic aberrations in human gastrointestinal cancers. MYC is a transcription factor that regulates a number of genes essential for the regulation of proliferation, transcription, apoptosis and DNA replication, and is one of the most frequently dysregulated proto-oncogenes in human cancers (Cell 2012;149:22–35). MYC was recently spotlighted from a different aspect by its identification as one of the four key pluripotency genes essential for the production of induced pluripotent stem cells, so-called iPS cells (Cell 2006;126:663–676). The MYC proto-oncogene itself is under tight transcriptional control by various host transcription factors including CNBP, FBP, and TCF, downstream of the WNT pathway (Genes Cancer 2010;1:547–554). The study by Wilkins and Sansom showed that a murine model with a deletion of both Apc and c-Myc evaded all the phenotypes of APC deficiency (Cancer Research 2008;68:4963–4966). Their data indicated that MYC is essential for the APC-deficient phenotype in intestine, and APC-deficient cells are “addicted” to MYC in the intestine. In the present study, the authors performed an integrated analysis and found that nearly 100% of CRCs had changes in MYC transcriptional targets, both those promoted by and those inhibited by MYC. The finding that enhanced MYC activity is a nearly ubiquitous event in CRC might provide novel therapeutic opportunities by targeting MYC itself or its target genes for future treatment of CRCs. The introduction of new therapeutic strategies, including cytotoxic chemotherapeutic and biologic agents, has led to great advances in the treatment of human CRCs. An understanding of the genetic characteristics of individual tumors is critical for designing future therapeutic approaches. For example, anti-epidermal growth factor receptor (EGFR) antibody (cetuximab, panitumumab) and anti-vascular endothelial growth factor antibody (bevacizumab) are the current key drugs in CRC chemotherapy, and many studies of the biomarkers to predict the performance of these drugs showed that there is a significant correlation between the efficacy of antiEGFR antibody drug and the KRAS mutation status of tumors. Namely, wild-type KRAS tumors show higher response rates compared with those with the KRAS mutation-type (N Engl J Med 2009;360:1408–1417). In addition, tumors with BRAF (V600E) mutation status show a poor response to anti-EGFR drugs, even if the tumor has the KRAS wild-type status (J Clin Oncol 2009;27:5924–5930). On the other hand, sorafenib, a clinically approved multikinase inhibitor targeting several
GASTROENTEROLOGY Vol. 145, No. 3
receptor tyrosine kinases including BRAF, can potentially restore the sensitivity of BRAF-mutated CRC to antiEGFR antibody therapy (J Clin Oncol 2008;26: 5705–5712). In parallel with trials using the existing drugs, researchers have made great efforts to determine new potential therapeutic targets. In this regard, information about the mutated genes identified in the current study, such as SOX9, ARID1A, CTNNB1, IGF2, and ERBB family, has putative implications for new therapeutic targets. Trastuzumab, an anti-ERBB2 monoclonal antibody, has been used clinically in chemotherapy for breast or gastric cancer (Nature 2011;9:16–32; Cancer Treat Rev 2013;39:60–67). CRC with overexpression of ERBB2 might respond to anti-ERBB2 therapy. The PI3K signaling pathway, including IGF2, IRS2, and PIK3CA is a candidate pathway for molecular targeted therapy, and studies of breast cancer indicate that PIK3CA plays an important role in acquiring resistance to anti-ERBB2 therapy (Ann Oncol 2010;21:255–262; Cancer Cell 2004;6:117–127). Investigation of the influence of PIK3CA mutations on sensitivity to ERBB2-targeted agents will contribute to a better understanding of the mechanism of drug resistance. What must be noted is that the mutation frequencies of the majority of the genes newly identified in the current study were significantly lower than those of the wellknown CRC-related genes. Indeed, the mutation rates of the SOX9, ARID1A, CTNNB1, and ERBB family genes in non-hypermutated CRCs are <10%, whereas >80% of those have mutations in APC, and about half have mutations in TP53 and KRAS. Thus, the efficacy of molecular targeted agents would vary according to the overall picture of the genetic alterations in the tumor tissue, especially when the mutation frequency of the candidate target gene sets is in low level. Integrated analysis based on the genetic and epigenetic information of each tumor tissue will be an essential for the development of personalized treatment for cancer patients. The success of gene-targeting therapy for treating cancer depends on the development of appropriate diagnostic surveys that can identify the characteristics of individual genetic alteration profiles. The era of treating CRC patients with a uniform treatment is over, and we must share the vision of personalized medicine to create better outcomes and to overcome cancer. TOMOYUKI GOTO HIROYUKI MARUSAWA TSUTOMU CHIBA Department of Gastroenterology and Hepatology Graduate School of Medicine Kyoto University Kyoto, Japan
SELECTED SUMMARIES
GASTROENTEROLOGY Vol. 145, No. 3
been useful in determining if this observation was related to anatomic location. Finally, regarding the overall findings, the average proximal serrated polyp detection rate in the current study (12%; range, 6%–22%) is similar to the detection rate in the study by Kahi et al (average 13%; range, 1%–18%). However, the average ADR is slightly lower in the current study (29%) compared with the Indiana study (38%). As stated, this could be owing to one endoscopist’s data “skewing the results.” Overall, the results are well within the suggested proximal serrated polyp detection rate of 5% for a corresponding ADR of 20%. Of note, all of the endoscopists have a median withdrawal time of 8 minutes, which is longer than current minimum recommendation for average withdrawal time (Am J Gastroenterol 2009;104:739–750). These withdrawal times along with the overall high ADR and proximal serrated polyp detection rate provide the reader with important reassurance that the colonoscopies in this study were performed with great care. In conclusion, the current study demonstrates that proximal serrated polyp detection rate, like ADR, varies among endoscopists. Furthermore, proximal serrated polyp detection rate, like ADR, is strongly correlated with the withdrawal time. A major strength of this study is that these investigators demonstrated this correlation after controlling for important patient factors including age and gender, as well as procedure factors such as bowel preparation. Clearly, spending more time looking in the colon increases the yield of polyp detection, either adenomatous or serrated. However, there are still unanswered questions. Unlike the 20% recommendation for ADR, there is no current “standard” for proximal serrated polyp detection rate that has been validated longitudinally. Another unknown is the optimal withdrawal time that endoscopists should “shoot for” to achieve this desired proximal serrated polyp detection rate. A minimum 6 minutes average withdrawal time is recommended for achieving an acceptable ADR, but does this recommendation need to be increased to achieve the “standard” proximal serrated polyp detection rate? Data from this study suggest that a withdrawal time of 8 minutes would be more than adequate to achieve the standard proximal serrated polyp detection rate of 5% in screening colonoscopy as recommended by Kahi et al. However, more studies are needed to determine the standard for proximal serrated polyp detection rate as well as the optimal minimum withdrawal time. TARUN RUSTAGI Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut JOSEPH C. ANDERSON Department of Veterans Affairs Medical Center White River Junction, Vermont and The Geisel School of Medicine at Dartmouth Medical Hanover, New Hampshire
LANDSCAPE OF GENETIC ABERRATIONS DETECTED IN HUMAN COLORECTAL CANCERS The Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–337. The Cancer Genome Atlas Project aimed to comprehensively profile genomic changes in many human cancer types. The project first targeted glioblastoma multiforme, lung cancer, and ovarian cancer, and in 2009 expanded to >20 different types of cancer. The results for glioblastoma multiforme and ovarian cancer have been so far published. To reveal the genetic aberrations accumulated in colorectal cancers, in their recently published paper in the Nature, researchers of the Cancer Genome Atlas Network conducted comprehensive multidimensional analyses, including exome sequence, DNA copy number, promoter methylation, and messenger RNA and microRNA expression in 276 samples of human colorectal carcinomas (CRC) as well as low-depth-of-coverage whole-genome sequencing in 97 CRC samples. Through extensive screening and subsequent validation experiments, they demonstrated that approximately 16% of the human CRC possesses a mutation rate of >12/106 bases, which they designated hypermutated CRC. Interestingly, three quarters of hypermutated CRC had high levels of microsatellite instability (MSI), and many hypermutated CRCs also showed CpG island methylator phenotype and/or mismatch-repair genes MLH1 methylation. The remaining one fourth of hypermutated CRC had somatic mutations in one or more mismatch repair genes or polymerase ε aberrations, and the mutation rate was >100/ 106 bases. On the other hand, non-hypermutated CRC had mutations not only in the well-known tumor-related genes, such as APC, TP53, KRAS, PIK3CA, SMAD4, but also in several other genes, including SMAD2, CTNNB1, FAM123B, SOX9, and ARID1A. Interestingly, TP53 and APC were significantly less mutated in hypermutated CRC than in non-hypermutated CRC. By contrast, BRAF (V600E), which was rarely mutated in non-hypermutated CRC, had a high mutation rate in hypermutated CRC. They deduced that these findings indicated different sequences of genetic events between hypermutated and non-hypermutated tumors. One thing to be noted is that although colon cancers differ from rectal cancers anatomically, they have very similar genomic alteration patterns, especially in nonhypermutated cancer. As for the biologic functions of the identified mutated genes, FAM123B, also known as WTX, is an X-linked negative regulator of WNT signaling, and SOX9 is related to differentiation in the intestinal stem cell niche. ARID1A is involved in chromatin remodeling, and mutations of ARID1A were recently reported in various types of gastrointestinal tumors, including gastric and liver cancers. This analysis also showed that IGF2 is among the most frequently overexpressed or amplified genes. IGF2
September 2013
overexpression activates the PI3K signaling pathway through IFG1R-IRS2-PIK3CA. They also demonstrated mutations and focal amplifications in ERBB2 (HER2). ERBB2 is associated with proliferation in normal cells, and ERBB2 mutations are found not only in CRC, but also in breast and gastric cancers. This comprehensive, integrative analysis of CRC revealed that samples could be grouped by hypermutation status. Moreover, the study identified recurrent alterations in 5 signaling pathways: The WNT signaling pathway (including APC, CTNNB1, ARID1A, SOX9, and FAM123B); the PI3K signaling pathway (including IGF2, IRS2, PTEN, and PIK3CA); the RTK-RAS signaling pathway (KRAS, BRAF, and ERBB family); the transforming growth factorb signaling pathway (SMAD2 and SMAD4); and the p53 signaling pathway (TP53). Finally, they clearly demonstrated that almost all CRC have changes in MYC transcriptional signal targets, indicating a critical role for MYC in the development of both hypermutated and nonhypermutated CRCs. Comment. CRCs arise through multiple genetic and
epigenetic events in a sequential order. To date, 2 distinct, major pathways are known to be involved in the development of CRC: The chromosomal instability (CIN) and MSI pathways (Nature 1998;396:643–649). CIN phenotypes exhibit aberration at the chromosomal level, such as losses and/or gains of whole chromosomes or large portions thereof, typically characterized by frequent lossof-heterozygosity, at tumor suppressor gene loci and/or numerical abnormalities of chromosomes, so-called aneuploidy. CRCs with the CIN feature typically develop via stepwise genomic events initiated by APC mutation, followed by the activation of KRAS and loss of function of p53 (N Engl J Med 1988;319:525–532). On the other hand, MSI is characterized by instability in stretches of DNA microsatellites caused by a loss of the DNA mismatch repair function. MSI is frequently associated with epigenetic instability characterized by the CpG island methylation phenotype, in which widespread CpG island hypermethylation at the promoter region of tumor suppressor genes and BRAF mutations are related to development of MSI tumors (Gastroenterology 2005;129:837–845). Clinically, CIN accounts for approximately 60%–70% of sporadic CRCs and CIN pathway is usually associated with a traditional “adenoma to carcinoma sequence,” whereas MSI is observed in 15%–20% of CRCs and is frequently related to the “serrated pathway,” describing the progression of sessile serrated adenomas to CRCs. In the present study, the authors conducted genome-wide analyses of >200 CRC samples. They found that 84% of the CRCs had a low mutation rate (mutation rates of <8.24/106 bases, defined as non-hypermutated), whereas the remaining 16% of CRCs had a high mutation rate (mutation rates of >12/106 bases, defined as hypermutated). Accordingly, the mutation frequency of well-known tumor-related genes, APC, KRAS, BRAF, TP53 was 81%, 43%, 3%, and 59% in non-hypermutated CRCs and 53%, 30%, 47%, and 17%
SELECTED SUMMARIES 687
in hypermutated CRCs, respectively. Around the same time, Seshagiri et al applied deep-sequencing to >70 pairs of primary CRCs and characterized their exomes, transcriptomes, and copy number alterations (Nature 2012;488:660–664). They observed that the mean nonsynonymous mutation frequency in MSI and microsatellitestable (mainly corresponding with non-hypermutated type in the current paper) tumors was 47 and 2.8 mutations per 106 bases, respectively. Consistent with the results shown in the current paper, the several well-known CRC-related tumor-related genes, such as APC, KRAS, TP53, and SMAD4, were frequently mutated in CRC samples, but they also reported several new genes recurrently mutated in CRCs (eg, the chromatin-remodeling genes TET1, TET2, and TET3, and receptor tyrosine kinase ERBB3). Because the tissue samples used in these studies were collected randomly from newly diagnosed patients with CRCs undergoing operative resection, we cannot fully evaluate the clinical background of these patients with CRCs. The mutational profiles, however, suggested that the hypermutated and non-hypermutated tumors determined in these studies basically correspond with the CIN and MSI phenotypes, respectively. Comprehensive integrative analysis using recently advanced technology has provided detailed information about the deregulated pathways in human CRCs. The present study demonstrated that >90% of CRCs had a deregulated WNT signaling pathway caused by biallelic inactivation of APC, activating mutations of CTNNB1, or mutations in SOX9, TCF7L2, DKK family members, AXIN2, FBXW7, FAM123B, and ARID1A (AT-rich interactive domain-containing protein 1A). Seshagiri et al revealed a critical role of WNT dysregulation in CRC tumorigenesis by showing multiple transcripts including recurrent gene fusions involving R-spondin family members RSPO2 and RSPO3 (Nature 2012;488:660–664). They showed that RSPO fusions were mutually exclusive with APC mutations, indicating that RSPO fusion expression was capable of leading to activation of the WNT pathway. Both studies also identified ARID1A as one of the most frequently mutated genes in CRC. ARID1A is a member of the SWI/SNF family and is also involved in the regulation of WNT signaling. Recently, mutations in ARID1A were reported in a variety of human cancers, such as 83% of MSI gastric cancer, 73% of Epstein-Barr virus–associated gastric cancers, and 11% of microsatellite-stable gastric cancers showed ARID1A inactivation or protein loss alteration (Nat Genet 2011;43:1219–1223). In breast cancer, Mamo et al identified ARID1A as a candidate tumor suppressor gene, and showed that ARID1A is intimately related to prognosis (Oncogene 2012;31:2090–2100). The finding that ARID1A mutation rates were higher in hypermutated CRC than in non-hypermutated CRC (37% vs 5%, respectively) was consistent with the mutational profile observed in gastric cancers showing the ARID1A mutation is frequently detectable in MSI tumors. Because ARID1A is also involved in chromatin remodeling and thus dysfunction of ARID1A has the potential to cause
688
SELECTED SUMMARIES
epigenetic instability (Nat Rev Cancer 2011;11:481–492), these findings may suggest a close correlation between genetic and epigenetic aberrations in human gastrointestinal cancers. MYC is a transcription factor that regulates a number of genes essential for the regulation of proliferation, transcription, apoptosis and DNA replication, and is one of the most frequently dysregulated proto-oncogenes in human cancers (Cell 2012;149:22–35). MYC was recently spotlighted from a different aspect by its identification as one of the four key pluripotency genes essential for the production of induced pluripotent stem cells, so-called iPS cells (Cell 2006;126:663–676). The MYC proto-oncogene itself is under tight transcriptional control by various host transcription factors including CNBP, FBP, and TCF, downstream of the WNT pathway (Genes Cancer 2010;1:547–554). The study by Wilkins and Sansom showed that a murine model with a deletion of both Apc and c-Myc evaded all the phenotypes of APC deficiency (Cancer Research 2008;68:4963–4966). Their data indicated that MYC is essential for the APC-deficient phenotype in intestine, and APC-deficient cells are “addicted” to MYC in the intestine. In the present study, the authors performed an integrated analysis and found that nearly 100% of CRCs had changes in MYC transcriptional targets, both those promoted by and those inhibited by MYC. The finding that enhanced MYC activity is a nearly ubiquitous event in CRC might provide novel therapeutic opportunities by targeting MYC itself or its target genes for future treatment of CRCs. The introduction of new therapeutic strategies, including cytotoxic chemotherapeutic and biologic agents, has led to great advances in the treatment of human CRCs. An understanding of the genetic characteristics of individual tumors is critical for designing future therapeutic approaches. For example, anti-epidermal growth factor receptor (EGFR) antibody (cetuximab, panitumumab) and anti-vascular endothelial growth factor antibody (bevacizumab) are the current key drugs in CRC chemotherapy, and many studies of the biomarkers to predict the performance of these drugs showed that there is a significant correlation between the efficacy of antiEGFR antibody drug and the KRAS mutation status of tumors. Namely, wild-type KRAS tumors show higher response rates compared with those with the KRAS mutation-type (N Engl J Med 2009;360:1408–1417). In addition, tumors with BRAF (V600E) mutation status show a poor response to anti-EGFR drugs, even if the tumor has the KRAS wild-type status (J Clin Oncol 2009;27:5924–5930). On the other hand, sorafenib, a clinically approved multikinase inhibitor targeting several
GASTROENTEROLOGY Vol. 145, No. 3
receptor tyrosine kinases including BRAF, can potentially restore the sensitivity of BRAF-mutated CRC to antiEGFR antibody therapy (J Clin Oncol 2008;26: 5705–5712). In parallel with trials using the existing drugs, researchers have made great efforts to determine new potential therapeutic targets. In this regard, information about the mutated genes identified in the current study, such as SOX9, ARID1A, CTNNB1, IGF2, and ERBB family, has putative implications for new therapeutic targets. Trastuzumab, an anti-ERBB2 monoclonal antibody, has been used clinically in chemotherapy for breast or gastric cancer (Nature 2011;9:16–32; Cancer Treat Rev 2013;39:60–67). CRC with overexpression of ERBB2 might respond to anti-ERBB2 therapy. The PI3K signaling pathway, including IGF2, IRS2, and PIK3CA is a candidate pathway for molecular targeted therapy, and studies of breast cancer indicate that PIK3CA plays an important role in acquiring resistance to anti-ERBB2 therapy (Ann Oncol 2010;21:255–262; Cancer Cell 2004;6:117–127). Investigation of the influence of PIK3CA mutations on sensitivity to ERBB2-targeted agents will contribute to a better understanding of the mechanism of drug resistance. What must be noted is that the mutation frequencies of the majority of the genes newly identified in the current study were significantly lower than those of the wellknown CRC-related genes. Indeed, the mutation rates of the SOX9, ARID1A, CTNNB1, and ERBB family genes in non-hypermutated CRCs are <10%, whereas >80% of those have mutations in APC, and about half have mutations in TP53 and KRAS. Thus, the efficacy of molecular targeted agents would vary according to the overall picture of the genetic alterations in the tumor tissue, especially when the mutation frequency of the candidate target gene sets is in low level. Integrated analysis based on the genetic and epigenetic information of each tumor tissue will be an essential for the development of personalized treatment for cancer patients. The success of gene-targeting therapy for treating cancer depends on the development of appropriate diagnostic surveys that can identify the characteristics of individual genetic alteration profiles. The era of treating CRC patients with a uniform treatment is over, and we must share the vision of personalized medicine to create better outcomes and to overcome cancer. TOMOYUKI GOTO HIROYUKI MARUSAWA TSUTOMU CHIBA Department of Gastroenterology and Hepatology Graduate School of Medicine Kyoto University Kyoto, Japan