EDITORIALS Hepatocellular Carcinoma: Optimal Staging Impacts Survival See “Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival,” by Kim H-D, Lim Y-S, Han S, et al, on page 1371.
O
ne of the major goals of radiologic imaging is the precise detection of cancer, in the hope that sensitive early diagnosis and accurate staging will facilitate the optimal management of cancer patients and favorably impact morbidity and mortality. In this issue of Gastroenterology, which highlights an increasingly prevalent and often lethal tumor, hepatocellular carcinoma (HCC), Kim et al1 have studied 700 patients and present evidence that an imaging strategy including gadoxetic acid-enhanced MRI in conjunction with multiphasic CT-based imaging can improve cancer staging in patients with cirrhosis by detecting additional sites of neoplasm, enhance treatment and, most important, improve survival.1 Contrast-enhanced CT and MRI are the radiologic mainstays for the diagnosis of HCC. The use of intravenous contrast is essential, because the sensitivity of unenhanced imaging is limited, especially for CT scanning. CT contrast agents are based on the radiodense element iodine, whereas those for MRI are based on the paramagnetic element gadolinium. With similar pharmacokinetic behavior, the agents are injected intravenously and pass into the capillary beds of viscera where, except in the central nervous system, the capillary endothelium is permeable to the contrast. After administration, the radiodensity of organ parenchyma on CT, or signal intensity on T1-weighted MRI, increases owing to the presence of contrast in the vessels and its accumulation in extracellular fluid.2 The timing and magnitude of the increase is determined by the physiology relating to local tissue characteristics and capillary perfusion. Radiologic diagnosis of HCC is facilitated by the dual blood supply to the liver and its biphasic perfusion, because blood containing intravenous contrast is received first via the hepatic artery and second via the portal vein. The nontumor liver parenchyma receives most of its blood supply from the portal vein, whereas neoplasms, including HCC, typically receive a greater proportion of flow from the hepatic artery as a result of tumor induced arterial neovascularity3 (although the difference may be reduced in cirrhosis). The lesions tend to enhance relative to normal liver during the so-called arterial phase after contrast administration, visualized as enhanced, hyperdense lesions on images typically acquired 20–40 seconds after the initiation of a contrast bolus. Over the next 30–60 seconds, this density (for CT) or signal pattern (for MRI) reverses, as the portal vein supplies increased contrast to the non-neoplastic liver; the HCC lesions typically become less dense than the surrounding 1274
tissues, a phenomenon termed “washout.” This characteristic enhancement pattern of most HCCs is well-recognized and in fact is one of the main criteria used to diagnose HCC on enhanced CT and MRI.4 Despite these classic features, the diagnosis of small liver lesions can be difficult. The cirrhotic liver is often heterogeneous, particularly after the administration of intravenous contrast, and it is possible to miss small neoplastic lesions owing to a lack of sensitivity. Compounding this, both normal and cirrhotic livers often have small, non-neoplastic areas of arterial phase hypervascularity that can mimic neoplasms. Such pseudolesions are often attributed to vascular shunting and may present false positive findings on either CT or MRI.5,6 Kim et al have explored a relatively new, nontypical MRI contrast agent, gadoxetic acid, or gadolinium ethoxybenzyl diethylenetriaminepentaacetic (Eovist, Bayer, Whippany, NJ; Primovist, Bayer, Osaka, Japan). Gadoxetic acid has the usual properties of an extracellular gadolinium chelate, which allows assessment of tumor vascularity in an arterial phase. In addition, however, it is hepatocyte targeting, enabling a hepatic “functional phase” assessment approximately 20 minutes after administration. Approximately 50% of an administered dose of gadoxetic acid will be taken up by hepatocytes, possibly less in cirrhotic liver, before excretion in the bile. Crucially, most HCCs will not take up gadoxetic acid, reportedly because they do not express the hepatocyte sinusoidal transporter required for uptake,7 and therefore appear as lesions with reduced signal compared with the surrounding liver. This property of gadoxetic acid may increase both the sensitivity and the specificity of the agent, especially for small lesions.8 A weakness, and reason it should not be used as an isolated staging tool, is poorer enhancement and less apparent washout in the arterial and venous phases as a consequence of the typical gadoxetic acid bolus containing only 25%-50% of the molar quantity of gadolinium relative to traditional agents. This can also detrimentally affect the ability to assess the hepatic vessels and detection of thrombus, for example. Over the last 10–15 years, cumulative studies have demonstrated improvements in the sensitivity and specificity of standard cross-sectional imaging. Earlier comparisons, from 2000 to 2002, of staging at preoperative imaging to pathologic stage assessed at liver explants reported sensitivities of 50%-60% (slightly better for MRI),9–11 with a specificity of >80%.9 In a metaanalysis published in 2006, the pooled sensitivities and specificities were 68% and 93%, respectively, for CT and 81% and 85% for MRI.12 In a very recent review, further advances have been reported, with per-lesion sensitivity for MRI of 79% (72% for CT) and per-patient sensitivity of MRI of 88%; the per-patient specificity of MRI was 94%. MRI generally outperformed CT.13 Not surprisingly, accuracy with both modalities for diagnosis of small HCC 2 and 169 with Child Pugh class C cirrhosis who were presumably deemed unsuitable for curative or palliative treatment. Other exclusions were based on age, atypical diagnostic imaging, or a nonstandard CT imaging protocol. These are reasonable exclusions, but included in combination >400 patients. Of the 700 patients included in the study, all had a quadruple phase CT scan. In 377, this was the only scan (group 1) whereas 323 had imaging with gadoxetic acid in addition to CT (group 2). The allocation to receive gadoxetic MRI was not a random event, but attributed to the preference of the practicing clinician. This too may have introduced selection bias. The other factor quite difficult to compare in a retrospective study is the impact of differences in the treatments between the 2 groups. Although treatment was delivered according to best practice in a busy center treating large numbers of patients with HCC, it was not protocol driven and many patients received >1 treatment. Having said all that, there is little doubt that additional nodules presumed to be HCC—74 in 53 patients from group 2, to be exact—were detected, and although the proportions of patients in groups 1 and 2 receiving potentially curative treatments (transplantation, resection, ablation) were not different, detection of additional nodules impacted Barcelona Clinic Liver Cancer (BCLC) stage in 42 cases and altered management decisions. Specific targeting of additional nodules included 27 additional transarterial chemoembolization and 9 radiofrequency ablation procedures, as well as 14 additional resections and 3 patients who underwent liver transplantation. The authors also point out that, in some instances, accurate staging led to avoidance of futile resection. Kim et al have gone to some lengths to ensure their data are as robust as possible, acknowledging the limitations of a retrospective study, including inverse probability treatment weighting and propensity score matching in their statistical analyses. A final point to acknowledge is that, although there is literature evidence supporting the possible benefit of gadoxetic acid in detecting small HCCs over traditional MRI with conventional gadolinium contrast agents, different MRI techniques and other contrast agents have not been rigorously compared by Kim et al during the same study
period. Thus, for example, it is possible that CT in combination with MRI with a traditional contrast agent for staging would have similar benefit. In conclusion, despite the limitations of a retrospective study, it seems that knowing about additional nodules at the outset, in a subgroup of patients with preserved liver function and preserved functional status, led to additional treatments for some patients while avoiding futile resections in others, thereby positively impacting the overall survival of patients with HCC. This study substantiates the importance of accurate staging at diagnosis. It may be pertinent also to raise the parallel matter of tumor grade. Routine biopsy of HCC for a formal assessment of histological grade from biopsy at diagnosis is a contentious issue.15,16 Perhaps, however, knowledge of this too would steer toward aggressive alternative treatment before surgery, or ultimately inform the avoidance of surgery, with improved overall survival despite the small risks of liver biopsy. In the absence of prospective, randomized, controlled studies providing guidance for selecting the best combination of imaging tools for assessing stage, or the role of tumor grade in clinical decision making for HCC, it is likely that debate on these key matters will continue, stimulated in this instance by Kim et al. HELEN L. REEVES Northern Institute for Cancer Research Newcastle University and Newcastle-upon-Tyne Hospitals NHS Foundation Trust Newcastle-upon-Tyne, United Kingdom ALEX M. AISEN Indiana University School of Medicine and Indiana University Health Indianapolis, Indiana
References 1. Kim HD, Lim YS, Han S, et al. Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival. Gastroenterology 2015; 148:1371–1382. 2. Bae KT. Optimization of contrast enhancement in thoracic MDCT. Radiol Clin North Am 2010;48:9–29. 3. Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR Am J Roentgenol 1994; 163:323–331. 4. Wald C, Russo MW, Heimbach JK, et al. New OPTN/ UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. Radiology 2013; 266:376–382. 5. Hwang SH, Yu JS, Kim KW, et al. Small hypervascular enhancing lesions on arterial phase images of multiphase dynamic computed tomography in cirrhotic liver: fate and implications. J Comput Assist Tomogr 2008;32:39–45. 6. Holland AE, Hecht EM, Hahn WY, et al. Importance of small (< or ¼ 20-mm) enhancing lesions seen only during the hepatic arterial phase at MR imaging of the cirrhotic 1275
EDITORIALS liver: evaluation and comparison with whole explanted liver. Radiology 2005;237:938–944. Tsuboyama T, Onishi H, Kim T, et al. Hepatocellular carcinoma: hepatocyte-selective enhancement at gadoxetic acid-enhanced MR imaging–correlation with expression of sinusoidal and canalicular transporters and bile accumulation. Radiology 2010;255:824–833. Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011; 261:834–844. Krinsky GA, Lee VS, Theise ND, et al. Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explantation correlation. Radiology 2001;219:445–454. Peterson MS, Baron RL, Marsh JW Jr, et al. Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 2000;217:743–749. de Ledinghen V, Laharie D, Lecesne R, et al. Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients. Eur J Gastroenterol Hepatol 2002; 14:159–165. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006; 101:513–523. Lee YJ, Lee JM, Lee JS, et al. Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging-a systematic review and meta-analysis. Radiology 2015:140690. Wu LM, Xu JR, Gu HY, et al. Is liver-specific gadoxetic acid-enhanced magnetic resonance imaging a reliable tool for detection of hepatocellular carcinoma in patients with chronic liver disease? Dig Dis Sci 2013;58:3313–3325. Sherman M, Bruix J. Biopsy for liver cancer: How to balance research needs with evidence-based clinical practice. Hepatology 2015;61:433–437. Torbenson M, Schirmacher P. Liver cancer biopsy - back to the future?! Hepatology 2015;61:431–433.
Reprint requests Address requests for reprints to: Helen L. Reeves, Paul O. Gorman Building, Northern Institute for Cancer Research, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.026
Polymerase Slippage Restoration of Frameshifted TGFBR2 in Colorectal Cancer: A Novel Paradigm See “Transforming growth factor b signaling in colorectal cancer cells with microsatellite instability despite biallelic mutations in TGFBR2,” by de Miranda NFCC, van Dinther M, van den Akker BEWM, et al, on page 1427.
T
he transforming growth factor (TGF)-b signaling pathway consists of a family of secreted TGF-b–like proteins (the TGF-b isoforms [TGF-b1, TGF-b2, and TGF-b3], activins, and others), the TGF-b receptors, and a variety of post-receptor signaling proteins. It was discovered >30 years ago and has been since shown to have a role in a variety of diseases, including colorectal cancer (CRC).1 These 3 decades of study have led to an in-depth understanding of TGF-b signaling deregulation in CRC. However, despite our detailed understanding of TGF-b signaling in CRC, in this issue of Gastroenterology, de Miranda et al show us that there remains much to learn.2 To appreciate the significance of the findings by de Miranda, it is important to understand some key aspects of TGF-b signaling. TGF-b mediates its effects on cells through a heteromeric TGF-b receptor complex that consists of type I (TGFBR1) and type II (TGFBR2) components. TGFBR1 and TGFBR2 are cell membrane–associated, single-pass transmembrane serine-threonine kinases that phosphorylate 1276
downstream signaling proteins upon activation and are the only known receptor complex for TGF-b.3 After becoming activated by TGF-b, TGFBR2 phosphorylates TGFBR1 in the GS box region, which activates TGFBR1. TGFBR1 then propagates the signal from the receptor to the nucleus through the phosphorylation of downstream proteins, including the SMAD proteins (SMAD2 and SMAD3) and non-SMAD proteins (including PI3K, p38MAPK, PKA, and RhoA).4–7 In epithelial cells, including those in the intestine, TGF-b can inhibit cell proliferation; induce apoptosis, senescence, and terminal differentiation; and maintain genomic stability, which has led to the conclusion that this pathway has tumor suppressor activities in cancers, including CRC. Indeed, a large body of evidence from in vitro, in vivo, and human studies has established that the TGF-b signaling pathway has a prominent role as a tumor suppressor pathway in CRC. Members of the TGF-b pathway, including TGFBR1, TGFBR2, SMAD2, SMAD4, and others, are commonly mutated or silenced in CRC, making this pathway the most commonly altered pathway in CRC.8 Overall, 20%-30% of CRCs have TGFBR2 mutations, and in microsatellite unstable (MSI) CRCs, approximately 90% of tumors have inactivating mutations in TGFBR2, which occur in a 10-bp polyadenine tract in exon 3, called BAT-R2.9–11 However, despite the substantial amount of data demonstrating the tumor suppressor effects of TGF-b, the story of TGF-b signaling in CRC seems to be more complex than this pathway simply being a CRC tumor suppressor
O
ne of the major goals of radiologic imaging is the precise detection of cancer, in the hope that sensitive early diagnosis and accurate staging will facilitate the optimal management of cancer patients and favorably impact morbidity and mortality. In this issue of Gastroenterology, which highlights an increasingly prevalent and often lethal tumor, hepatocellular carcinoma (HCC), Kim et al1 have studied 700 patients and present evidence that an imaging strategy including gadoxetic acid-enhanced MRI in conjunction with multiphasic CT-based imaging can improve cancer staging in patients with cirrhosis by detecting additional sites of neoplasm, enhance treatment and, most important, improve survival.1 Contrast-enhanced CT and MRI are the radiologic mainstays for the diagnosis of HCC. The use of intravenous contrast is essential, because the sensitivity of unenhanced imaging is limited, especially for CT scanning. CT contrast agents are based on the radiodense element iodine, whereas those for MRI are based on the paramagnetic element gadolinium. With similar pharmacokinetic behavior, the agents are injected intravenously and pass into the capillary beds of viscera where, except in the central nervous system, the capillary endothelium is permeable to the contrast. After administration, the radiodensity of organ parenchyma on CT, or signal intensity on T1-weighted MRI, increases owing to the presence of contrast in the vessels and its accumulation in extracellular fluid.2 The timing and magnitude of the increase is determined by the physiology relating to local tissue characteristics and capillary perfusion. Radiologic diagnosis of HCC is facilitated by the dual blood supply to the liver and its biphasic perfusion, because blood containing intravenous contrast is received first via the hepatic artery and second via the portal vein. The nontumor liver parenchyma receives most of its blood supply from the portal vein, whereas neoplasms, including HCC, typically receive a greater proportion of flow from the hepatic artery as a result of tumor induced arterial neovascularity3 (although the difference may be reduced in cirrhosis). The lesions tend to enhance relative to normal liver during the so-called arterial phase after contrast administration, visualized as enhanced, hyperdense lesions on images typically acquired 20–40 seconds after the initiation of a contrast bolus. Over the next 30–60 seconds, this density (for CT) or signal pattern (for MRI) reverses, as the portal vein supplies increased contrast to the non-neoplastic liver; the HCC lesions typically become less dense than the surrounding 1274
tissues, a phenomenon termed “washout.” This characteristic enhancement pattern of most HCCs is well-recognized and in fact is one of the main criteria used to diagnose HCC on enhanced CT and MRI.4 Despite these classic features, the diagnosis of small liver lesions can be difficult. The cirrhotic liver is often heterogeneous, particularly after the administration of intravenous contrast, and it is possible to miss small neoplastic lesions owing to a lack of sensitivity. Compounding this, both normal and cirrhotic livers often have small, non-neoplastic areas of arterial phase hypervascularity that can mimic neoplasms. Such pseudolesions are often attributed to vascular shunting and may present false positive findings on either CT or MRI.5,6 Kim et al have explored a relatively new, nontypical MRI contrast agent, gadoxetic acid, or gadolinium ethoxybenzyl diethylenetriaminepentaacetic (Eovist, Bayer, Whippany, NJ; Primovist, Bayer, Osaka, Japan). Gadoxetic acid has the usual properties of an extracellular gadolinium chelate, which allows assessment of tumor vascularity in an arterial phase. In addition, however, it is hepatocyte targeting, enabling a hepatic “functional phase” assessment approximately 20 minutes after administration. Approximately 50% of an administered dose of gadoxetic acid will be taken up by hepatocytes, possibly less in cirrhotic liver, before excretion in the bile. Crucially, most HCCs will not take up gadoxetic acid, reportedly because they do not express the hepatocyte sinusoidal transporter required for uptake,7 and therefore appear as lesions with reduced signal compared with the surrounding liver. This property of gadoxetic acid may increase both the sensitivity and the specificity of the agent, especially for small lesions.8 A weakness, and reason it should not be used as an isolated staging tool, is poorer enhancement and less apparent washout in the arterial and venous phases as a consequence of the typical gadoxetic acid bolus containing only 25%-50% of the molar quantity of gadolinium relative to traditional agents. This can also detrimentally affect the ability to assess the hepatic vessels and detection of thrombus, for example. Over the last 10–15 years, cumulative studies have demonstrated improvements in the sensitivity and specificity of standard cross-sectional imaging. Earlier comparisons, from 2000 to 2002, of staging at preoperative imaging to pathologic stage assessed at liver explants reported sensitivities of 50%-60% (slightly better for MRI),9–11 with a specificity of >80%.9 In a metaanalysis published in 2006, the pooled sensitivities and specificities were 68% and 93%, respectively, for CT and 81% and 85% for MRI.12 In a very recent review, further advances have been reported, with per-lesion sensitivity for MRI of 79% (72% for CT) and per-patient sensitivity of MRI of 88%; the per-patient specificity of MRI was 94%. MRI generally outperformed CT.13 Not surprisingly, accuracy with both modalities for diagnosis of small HCC 2 and 169 with Child Pugh class C cirrhosis who were presumably deemed unsuitable for curative or palliative treatment. Other exclusions were based on age, atypical diagnostic imaging, or a nonstandard CT imaging protocol. These are reasonable exclusions, but included in combination >400 patients. Of the 700 patients included in the study, all had a quadruple phase CT scan. In 377, this was the only scan (group 1) whereas 323 had imaging with gadoxetic acid in addition to CT (group 2). The allocation to receive gadoxetic MRI was not a random event, but attributed to the preference of the practicing clinician. This too may have introduced selection bias. The other factor quite difficult to compare in a retrospective study is the impact of differences in the treatments between the 2 groups. Although treatment was delivered according to best practice in a busy center treating large numbers of patients with HCC, it was not protocol driven and many patients received >1 treatment. Having said all that, there is little doubt that additional nodules presumed to be HCC—74 in 53 patients from group 2, to be exact—were detected, and although the proportions of patients in groups 1 and 2 receiving potentially curative treatments (transplantation, resection, ablation) were not different, detection of additional nodules impacted Barcelona Clinic Liver Cancer (BCLC) stage in 42 cases and altered management decisions. Specific targeting of additional nodules included 27 additional transarterial chemoembolization and 9 radiofrequency ablation procedures, as well as 14 additional resections and 3 patients who underwent liver transplantation. The authors also point out that, in some instances, accurate staging led to avoidance of futile resection. Kim et al have gone to some lengths to ensure their data are as robust as possible, acknowledging the limitations of a retrospective study, including inverse probability treatment weighting and propensity score matching in their statistical analyses. A final point to acknowledge is that, although there is literature evidence supporting the possible benefit of gadoxetic acid in detecting small HCCs over traditional MRI with conventional gadolinium contrast agents, different MRI techniques and other contrast agents have not been rigorously compared by Kim et al during the same study
period. Thus, for example, it is possible that CT in combination with MRI with a traditional contrast agent for staging would have similar benefit. In conclusion, despite the limitations of a retrospective study, it seems that knowing about additional nodules at the outset, in a subgroup of patients with preserved liver function and preserved functional status, led to additional treatments for some patients while avoiding futile resections in others, thereby positively impacting the overall survival of patients with HCC. This study substantiates the importance of accurate staging at diagnosis. It may be pertinent also to raise the parallel matter of tumor grade. Routine biopsy of HCC for a formal assessment of histological grade from biopsy at diagnosis is a contentious issue.15,16 Perhaps, however, knowledge of this too would steer toward aggressive alternative treatment before surgery, or ultimately inform the avoidance of surgery, with improved overall survival despite the small risks of liver biopsy. In the absence of prospective, randomized, controlled studies providing guidance for selecting the best combination of imaging tools for assessing stage, or the role of tumor grade in clinical decision making for HCC, it is likely that debate on these key matters will continue, stimulated in this instance by Kim et al. HELEN L. REEVES Northern Institute for Cancer Research Newcastle University and Newcastle-upon-Tyne Hospitals NHS Foundation Trust Newcastle-upon-Tyne, United Kingdom ALEX M. AISEN Indiana University School of Medicine and Indiana University Health Indianapolis, Indiana
References 1. Kim HD, Lim YS, Han S, et al. Evaluation of early-stage hepatocellular carcinoma by magnetic resonance imaging with gadoxetic acid detects additional lesions and increases overall survival. Gastroenterology 2015; 148:1371–1382. 2. Bae KT. Optimization of contrast enhancement in thoracic MDCT. Radiol Clin North Am 2010;48:9–29. 3. Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR Am J Roentgenol 1994; 163:323–331. 4. Wald C, Russo MW, Heimbach JK, et al. New OPTN/ UNOS policy for liver transplant allocation: standardization of liver imaging, diagnosis, classification, and reporting of hepatocellular carcinoma. Radiology 2013; 266:376–382. 5. Hwang SH, Yu JS, Kim KW, et al. Small hypervascular enhancing lesions on arterial phase images of multiphase dynamic computed tomography in cirrhotic liver: fate and implications. J Comput Assist Tomogr 2008;32:39–45. 6. Holland AE, Hecht EM, Hahn WY, et al. Importance of small (< or ¼ 20-mm) enhancing lesions seen only during the hepatic arterial phase at MR imaging of the cirrhotic 1275
EDITORIALS liver: evaluation and comparison with whole explanted liver. Radiology 2005;237:938–944. Tsuboyama T, Onishi H, Kim T, et al. Hepatocellular carcinoma: hepatocyte-selective enhancement at gadoxetic acid-enhanced MR imaging–correlation with expression of sinusoidal and canalicular transporters and bile accumulation. Radiology 2010;255:824–833. Sano K, Ichikawa T, Motosugi U, et al. Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging. Radiology 2011; 261:834–844. Krinsky GA, Lee VS, Theise ND, et al. Hepatocellular carcinoma and dysplastic nodules in patients with cirrhosis: prospective diagnosis with MR imaging and explantation correlation. Radiology 2001;219:445–454. Peterson MS, Baron RL, Marsh JW Jr, et al. Pretransplantation surveillance for possible hepatocellular carcinoma in patients with cirrhosis: epidemiology and CT-based tumor detection rate in 430 cases with surgical pathologic correlation. Radiology 2000;217:743–749. de Ledinghen V, Laharie D, Lecesne R, et al. Detection of nodules in liver cirrhosis: spiral computed tomography or magnetic resonance imaging? A prospective study of 88 nodules in 34 patients. Eur J Gastroenterol Hepatol 2002; 14:159–165. Colli A, Fraquelli M, Casazza G, et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematic review. Am J Gastroenterol 2006; 101:513–523. Lee YJ, Lee JM, Lee JS, et al. Hepatocellular carcinoma: diagnostic performance of multidetector CT and MR imaging-a systematic review and meta-analysis. Radiology 2015:140690. Wu LM, Xu JR, Gu HY, et al. Is liver-specific gadoxetic acid-enhanced magnetic resonance imaging a reliable tool for detection of hepatocellular carcinoma in patients with chronic liver disease? Dig Dis Sci 2013;58:3313–3325. Sherman M, Bruix J. Biopsy for liver cancer: How to balance research needs with evidence-based clinical practice. Hepatology 2015;61:433–437. Torbenson M, Schirmacher P. Liver cancer biopsy - back to the future?! Hepatology 2015;61:431–433.
Reprint requests Address requests for reprints to: Helen L. Reeves, Paul O. Gorman Building, Northern Institute for Cancer Research, The Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. e-mail: [email protected]. Conflicts of interest The authors disclose no conflicts. © 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.04.026
Polymerase Slippage Restoration of Frameshifted TGFBR2 in Colorectal Cancer: A Novel Paradigm See “Transforming growth factor b signaling in colorectal cancer cells with microsatellite instability despite biallelic mutations in TGFBR2,” by de Miranda NFCC, van Dinther M, van den Akker BEWM, et al, on page 1427.
T
he transforming growth factor (TGF)-b signaling pathway consists of a family of secreted TGF-b–like proteins (the TGF-b isoforms [TGF-b1, TGF-b2, and TGF-b3], activins, and others), the TGF-b receptors, and a variety of post-receptor signaling proteins. It was discovered >30 years ago and has been since shown to have a role in a variety of diseases, including colorectal cancer (CRC).1 These 3 decades of study have led to an in-depth understanding of TGF-b signaling deregulation in CRC. However, despite our detailed understanding of TGF-b signaling in CRC, in this issue of Gastroenterology, de Miranda et al show us that there remains much to learn.2 To appreciate the significance of the findings by de Miranda, it is important to understand some key aspects of TGF-b signaling. TGF-b mediates its effects on cells through a heteromeric TGF-b receptor complex that consists of type I (TGFBR1) and type II (TGFBR2) components. TGFBR1 and TGFBR2 are cell membrane–associated, single-pass transmembrane serine-threonine kinases that phosphorylate 1276
downstream signaling proteins upon activation and are the only known receptor complex for TGF-b.3 After becoming activated by TGF-b, TGFBR2 phosphorylates TGFBR1 in the GS box region, which activates TGFBR1. TGFBR1 then propagates the signal from the receptor to the nucleus through the phosphorylation of downstream proteins, including the SMAD proteins (SMAD2 and SMAD3) and non-SMAD proteins (including PI3K, p38MAPK, PKA, and RhoA).4–7 In epithelial cells, including those in the intestine, TGF-b can inhibit cell proliferation; induce apoptosis, senescence, and terminal differentiation; and maintain genomic stability, which has led to the conclusion that this pathway has tumor suppressor activities in cancers, including CRC. Indeed, a large body of evidence from in vitro, in vivo, and human studies has established that the TGF-b signaling pathway has a prominent role as a tumor suppressor pathway in CRC. Members of the TGF-b pathway, including TGFBR1, TGFBR2, SMAD2, SMAD4, and others, are commonly mutated or silenced in CRC, making this pathway the most commonly altered pathway in CRC.8 Overall, 20%-30% of CRCs have TGFBR2 mutations, and in microsatellite unstable (MSI) CRCs, approximately 90% of tumors have inactivating mutations in TGFBR2, which occur in a 10-bp polyadenine tract in exon 3, called BAT-R2.9–11 However, despite the substantial amount of data demonstrating the tumor suppressor effects of TGF-b, the story of TGF-b signaling in CRC seems to be more complex than this pathway simply being a CRC tumor suppressor
