- Email: [email protected]
Next Generation Multigene Panel Testing: The Next Step for Identification of Hereditary Colorectal Cancer Syndromes?
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Next Generation Multigene Panel Testing: The Next step for identification of Hereditary Colorectal Cancer Syndromes?
Q2
See “Identification of a variety of mutations in cancer predisposition genes in patients with suspected syndrome,” by Yurgelun MB, Allen B, Kaldate RR, et al, on page 000.
T
his issue of Gastroenterology presents a manuscript by Yurgelun et al1 that addresses the question of whether multigene panel testing offers “meaningful advantages over targeted criteria-based genetic testing” in patients meeting criteria for the most commonly recognized hereditary colorectal cancer (CRC) condition, Lynch syndrome (LS).1 LS accounts for 2%–4% of all CRC and is caused by germline mutations in mismatch repair genes.2,3 Identifying these high-risk patients is a major issue, because morbidity and mortality from CRC and extracolonic cancers in patients and their relatives can be decreased by early and intensive screening. Although early detection of LS is important, a considerable proportion of patients remain unrecognized. The traditional approach for hereditary cancer risk assessment is based on phenotype-driven genetic testing, in which individuals who meet clinical criteria, undergo targeted genetic testing for the most likely genetic causes.4 Initial strategies to identify individuals with LS included fulfillment of the Amsterdam criteria (Table 1), which have been shown to have limited sensitivity for the identification of mutation carriers.5 The Bethesda guidelines (Table 1) were developed to identify individuals who deserve further evaluation with microsatellite instability and/or immunohistochemistry tumor testing for deficient mismatch repair. However, studies have shown that nearly 10% of mutation carriers will not be identified for testing based solely on the Bethesda guidelines.6 Studies have shown that 28% of patients with LS would be missed using only clinical criteria.7 Consequently, in an effort to decrease morbidity and mortality of relatives of patients with LS, some institutions are adopting Universal testing, which has been endorsed by the National Comprehensive Cancer Network (NCCN). Labadaum et al8 evaluated this universal strategy and determined that implementing testing in patients 70 years with newly diagnosed CRC is cost effective. The benefit to cost ratio depended on the number of a proband’s relatives who would benefit from cancer risk reduction strategies.8 Multigene panel testing has emerged as a tool for hereditary cancer risk assessment, which allows simultaneous analysis of multiple susceptibility genes. Yurgelun et al1 aimed to determine the frequency of non-LS gene mutations detected by a multigene panel among individuals undergoing clinical genetic testing for LS. A high-impact point
this manuscript addresses is that limiting germline testing to LS genes could lead to missing other mutations in high penetrance cancer susceptibility genes. This cohort included individuals who fulfilled NCCN criteria for LS and had a Prediction of Mutations in MLH1 AND MLH2 (PREMM) score of 5%, but whose tumors had not been tested for LS. Multigene panel testing identified unsuspected mutations in non-LS susceptibility genes in this cohort. In total, 14.4% of subjects were found to carry 1 pathogenic mutation. Of the pathogenic mutations identified by the multigene panel, 75% were in high penetrance genes with the majority arising in LS genes. However, non-LS mutations were detected in 5.6% of individuals undergoing LS testing. The most common unexpected findings were BRCA1/2, APC, and biallelic MUTYH mutations. The finding of BRCA1/2 mutations in 15 probands (8% of all mutation carriers) being evaluated for LS, none of whom had breast cancer, demonstrates the importance of genetic testing with a multigene panel to not overlook any actionable genetic findings because the clinical phenotype does not meet a particular guideline. Therefore, the phenotypic spectrum of LS can overlap with other hereditary cancer syndromes. Management of patients with unexpected high penetrance cancer susceptibility gene mutations is critically important and may need to take into account phenotype as well as genotype. With the emergence of more extensive genetic testing either in the form of multigene panels or ultimately with whole genome sequencing, we need to learn how to interpret these complex results effectively. The authors of this study highlight this treatment dilemma in the context of “deleterious” CDH1 mutations found by panel testing in members from a kindred that has never manifested gastric cancer. As more kindreds with CDH1 mutations are detected, our understanding of the actual risk for gastric cancer and the need for prophylactic gastrectomy in CDH1 mutation carriers may need to be revised. How aggressive we should be in the context of incidental findings still needs to be elucidated. Still, this study provides a glimpse into the complexity of genetic screening and the breadth and severity of phenotypes that a particular genetic mutation may produce. This will be key in tailoring cancer prevention strategies. However, this increased test sensitivity comes at the expense of detecting mutations in moderate penetrance genes and variants of uncertain significance (VUS) that may lead to unnecessary testing. Limited knowledge about the risk of cancer associated with VUS is an important barrier to providing appropriate care for individuals found to carry these genetic mutations.9 A study by Cragun et al10 that evaluated panel-based testing for inherited CRC, showed that VUS were found in 20% of the individuals tested, and nearly one-half (48%) occurred in one of the genes Gastroenterology 2015;-:1–3
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Table 1.Amsterdam Criteria and Revised Bethesda Guidelines Amsterdam Criteria Ia,b Three or more relatives with histologically verified CRC, 1 of which is the first-degree relative of the other 2. Two or more generations with CRC. One or more CRC cases diagnosed before the age of 50 years. Familial adenomatous polyposis should be excluded. Revised Bethesda Guidelinesc CRC diagnosed before the age of 50 years. Presence of synchronous or metachronous CRC or other LS-associated cancers. CRC with MSI-high pathologic associated features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) diagnosed before the age of 60 years. Patient with CRC and who has CRC or LS-associated cancer diagnosed in 1 first-degree relative <50 years old. Patient with CRC and who has CRC or LS-associated cancer at any age in 2 first- or second-degree relatives.
CRC, colorectal cancer; LS, Lynch syndrome; MSI, microsatellite instability. a For Amsterdam Criteria II, substitute CRC with any LS-associated cancer. LS-associated cancer includes endometrial, gastric, ovarian, pancreatic, ureter, renal pelvis, small bowel, brain, and hepatobiliary cancer. b For Amsterdam Criteria I and II, all criteria must be met for clinical diagnosis of LS. c If any of the Bethesda guidelines are met, then LS genetic testing should be considered.
associated with LS. An example of a VUS found in one of the genes associated with LS is the V509A alteration in MSH6. This alteration has been reported previously in the literature and disease-specific databases. However, a study evaluating the role of MSH6 mutation in individuals from LS and LS-like families determined that this alteration was also present in 1.8% of healthy controls.11 This indicates that this mutation is not pathogenic for LS, and therefore, the more intensive surveillance testing used for LS patients is not warranted. In their manuscript, Yurgelun et al1 showed that 1 VUS was identified in 38% of the cohort. The most common genes in which VUS were discovered were ATM, APC, NBN, and BRIP1. VUS should not be used to guide the management of a patient and should not be misinterpreted as deleterious mutations. A study by Plon et al12 explored the impact of genetic test results in clinical decision making. They showed that management decisions demonstrated the “uncertainty” associated with VUS.12 It is expected that with more widespread testing, the ability to categorize VUS will improve.10 The optimal management of carriers of moderatepenetrance mutations remains unclear, even for genes like CHEK2, for which there is extensive evidence.4 Although testing for CHEK2 has been available for years, management of patients with CHEK2 mutations is not well-established, and screening recommendations are based mainly on personal and family history.10 There is the concern that physicians may have limited information on which to base recommendations for patient care. This ultimately could lead to unnecessary testing or approaches, such as prophylactic surgery, which historically has been reserved for patients with actionable high penetrance mutations. These findings suggest that appropriately selected patients with a high likelihood of having deleterious mutations may be the ones to benefit the most from this strategy. Patients undergoing multigene panel testing should first be educated about the implications of these results for themselves and their families. The evaluation of hereditary cancer syndromes is evolving with the emergence of next-generation multigene
panel testing. Despite the benefits that these multigene panels have to offer, many have questioned the benefit of testing multiple genes with different modes of inheritance and penetrance that may lead to increased costs for surveillance and unnecessary treatment.13 Gallegos et al13 performed a cost-effectiveness analysis of a nextgeneration multigene panel testing in the diagnosis of patients evaluated for suspected hereditary CRC syndromes compared with the sequential evaluation for LS recommended by current guidelines.13 This study revealed that next-generation sequencing panels that include highly penetrant genes associated with hereditary CRC syndromes provide clinical benefits in a cost-effective manner.13 The estimated costs of multigene panel testing range between $3000 and $4000. For coverage, insurance companies take into consideration several criteria, including personal history of early-onset cancer and family history. Companies also have financial assistance programs to help patients with copay costs. Questions remain regarding the integration of a multigene panel into a screening strategy and identification of eligibility criteria to direct testing with a multigene panel. To ensure the adequate implementation of this strategy, it will be critical to first identify which clinical features would be necessary to warrant further testing with next generation multigene panels. Multigene panel testing may be useful when genetic heterogeneity confounds the clinician’s ability to predict which gene will be mutated based on the proband phenotype and family history.4 Our understanding of the clinical phenotypes that represent risk for a hereditary CRC syndrome may need to be iteratively extended as the results of multigene panel testing are applied in the clinical setting. Yurgelun et al1 provide us with early insights of the use of next generation sequencing in a high-risk cohort. As technology evolves, approaches for hereditary cancer risk assessment will change. Next-generation sequencing is a step closer to individualized care. Results will not only have an impact on the proband, but also on the family members. Targeted genetic testing will allow us to predict risk of CRC, and extracolonic cancers and will help us to tailor a specific
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screening and surveillance strategy. Although questions remain to be answered, this study shows the potential of next generation sequencing with a multigene panel for the evaluation of hereditary cancer syndromes. Q5
VEROUSHKA BALLESTER LISA BOARDMAN Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota
8.
9.
10.
References
Q3
1. Yurgelun MB, Allen B, Kaldate RR, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015. 2. Stoffel EM, Kastrinos F. Familial colorectal cancer, beyond Lynch syndrome. Clin Gastroenterol Hepatol 2014;12:1059–1068. 3. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening of Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788. 4. Domcheck SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 2013;31:1267–1270. 5. Kievit W, de Bruin JH, Adang EM, et al. Current clinical selection strategies for identification of hereditary nonpolyposis colorectal cancer families are inadequate: a meta-analysis. Clin Genet 2004;65:308–316. 6. Balmana J, Balaguer F, Castellvi-Bel S, et al. Comparison of predictive models, clinical criteria and molecular tumor screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J Med Genet 2008;45:557–563. 7. Giardello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome:
11.
12.
13.
a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2014; 109:1159–1179. Labadaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 2011;155:69–79. Farrugia DJ, Argal MK, Pankratz VS, et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res 2008;68:3523–3531. Cragun D, Radford C, Dolinski JS, et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet 2014;86:510–520. Peterlongo P, Nafa K, Lerman GS, et al. MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 2003;107:571–579. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet Med 2011;13:148–154. Gallegos CJ, Shirts BH, Bennette CS, et al. Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol 2015 May 4. pii: JCO.2014.59. 3665.
Q4
Reprint requests Address requests for reprints to: Lisa Boardman, MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected].
Conflicts of interest The authors disclose no conflicts.
Q1
© 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.07.025
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Next Generation Multigene Panel Testing: The Next step for identification of Hereditary Colorectal Cancer Syndromes?
Q2
See “Identification of a variety of mutations in cancer predisposition genes in patients with suspected syndrome,” by Yurgelun MB, Allen B, Kaldate RR, et al, on page 000.
T
his issue of Gastroenterology presents a manuscript by Yurgelun et al1 that addresses the question of whether multigene panel testing offers “meaningful advantages over targeted criteria-based genetic testing” in patients meeting criteria for the most commonly recognized hereditary colorectal cancer (CRC) condition, Lynch syndrome (LS).1 LS accounts for 2%–4% of all CRC and is caused by germline mutations in mismatch repair genes.2,3 Identifying these high-risk patients is a major issue, because morbidity and mortality from CRC and extracolonic cancers in patients and their relatives can be decreased by early and intensive screening. Although early detection of LS is important, a considerable proportion of patients remain unrecognized. The traditional approach for hereditary cancer risk assessment is based on phenotype-driven genetic testing, in which individuals who meet clinical criteria, undergo targeted genetic testing for the most likely genetic causes.4 Initial strategies to identify individuals with LS included fulfillment of the Amsterdam criteria (Table 1), which have been shown to have limited sensitivity for the identification of mutation carriers.5 The Bethesda guidelines (Table 1) were developed to identify individuals who deserve further evaluation with microsatellite instability and/or immunohistochemistry tumor testing for deficient mismatch repair. However, studies have shown that nearly 10% of mutation carriers will not be identified for testing based solely on the Bethesda guidelines.6 Studies have shown that 28% of patients with LS would be missed using only clinical criteria.7 Consequently, in an effort to decrease morbidity and mortality of relatives of patients with LS, some institutions are adopting Universal testing, which has been endorsed by the National Comprehensive Cancer Network (NCCN). Labadaum et al8 evaluated this universal strategy and determined that implementing testing in patients 70 years with newly diagnosed CRC is cost effective. The benefit to cost ratio depended on the number of a proband’s relatives who would benefit from cancer risk reduction strategies.8 Multigene panel testing has emerged as a tool for hereditary cancer risk assessment, which allows simultaneous analysis of multiple susceptibility genes. Yurgelun et al1 aimed to determine the frequency of non-LS gene mutations detected by a multigene panel among individuals undergoing clinical genetic testing for LS. A high-impact point
this manuscript addresses is that limiting germline testing to LS genes could lead to missing other mutations in high penetrance cancer susceptibility genes. This cohort included individuals who fulfilled NCCN criteria for LS and had a Prediction of Mutations in MLH1 AND MLH2 (PREMM) score of 5%, but whose tumors had not been tested for LS. Multigene panel testing identified unsuspected mutations in non-LS susceptibility genes in this cohort. In total, 14.4% of subjects were found to carry 1 pathogenic mutation. Of the pathogenic mutations identified by the multigene panel, 75% were in high penetrance genes with the majority arising in LS genes. However, non-LS mutations were detected in 5.6% of individuals undergoing LS testing. The most common unexpected findings were BRCA1/2, APC, and biallelic MUTYH mutations. The finding of BRCA1/2 mutations in 15 probands (8% of all mutation carriers) being evaluated for LS, none of whom had breast cancer, demonstrates the importance of genetic testing with a multigene panel to not overlook any actionable genetic findings because the clinical phenotype does not meet a particular guideline. Therefore, the phenotypic spectrum of LS can overlap with other hereditary cancer syndromes. Management of patients with unexpected high penetrance cancer susceptibility gene mutations is critically important and may need to take into account phenotype as well as genotype. With the emergence of more extensive genetic testing either in the form of multigene panels or ultimately with whole genome sequencing, we need to learn how to interpret these complex results effectively. The authors of this study highlight this treatment dilemma in the context of “deleterious” CDH1 mutations found by panel testing in members from a kindred that has never manifested gastric cancer. As more kindreds with CDH1 mutations are detected, our understanding of the actual risk for gastric cancer and the need for prophylactic gastrectomy in CDH1 mutation carriers may need to be revised. How aggressive we should be in the context of incidental findings still needs to be elucidated. Still, this study provides a glimpse into the complexity of genetic screening and the breadth and severity of phenotypes that a particular genetic mutation may produce. This will be key in tailoring cancer prevention strategies. However, this increased test sensitivity comes at the expense of detecting mutations in moderate penetrance genes and variants of uncertain significance (VUS) that may lead to unnecessary testing. Limited knowledge about the risk of cancer associated with VUS is an important barrier to providing appropriate care for individuals found to carry these genetic mutations.9 A study by Cragun et al10 that evaluated panel-based testing for inherited CRC, showed that VUS were found in 20% of the individuals tested, and nearly one-half (48%) occurred in one of the genes Gastroenterology 2015;-:1–3
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Table 1.Amsterdam Criteria and Revised Bethesda Guidelines Amsterdam Criteria Ia,b Three or more relatives with histologically verified CRC, 1 of which is the first-degree relative of the other 2. Two or more generations with CRC. One or more CRC cases diagnosed before the age of 50 years. Familial adenomatous polyposis should be excluded. Revised Bethesda Guidelinesc CRC diagnosed before the age of 50 years. Presence of synchronous or metachronous CRC or other LS-associated cancers. CRC with MSI-high pathologic associated features (Crohn-like lymphocytic reaction, mucinous/signet cell differentiation, or medullary growth pattern) diagnosed before the age of 60 years. Patient with CRC and who has CRC or LS-associated cancer diagnosed in 1 first-degree relative <50 years old. Patient with CRC and who has CRC or LS-associated cancer at any age in 2 first- or second-degree relatives.
CRC, colorectal cancer; LS, Lynch syndrome; MSI, microsatellite instability. a For Amsterdam Criteria II, substitute CRC with any LS-associated cancer. LS-associated cancer includes endometrial, gastric, ovarian, pancreatic, ureter, renal pelvis, small bowel, brain, and hepatobiliary cancer. b For Amsterdam Criteria I and II, all criteria must be met for clinical diagnosis of LS. c If any of the Bethesda guidelines are met, then LS genetic testing should be considered.
associated with LS. An example of a VUS found in one of the genes associated with LS is the V509A alteration in MSH6. This alteration has been reported previously in the literature and disease-specific databases. However, a study evaluating the role of MSH6 mutation in individuals from LS and LS-like families determined that this alteration was also present in 1.8% of healthy controls.11 This indicates that this mutation is not pathogenic for LS, and therefore, the more intensive surveillance testing used for LS patients is not warranted. In their manuscript, Yurgelun et al1 showed that 1 VUS was identified in 38% of the cohort. The most common genes in which VUS were discovered were ATM, APC, NBN, and BRIP1. VUS should not be used to guide the management of a patient and should not be misinterpreted as deleterious mutations. A study by Plon et al12 explored the impact of genetic test results in clinical decision making. They showed that management decisions demonstrated the “uncertainty” associated with VUS.12 It is expected that with more widespread testing, the ability to categorize VUS will improve.10 The optimal management of carriers of moderatepenetrance mutations remains unclear, even for genes like CHEK2, for which there is extensive evidence.4 Although testing for CHEK2 has been available for years, management of patients with CHEK2 mutations is not well-established, and screening recommendations are based mainly on personal and family history.10 There is the concern that physicians may have limited information on which to base recommendations for patient care. This ultimately could lead to unnecessary testing or approaches, such as prophylactic surgery, which historically has been reserved for patients with actionable high penetrance mutations. These findings suggest that appropriately selected patients with a high likelihood of having deleterious mutations may be the ones to benefit the most from this strategy. Patients undergoing multigene panel testing should first be educated about the implications of these results for themselves and their families. The evaluation of hereditary cancer syndromes is evolving with the emergence of next-generation multigene
panel testing. Despite the benefits that these multigene panels have to offer, many have questioned the benefit of testing multiple genes with different modes of inheritance and penetrance that may lead to increased costs for surveillance and unnecessary treatment.13 Gallegos et al13 performed a cost-effectiveness analysis of a nextgeneration multigene panel testing in the diagnosis of patients evaluated for suspected hereditary CRC syndromes compared with the sequential evaluation for LS recommended by current guidelines.13 This study revealed that next-generation sequencing panels that include highly penetrant genes associated with hereditary CRC syndromes provide clinical benefits in a cost-effective manner.13 The estimated costs of multigene panel testing range between $3000 and $4000. For coverage, insurance companies take into consideration several criteria, including personal history of early-onset cancer and family history. Companies also have financial assistance programs to help patients with copay costs. Questions remain regarding the integration of a multigene panel into a screening strategy and identification of eligibility criteria to direct testing with a multigene panel. To ensure the adequate implementation of this strategy, it will be critical to first identify which clinical features would be necessary to warrant further testing with next generation multigene panels. Multigene panel testing may be useful when genetic heterogeneity confounds the clinician’s ability to predict which gene will be mutated based on the proband phenotype and family history.4 Our understanding of the clinical phenotypes that represent risk for a hereditary CRC syndrome may need to be iteratively extended as the results of multigene panel testing are applied in the clinical setting. Yurgelun et al1 provide us with early insights of the use of next generation sequencing in a high-risk cohort. As technology evolves, approaches for hereditary cancer risk assessment will change. Next-generation sequencing is a step closer to individualized care. Results will not only have an impact on the proband, but also on the family members. Targeted genetic testing will allow us to predict risk of CRC, and extracolonic cancers and will help us to tailor a specific
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screening and surveillance strategy. Although questions remain to be answered, this study shows the potential of next generation sequencing with a multigene panel for the evaluation of hereditary cancer syndromes. Q5
VEROUSHKA BALLESTER LISA BOARDMAN Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota
8.
9.
10.
References
Q3
1. Yurgelun MB, Allen B, Kaldate RR, et al. Identification of a variety of mutations in cancer predisposition genes in patients with suspected Lynch syndrome. Gastroenterology 2015. 2. Stoffel EM, Kastrinos F. Familial colorectal cancer, beyond Lynch syndrome. Clin Gastroenterol Hepatol 2014;12:1059–1068. 3. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening of Lynch syndrome among patients with colorectal cancer. J Clin Oncol 2008;26:5783–5788. 4. Domcheck SM, Bradbury A, Garber JE, et al. Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 2013;31:1267–1270. 5. Kievit W, de Bruin JH, Adang EM, et al. Current clinical selection strategies for identification of hereditary nonpolyposis colorectal cancer families are inadequate: a meta-analysis. Clin Genet 2004;65:308–316. 6. Balmana J, Balaguer F, Castellvi-Bel S, et al. Comparison of predictive models, clinical criteria and molecular tumor screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J Med Genet 2008;45:557–563. 7. Giardello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome:
11.
12.
13.
a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol 2014; 109:1159–1179. Labadaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syndrome among patients with colorectal cancer: a cost-effectiveness analysis. Ann Intern Med 2011;155:69–79. Farrugia DJ, Argal MK, Pankratz VS, et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res 2008;68:3523–3531. Cragun D, Radford C, Dolinski JS, et al. Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet 2014;86:510–520. Peterlongo P, Nafa K, Lerman GS, et al. MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 2003;107:571–579. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet Med 2011;13:148–154. Gallegos CJ, Shirts BH, Bennette CS, et al. Next-generation sequencing panels for the diagnosis of colorectal cancer and polyposis syndromes: a cost-effectiveness analysis. J Clin Oncol 2015 May 4. pii: JCO.2014.59. 3665.
Q4
Reprint requests Address requests for reprints to: Lisa Boardman, MD, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905. e-mail: [email protected].
Conflicts of interest The authors disclose no conflicts.
Q1
© 2015 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2015.07.025
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