Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Clinical Cancer Research
CCR Translations See related article by Guarinos et al., p. 1158
Establishing a Diagnostic Road Map for MUTYH-Associated Polyposis Ester Borras1, Melissa W. Taggart2, Patrick M. Lynch3, and Eduardo Vilar1
The analysis of MUTYH-associated polyposis cases of the EPIPOLIP cohort confirms the importance of including serrated polyps in the diagnostic work-up of patients with oligopolyposis, suggests a role for screening polyps for the somatic c.34G>T KRAS mutation, and allows the implementation of a genetic testing strategy based on population data. Clin Cancer Res; 20(5); 1061–3. 2014 AACR.
In this issue of Clinical Cancer Research, Guarinos and colleagues (1) report on a rational genetic workflow that can be applied in cases of suspected MUTYH-associated polyposis (MAP) and confirm the importance of considering polyps with serrated histology, as well as the role of somatic mutations in KRAS as an aid in the diagnosis of MAP. MAP is an autosomal recessive polyposis syndrome predisposing to colorectal cancer (2) caused by biallelic mutations in the MUTYH gene. MUTYH is involved in the initial steps of the base-excision repair (BER) pathway (3), which prevents somatic mutations induced by oxidative damage (8-oxo-G). MUTYH recognizes 8-oxo-G:A mismatches and excises this error from the DNA. Patients harboring germline MUTYH mutations accumulate G:C to T:A (G>T) transversions in secondary genes (4), such as loss-of-function mutations observed in APC and KRAS, which are critical in the early steps of the colonic epithelium’s transition to adenoma and carcinoma (5). The genetic diagnostic work-up for patients with MAP is complicated because of variations in the genetic features of this disease among populations and the need to exclude other polyposis syndromes. Clinically, most patients with MAP present with ten to hundreds of polyps, which are predominantly located in the proximal colon. The mean age of patients at diagnosis is approximately 45 years, whereas the mean age of patients with MAP who develop colorectal cancer is 50 years, which translates into a simultaneous diagnosis of colorectal cancer and polyposis in 50% of individuals affected by MAP (6). In regard to the histology of the intestinal polyps, it has been reported that patients with MAP present not only with adenomas but also with serrated polyps, such as hyperplastic polyps and sessile
Authors' Affiliations: Departments of 1Clinical Cancer Prevention, 2 Pathology, and 3Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas Corresponding Author: Eduardo Vilar, Department of Clinical Cancer Prevention, Unit 1360, The University of Texas MD Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439. Phone: 713-7451836; Fax: 713-834-6397; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-13-3295 2014 American Association for Cancer Research.
serrated adenomas (5, 7). Correlations between the intestinal features (number and type of polyps) and the genotype of patients with MAP vary between populations and are not well characterized, mostly because of the low frequency of this condition. Therefore, there is no consensus on the most appropriate genetic testing workflow for patients with suspected MAP (8). Guarinos and colleagues aimed to address this problem by analyzing a multi-institutional cohort of patients from Spain presenting with modest colonic polyp burdens (10 or more lesions) in order to establish genotype–phenotype correlates and suggested a diagnostic strategy. A total of 405 patients were included in this cohort. Biallelic mutations in MUTYH were identified in 27 of the patients (7%), with classical mutations c.536A>G, p.Y179C and c.1187G>A, p. G396D as the most frequently found. Of note, 41% of patients with MAP presented with serrated polyps (hyperplastic, traditional serrated adenomas, sessile serrated polyps, and/or mixed hyperplastic/adenomatous polyps) and at least 10% of polyps in 85% of patients with MAP harbored the c.34G>T (p.G12C) KRAS mutation. On the basis of these findings, the authors devised a genetic testing strategy for MUTYH and proposed an initial step that tested for the most common mutations in their population (c.536A>G, p.Y179C; c.1187G>A, p. G396D; and c.1227_1228dup, p.E410GfsX43). Second, patients found to be heterozygous for one of these alterations underwent whole-gene sequencing. This approach demonstrated good sensitivity (96%) and specificity (100%) in the context of this Caucasian Spanish population. We believe that this strategy could be extrapolated to other countries with a population showing a similar genetic background by including modifications based on the discovery of specific founder mutations. For instance, it is well known that 70% of Caucasian patients with MAP harbor either the p.Y179C or the p.G396D mutation (4). However, at this time, the step-wise approach taken by Guarinos and colleagues may not be applicable to other non-Caucasian populations, such as Asian, African-American, Hispanic, and Jewish populations, in which the mutational spectra have not yet been well studied and for whom, therefore,
www.aacrjournals.org
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
1061
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Borras et al.
whole-gene sequencing will be the most appropriate genetic diagnostic strategy (ref. 4; Fig. 1). Furthermore, it has been suggested that there is a genotype–phenotype association for common MUTYH mutations in Caucasians, with more significant polyp burden and earlier age of onset in carriers of the p.Y176C allele (9). Guarinos and colleagues reported that patients who were homozygous for the p.Y176C variant had an earlier mean age of onset of polyposis than patients heterozygous or carrying other variants. Also, they reported that the p.G396D variant was strongly associated with the presence of serrated polyps, even in heterozygotes. This observation is consistent with findings in in vitro studies and the fact that p.G396D is less catalytically compromised than the p.Y176C variant (10). The association of MAP with serrated polyps has been described previously, although in smaller series of patients (5, 7). This association raises an important diagnostic point for clinicians, as the work-up of patients with oligopolyposis would now have to take into consideration not only the total count of polyps, but also the presence of serrated lesions. Based on these two factors, the use of dye-spray
colonoscopy in routine surveillance acquires a further dimension. In addition, no patients with serrated polyps were found to have APC mutations, and thus when serrated polyps are identified in the setting of oligopolyposis, the finding of c.34G>T KRAS mutation in codon 12 could facilitate the diagnosis of MAP. In this context, the incorporation of KRAS testing as a first step in the diagnostic work-up of mixed adenomatous and serrated oligopolyposis could be advocated. Of note, this specific G>T transversion is found in less than 8% of colorectal cancer harboring KRAS mutations (4, 11). Nonetheless, although biopsies of polyps usually render sufficient amounts of DNA to perform molecular analysis of KRAS mutations using classical Sanger sequencing or pyrosequencing strategies, the development of alternative strategies based on immunohistochemistry for specific KRAS mutations (similar to the staining for V600E BRAF mutation) would represent a significant advance toward simplifying the diagnosis of MAP. In many regards, the parallels between the carcinogenesis processes of MAP and the better-known Lynch syndrome may be useful in understanding the biology of MAP. The
• Oligopolyposis (1–10 colonic adenomas) before age 40 • 10–100 colonic adenomas and/or serrated polyps (SSA, TSA, HPP, and mixed serrated/adenomatous polyps) • Colonic polyposis in the absence of a germline APC mutation • CRC with KRAS mutation c.34G>T in codon 12 • Family history of CRC consistent with AR inheritance
Caucasian patient Look for c.536A>G, c.1187G>A and founder mutations adapted for each country
No mutation detected
Heterozygous mutation detected
Biallelic mutation detected
Other ethnicity Whole-gene MUTYH sequencing
No mutation detected
Heterozygous mutation detected
Biallelic mutation detected
Whole MUTYH gene analysis
No second mutation detected
Figure 1. Our proposed genetic diagnostic work-up of patients with suspected MAP based on previous reports and the findings presented by Guarinos et al. (1). CRC, colorectal cancer; MAP, MUTYHassociated polyposis; AR, autosomal recessive; HPP, hyperplastic polyps; SSA, sessile serrated adenomas; TSA, traditional serrated adenomas.
Second mutation detected
MAP not confirmed
MAP confirmed
MAP not confirmed
MAP confirmed
Moderate risk for CRC
High risk for CRC
Moderate risk for CRC
High risk for CRC
© 2014 American Association for Cancer Research
1062
Clin Cancer Res; 20(5) March 1, 2014
Clinical Cancer Research
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Genetic Work-up and Genotype–Phenotype Correlations in MAP
similarity between these entities is not restricted to their similar clinical presentation, with frequent involvement of the proximal colon, a higher rate of mucinous histology, and the presence of tumor-infiltrating lymphocytes (12); in addition, they share similar features in their molecular pathogenesis. That is, both syndromes arise because of the presence of germline mutations in genes involved in DNA repair systems (BER in MAP and mismatch repair in Lynch syndrome). These initial mutations introduce secondary hits in key oncogenes or tumor suppressor genes in the form of G>T transversions in MAP or contractions or expansions of microsatellite tracts in Lynch syndrome. Finally, the application of new technologies such as nextgeneration sequencing in the routine management of oncologic patients is rapidly becoming a reality. Because steadily decreasing amounts of genomic material are required for these analyses, we expect that gene panels will soon be incorporated into the routine study of samples with low DNA yields such as polyps in high-risk populations. This approach will allow us to detect higher-than-normal rates of G>T transversions in polyps or even in normal mucosa, raising a suspicion for germline defects in the BER pathway
and, therefore, enabling early diagnosis and detection of MAP, which will lead to the implementation of screening and preventive measures much earlier and thereby contributing to a decrease in the incidence of colorectal cancer in this population. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
Authors' Contributions Conception and design: E. Borras, E. Vilar Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.M. Lynch Writing, review, and/or revision of the manuscript: E. Borras, M. Taggart, P.M. Lynch, E. Vilar Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): E. Borras Study supervision: E. Vilar
Grant Support This work was supported by the Janice Davis Gordon Memorial Postdoctoral Fellowship in Colorectal Cancer Prevention from The University of Texas MD Anderson Cancer Center (to E. Borras). Received January 6, 2014; accepted January 6, 2014; published OnlineFirst January 31, 2014.
References 1.
2.
3.
4. 5.
6.
rez M, Egoavil C, Rodríquez-Soler M, Pe rez-Carbonell Guarinos C, Jua L, Salas R, et al. Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. Clin Cancer Res 2014;20:1158–68. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, et al. Inherited variants of MYH associated with somatic G:C!T: a mutations in colorectal tumors. Nat Genet 2002; 30:227–32. Barnes DE, Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 2004;38:445–76. Nielsen M, Morreau H, Vasen HF, Hes FJ. MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 2011;79:1–16. Boparai KS, Dekker E, Van Eeden S, Polak MM, Bartelsman JF, Mathus-Vliegen EM, et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 2008;135:2014–8. Out AA, Tops CM, Nielsen M, Weiss MM, van Minderhout IJ, Fokkema IF, et al. Leiden open variation database of the MUTYH gene. Hum Mutat 2010;31:1205–15.
www.aacrjournals.org
7.
O'Shea AM, Cleary SP, Croitoru MA, Kim H, Berk T, Monga N, et al. Pathological features of colorectal carcinomas in MYH-associated polyposis. Histopathology 2008;53:184–94. 8. Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E. MUTYHassociated polyposis—variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 2010;78:353–63. 9. Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology 2009;136:471–6. 10. David SS, O'Shea VL, Kundu S. Base-excision repair of oxidative DNA damage. Nature 2007;447:941–50. 11. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer 2001;85:692–6. 12. Nielsen M, de Miranda NF, van Puijenbroek M, Jordanova ES, Middeldorp A, van Wezel T, et al. Colorectal carcinomas in MUTYHassociated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer 2009;9:184.
Clin Cancer Res; 20(5) March 1, 2014
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
1063
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Establishing a Diagnostic Road Map for MUTYH-Associated Polyposis Ester Borras, Melissa W. Taggart, Patrick M. Lynch, et al. Clin Cancer Res 2014;20:1061-1063. Published OnlineFirst January 31, 2014.
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Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-3295 Access the most recent supplemental material at: http://clincancerres.aacrjournals.org/content/suppl/2014/03/04/1078-0432.CCR-13-3295.DC1.html
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Clinical Cancer Research
CCR Translations See related article by Guarinos et al., p. 1158
Establishing a Diagnostic Road Map for MUTYH-Associated Polyposis Ester Borras1, Melissa W. Taggart2, Patrick M. Lynch3, and Eduardo Vilar1
The analysis of MUTYH-associated polyposis cases of the EPIPOLIP cohort confirms the importance of including serrated polyps in the diagnostic work-up of patients with oligopolyposis, suggests a role for screening polyps for the somatic c.34G>T KRAS mutation, and allows the implementation of a genetic testing strategy based on population data. Clin Cancer Res; 20(5); 1061–3. 2014 AACR.
In this issue of Clinical Cancer Research, Guarinos and colleagues (1) report on a rational genetic workflow that can be applied in cases of suspected MUTYH-associated polyposis (MAP) and confirm the importance of considering polyps with serrated histology, as well as the role of somatic mutations in KRAS as an aid in the diagnosis of MAP. MAP is an autosomal recessive polyposis syndrome predisposing to colorectal cancer (2) caused by biallelic mutations in the MUTYH gene. MUTYH is involved in the initial steps of the base-excision repair (BER) pathway (3), which prevents somatic mutations induced by oxidative damage (8-oxo-G). MUTYH recognizes 8-oxo-G:A mismatches and excises this error from the DNA. Patients harboring germline MUTYH mutations accumulate G:C to T:A (G>T) transversions in secondary genes (4), such as loss-of-function mutations observed in APC and KRAS, which are critical in the early steps of the colonic epithelium’s transition to adenoma and carcinoma (5). The genetic diagnostic work-up for patients with MAP is complicated because of variations in the genetic features of this disease among populations and the need to exclude other polyposis syndromes. Clinically, most patients with MAP present with ten to hundreds of polyps, which are predominantly located in the proximal colon. The mean age of patients at diagnosis is approximately 45 years, whereas the mean age of patients with MAP who develop colorectal cancer is 50 years, which translates into a simultaneous diagnosis of colorectal cancer and polyposis in 50% of individuals affected by MAP (6). In regard to the histology of the intestinal polyps, it has been reported that patients with MAP present not only with adenomas but also with serrated polyps, such as hyperplastic polyps and sessile
Authors' Affiliations: Departments of 1Clinical Cancer Prevention, 2 Pathology, and 3Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas Corresponding Author: Eduardo Vilar, Department of Clinical Cancer Prevention, Unit 1360, The University of Texas MD Anderson Cancer Center, PO Box 301439, Houston, TX 77230-1439. Phone: 713-7451836; Fax: 713-834-6397; E-mail: [email protected] doi: 10.1158/1078-0432.CCR-13-3295 2014 American Association for Cancer Research.
serrated adenomas (5, 7). Correlations between the intestinal features (number and type of polyps) and the genotype of patients with MAP vary between populations and are not well characterized, mostly because of the low frequency of this condition. Therefore, there is no consensus on the most appropriate genetic testing workflow for patients with suspected MAP (8). Guarinos and colleagues aimed to address this problem by analyzing a multi-institutional cohort of patients from Spain presenting with modest colonic polyp burdens (10 or more lesions) in order to establish genotype–phenotype correlates and suggested a diagnostic strategy. A total of 405 patients were included in this cohort. Biallelic mutations in MUTYH were identified in 27 of the patients (7%), with classical mutations c.536A>G, p.Y179C and c.1187G>A, p. G396D as the most frequently found. Of note, 41% of patients with MAP presented with serrated polyps (hyperplastic, traditional serrated adenomas, sessile serrated polyps, and/or mixed hyperplastic/adenomatous polyps) and at least 10% of polyps in 85% of patients with MAP harbored the c.34G>T (p.G12C) KRAS mutation. On the basis of these findings, the authors devised a genetic testing strategy for MUTYH and proposed an initial step that tested for the most common mutations in their population (c.536A>G, p.Y179C; c.1187G>A, p. G396D; and c.1227_1228dup, p.E410GfsX43). Second, patients found to be heterozygous for one of these alterations underwent whole-gene sequencing. This approach demonstrated good sensitivity (96%) and specificity (100%) in the context of this Caucasian Spanish population. We believe that this strategy could be extrapolated to other countries with a population showing a similar genetic background by including modifications based on the discovery of specific founder mutations. For instance, it is well known that 70% of Caucasian patients with MAP harbor either the p.Y179C or the p.G396D mutation (4). However, at this time, the step-wise approach taken by Guarinos and colleagues may not be applicable to other non-Caucasian populations, such as Asian, African-American, Hispanic, and Jewish populations, in which the mutational spectra have not yet been well studied and for whom, therefore,
www.aacrjournals.org
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
1061
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Borras et al.
whole-gene sequencing will be the most appropriate genetic diagnostic strategy (ref. 4; Fig. 1). Furthermore, it has been suggested that there is a genotype–phenotype association for common MUTYH mutations in Caucasians, with more significant polyp burden and earlier age of onset in carriers of the p.Y176C allele (9). Guarinos and colleagues reported that patients who were homozygous for the p.Y176C variant had an earlier mean age of onset of polyposis than patients heterozygous or carrying other variants. Also, they reported that the p.G396D variant was strongly associated with the presence of serrated polyps, even in heterozygotes. This observation is consistent with findings in in vitro studies and the fact that p.G396D is less catalytically compromised than the p.Y176C variant (10). The association of MAP with serrated polyps has been described previously, although in smaller series of patients (5, 7). This association raises an important diagnostic point for clinicians, as the work-up of patients with oligopolyposis would now have to take into consideration not only the total count of polyps, but also the presence of serrated lesions. Based on these two factors, the use of dye-spray
colonoscopy in routine surveillance acquires a further dimension. In addition, no patients with serrated polyps were found to have APC mutations, and thus when serrated polyps are identified in the setting of oligopolyposis, the finding of c.34G>T KRAS mutation in codon 12 could facilitate the diagnosis of MAP. In this context, the incorporation of KRAS testing as a first step in the diagnostic work-up of mixed adenomatous and serrated oligopolyposis could be advocated. Of note, this specific G>T transversion is found in less than 8% of colorectal cancer harboring KRAS mutations (4, 11). Nonetheless, although biopsies of polyps usually render sufficient amounts of DNA to perform molecular analysis of KRAS mutations using classical Sanger sequencing or pyrosequencing strategies, the development of alternative strategies based on immunohistochemistry for specific KRAS mutations (similar to the staining for V600E BRAF mutation) would represent a significant advance toward simplifying the diagnosis of MAP. In many regards, the parallels between the carcinogenesis processes of MAP and the better-known Lynch syndrome may be useful in understanding the biology of MAP. The
• Oligopolyposis (1–10 colonic adenomas) before age 40 • 10–100 colonic adenomas and/or serrated polyps (SSA, TSA, HPP, and mixed serrated/adenomatous polyps) • Colonic polyposis in the absence of a germline APC mutation • CRC with KRAS mutation c.34G>T in codon 12 • Family history of CRC consistent with AR inheritance
Caucasian patient Look for c.536A>G, c.1187G>A and founder mutations adapted for each country
No mutation detected
Heterozygous mutation detected
Biallelic mutation detected
Other ethnicity Whole-gene MUTYH sequencing
No mutation detected
Heterozygous mutation detected
Biallelic mutation detected
Whole MUTYH gene analysis
No second mutation detected
Figure 1. Our proposed genetic diagnostic work-up of patients with suspected MAP based on previous reports and the findings presented by Guarinos et al. (1). CRC, colorectal cancer; MAP, MUTYHassociated polyposis; AR, autosomal recessive; HPP, hyperplastic polyps; SSA, sessile serrated adenomas; TSA, traditional serrated adenomas.
Second mutation detected
MAP not confirmed
MAP confirmed
MAP not confirmed
MAP confirmed
Moderate risk for CRC
High risk for CRC
Moderate risk for CRC
High risk for CRC
© 2014 American Association for Cancer Research
1062
Clin Cancer Res; 20(5) March 1, 2014
Clinical Cancer Research
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Genetic Work-up and Genotype–Phenotype Correlations in MAP
similarity between these entities is not restricted to their similar clinical presentation, with frequent involvement of the proximal colon, a higher rate of mucinous histology, and the presence of tumor-infiltrating lymphocytes (12); in addition, they share similar features in their molecular pathogenesis. That is, both syndromes arise because of the presence of germline mutations in genes involved in DNA repair systems (BER in MAP and mismatch repair in Lynch syndrome). These initial mutations introduce secondary hits in key oncogenes or tumor suppressor genes in the form of G>T transversions in MAP or contractions or expansions of microsatellite tracts in Lynch syndrome. Finally, the application of new technologies such as nextgeneration sequencing in the routine management of oncologic patients is rapidly becoming a reality. Because steadily decreasing amounts of genomic material are required for these analyses, we expect that gene panels will soon be incorporated into the routine study of samples with low DNA yields such as polyps in high-risk populations. This approach will allow us to detect higher-than-normal rates of G>T transversions in polyps or even in normal mucosa, raising a suspicion for germline defects in the BER pathway
and, therefore, enabling early diagnosis and detection of MAP, which will lead to the implementation of screening and preventive measures much earlier and thereby contributing to a decrease in the incidence of colorectal cancer in this population. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
Authors' Contributions Conception and design: E. Borras, E. Vilar Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): P.M. Lynch Writing, review, and/or revision of the manuscript: E. Borras, M. Taggart, P.M. Lynch, E. Vilar Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): E. Borras Study supervision: E. Vilar
Grant Support This work was supported by the Janice Davis Gordon Memorial Postdoctoral Fellowship in Colorectal Cancer Prevention from The University of Texas MD Anderson Cancer Center (to E. Borras). Received January 6, 2014; accepted January 6, 2014; published OnlineFirst January 31, 2014.
References 1.
2.
3.
4. 5.
6.
rez M, Egoavil C, Rodríquez-Soler M, Pe rez-Carbonell Guarinos C, Jua L, Salas R, et al. Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. Clin Cancer Res 2014;20:1158–68. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, et al. Inherited variants of MYH associated with somatic G:C!T: a mutations in colorectal tumors. Nat Genet 2002; 30:227–32. Barnes DE, Lindahl T. Repair and genetic consequences of endogenous DNA base damage in mammalian cells. Annu Rev Genet 2004;38:445–76. Nielsen M, Morreau H, Vasen HF, Hes FJ. MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol 2011;79:1–16. Boparai KS, Dekker E, Van Eeden S, Polak MM, Bartelsman JF, Mathus-Vliegen EM, et al. Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 2008;135:2014–8. Out AA, Tops CM, Nielsen M, Weiss MM, van Minderhout IJ, Fokkema IF, et al. Leiden open variation database of the MUTYH gene. Hum Mutat 2010;31:1205–15.
www.aacrjournals.org
7.
O'Shea AM, Cleary SP, Croitoru MA, Kim H, Berk T, Monga N, et al. Pathological features of colorectal carcinomas in MYH-associated polyposis. Histopathology 2008;53:184–94. 8. Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E. MUTYHassociated polyposis—variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 2010;78:353–63. 9. Nielsen M, Joerink-van de Beld MC, Jones N, Vogt S, Tops CM, Vasen HF, et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology 2009;136:471–6. 10. David SS, O'Shea VL, Kundu S. Base-excision repair of oxidative DNA damage. Nature 2007;447:941–50. 11. Andreyev HJ, Norman AR, Cunningham D, Oates J, Dix BR, Iacopetta BJ, et al. Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study. Br J Cancer 2001;85:692–6. 12. Nielsen M, de Miranda NF, van Puijenbroek M, Jordanova ES, Middeldorp A, van Wezel T, et al. Colorectal carcinomas in MUTYHassociated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer 2009;9:184.
Clin Cancer Res; 20(5) March 1, 2014
Downloaded from clincancerres.aacrjournals.org on September 12, 2015. © 2014 American Association for Cancer Research.
1063
Published OnlineFirst January 31, 2014; DOI: 10.1158/1078-0432.CCR-13-3295
Establishing a Diagnostic Road Map for MUTYH-Associated Polyposis Ester Borras, Melissa W. Taggart, Patrick M. Lynch, et al. Clin Cancer Res 2014;20:1061-1063. Published OnlineFirst January 31, 2014.
Updated version Supplementary Material
Cited articles
E-mail alerts Reprints and Subscriptions Permissions
Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-13-3295 Access the most recent supplemental material at: http://clincancerres.aacrjournals.org/content/suppl/2014/03/04/1078-0432.CCR-13-3295.DC1.html
This article cites 12 articles, 1 of which you can access for free at: http://clincancerres.aacrjournals.org/content/20/5/1061.full.html#ref-list-1
Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
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