nach oben

Erschienen in:

01.04.2014 | Review Article

MUTYH-associated colorectal cancer and adenomatous polyposis

verfasst von: Satoru Yamaguchi, Hideo Ogata, Daisuke Katsumata, Masanobu Nakajima, Takaaki Fujii, Soichi Tsutsumi, Takayuki Asao, Kinro Sasaki, Hiroyuki Kuwano, Hiroyuki Kato

Erschienen in: Surgery Today | Ausgabe 4/2014

Einloggen, um Zugang zu erhalten

Abstract

MUTYH-associated polyposis (MAP) was first described in 2002. MUTYH is a component of a base excision repair system that protects the genomic information from oxidative damage. When the MUTYH gene product is impaired by bi-allelic germline mutation, it leads to the mutation of cancer-related genes, such as the APC and/or the KRAS genes, via G to T transversion. MAP is a hereditary colorectal cancer syndrome inherited in an autosomal-recessive fashion. The clinical features of MAP include the presence of 10–100 adenomatous polyps in the colon, and early onset of colorectal cancer. Ethnic and geographical differences in the pattern of the MUTYH gene mutations have been suggested. In Caucasian patients, c.536A>G (Y179C) and c.1187G>A (G396D) mutations are frequently detected. In the Asian population, Y179C and G396D are uncommon, whereas other variants are suggested to be the major causes of MAP. We herein review the literature on MUTYH-associated colorectal cancer and adenomatous polyposis.

Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMed

Yiu HY, Whittemore AS, Shibata A. Increasing colorectal cancer incidence rates in Japan. Int J Cancer. 2004;109:777–81.CrossRefPubMed

Vargas AJ, Thompson PA. Diet and nutrient factors in colorectal cancer risk. Nutr Clin Pract. 2012;27:613–23.CrossRefPubMed

Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85.CrossRefPubMed

Gala M, Chung DC. Hereditary colon cancer syndromes. Semin Oncol. 2011;38:490–9.CrossRefPubMed

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.CrossRefPubMed

Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783–8.PubMedCentralPubMed

Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J, et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–8.PubMed

Duval A, Hamelin R. Mutations at coding repeat sequences in mismatch repair-deficient human cancers: toward a new concept of target genes for instability. Cancer Res. 2002;62:2447–54.PubMed

10.

Park J, Betel D, Gryfe R, Michalickova K, Di Nicola N, Gallinger S, et al. Mutation profiling of mismatch repair-deficient colorectal cancers using an in silico genome scan to identify coding microsatellites. Cancer Res. 2002;62:1284–8.PubMed

11.

Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003;348:919–32.PubMed

12.

Maeda T, Cannom RR, Beart RW Jr, Etzioni DA. Decision model of segmental compared with total abdominal colectomy for colon cancer in hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2010;28:1175–80.PubMed

13.

Arnold CN, Goel A, Boland CR. Role of hMLH1 promoter hypermethylation in drug resistance to 5-fluorouracil in colorectal cancer cell lines. Int J Cancer. 2003;106:66–73.PubMed

14.

Des Guetz G, Schischmanoff O, Nicolas P, Perret GY, Morere JF, Uzzan B. Does microsatellite instability predict the efficacy of adjuvant chemotherapy in colorectal cancer? A systematic review with meta-analysis. Eur J Cancer. 2009;45:1890–6.

15.

Nagy R, Sweet K, Eng C. Highly penetrant hereditary cancer syndromes. Oncogene. 2004;23:6445–70.PubMed

16.

Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1996;24:121–4.PubMedCentralPubMed

17.

Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044–58.PubMedCentralPubMed

18.

Bulow S. Results of national registration of familial adenomatous polyposis. Gut. 2003;52:742–6.PubMedCentralPubMed

19.

Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.PubMed

20.

Knudsen AL, Bisgaard ML, Bulow S. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003;2:43–55.PubMed

21.

Heinimann K, Mullhaupt B, Weber W, Attenhofer M, Scott RJ, Fried M, et al. Phenotypic differences in familial adenomatous polyposis based on APC gene mutation status. Gut. 1998;43:675–9.PubMedCentralPubMed

22.

Matsumoto T, Iida M, Kobori Y, Mizuno M, Nakamura S, Hizawa K, et al. Genetic predisposition to clinical manifestations in familial adenomatous polyposis with special reference to duodenal lesions. Am J Gastroenterol. 2002;97:180–5.PubMed

23.

Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76:1–18.PubMedCentralPubMed

24.

Tchou J, Kasai H, Shibutani S, Chung MH, Laval J, Grollman AP, et al. 8-Oxoguanine (8-hydroxyguanine) DNA glycosylase and its substrate specificity. Proc Natl Acad Sci USA. 1991;88:4690–4.PubMedCentralPubMed

25.

Shibutani S, Takeshita M, Grollman AP. Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG. Nature. 1991;349:431–4.PubMed

26.

Cheng KC, Cahill DS, Kasai H, Nishimura S, Loeb LA. 8-Hydroxyguanine, an abundant form of oxidative DNA damage, causes G→T and A→C substitutions. J Biol Chem. 1992;267:166–72.PubMed

27.

Michaels ML, Tchou J, Grollman AP, Miller JH. A repair system for 8-oxo-7,8-dihydrodeoxyguanine. Biochemistry. 1992;31:10964–8.PubMed

28.

Aburatani H, Hippo Y, Ishida T, Takashima R, Matsuba C, Kodama T, et al. Cloning and characterization of mammalian 8-hydroxyguanine-specific DNA glycosylase/apurinic, apyrimidinic lyase, a functional mutM homologue. Cancer Res. 1997;57:2151–6.PubMed

29.

Arai K, Morishita K, Shinmura K, Kohno T, Kim SR, Nohmi T, et al. Cloning of a human homolog of the yeast OGG1 gene that is involved in the repair of oxidative DNA damage. Oncogene. 1997;14:2857–61.PubMed

30.

Lu R, Nash HM, Verdine GL. A mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancer. Curr Biol. 1997;7:397–407.PubMed

31.

Rosenquist TA, Zharkov DO, Grollman AP. Cloning and characterization of a mammalian 8-oxoguanine DNA glycosylase. Proc Natl Acad Sci USA. 1997;94:7429–34.PubMedCentralPubMed

32.

Radicella JP, Dherin C, Desmaze C, Fox MS, Boiteux S. Cloning and characterization of hOGG1, a human homolog of the OGG1 gene of Saccharomyces cerevisiae. Proc Natl Acad Sci USA. 1997;94:8010–5.PubMedCentralPubMed

33.

Au KG, Clark S, Miller JH, Modrich P. Escherichia coli mutY gene encodes an adenine glycosylase active on G-A mispairs. Proc Natl Acad Sci USA. 1989;86:8877–81.PubMedCentralPubMed

34.

Slupska MM, Baikalov C, Luther WM, Chiang JH, Wei YF, Miller JH. Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage. J Bacteriol. 1996;178:3885–92.PubMedCentralPubMed

35.

Maki H, Sekiguchi M. MutT protein specifically hydrolyses a potent mutagenic substrate for DNA synthesis. Nature. 1992;355:273–5.PubMed

36.

Sakumi K, Furuichi M, Tsuzuki T, Kakuma T, Kawabata S, Maki H, et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8-oxo-dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem. 1993;268:23524–30.PubMed

37.

Hung RJ, Hall J, Brennan P, Boffetta P. Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol. 2005;162:925–42.PubMed

38.

Takao M, Zhang QM, Yonei S, Yasui A. Differential subcellular localization of human MutY homolog (hMYH) and the functional activity of adenine:8-oxoguanine DNA glycosylase. Nucleic Acids Res. 1999;27:3638–44.PubMedCentralPubMed

39.

Shinmura K, Yamaguchi S, Saitoh T, Takeuchi-Sasaki M, Kim SR, Nohmi T, et al. Adenine excisional repair function of MYH protein on the adenine:8-hydroxyguanine base pair in double-stranded DNA. Nucleic Acids Res. 2000;28:4912–8.PubMedCentralPubMed

40.

Ohtsubo T, Nishioka K, Imaiso Y, Iwai S, Shimokawa H, Oda H, et al. Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydroxyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucleic Acids Res. 2000;28:1355–64.PubMedCentralPubMed

41.

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.PubMed

42.

Yamaguchi S, Shinmura K, Saitoh T, Takenoshita S, Kuwano H, Yokota J. A single nucleotide polymorphism at the splice donor site of the human MYH base excision repair genes results in reduced translation efficiency of its transcripts. Genes Cells. 2002;7:461–74.PubMed

43.

Tao H, Shinmura K, Hanaoka T, Natsukawa S, Shaura K, Koizumi Y, et al. A novel splice-site variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus. Carcinogenesis. 2004;25:1859–66.PubMed

44.

Torrezan GT, da Silva FC, Krepischi AC, Santos EM, Ferreira Fde O, Rossi BM, et al. Breakpoint characterization of a novel large intragenic deletion of MUTYH detected in a MAP patient: case report. BMC Med Genet. 2011;12:128.

45.

Shinmura K, Yamaguchi S, Saitoh T, Kohno T, Yokota J. Somatic mutations and single nucleotide polymorphisms of base excision repair genes involved in the repair of 8-hydroxyguanine in damaged DNA. Cancer Lett. 2001;166:65–9.PubMed

46.

Jones S, Emmerson P, Maynard J, Best JM, Jordan S, Williams GT, et al. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C → T:A mutations. Hum Mol Genet. 2002;11:2961–7.PubMed

47.

Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, et al. Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 2003;348:791–9.PubMed

48.

Jones S, Lambert S, Williams GT, Best JM, Sampson JR, Cheadle JP. Increased frequency of the k-ras G12C mutation in MYH polyposis colorectal adenomas. Br J Cancer. 2004;90:1591–3.PubMedCentralPubMed

49.

Nielsen M, de Miranda NF, van Puijenbroek M, Jordanova ES, Middeldorp A, van Wezel T, et al. Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas. BMC Cancer. 2009;9:184.PubMedCentralPubMed

50.

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.PubMed

51.

Farrington SM, Tenesa A, Barnetson R, Wiltshire A, Prendergast J, Porteous M, et al. Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet. 2005;77:112–9.PubMedCentralPubMed

52.

Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 2009;27:3975–80.PubMed

53.

Theodoratou E, Campbell H, Tenesa A, Houlston R, Webb E, Lubbe S, et al. A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants. Br J Cancer. 2010;103:1875–84.PubMedCentralPubMed

54.

Plotz G, Casper M, Raedle J, Hinrichsen I, Heckel V, Brieger A, et al. MUTYH gene expression and alternative splicing in controls and polyposis patients. Hum Mutat. 2012;33:1067–74.PubMed

55.

Sakamoto K, Tominaga Y, Yamauchi K, Nakatsu Y, Sakumi K, Yoshiyama K, et al. MUTYH-null mice are susceptible to spontaneous and oxidative stress induced intestinal tumorigenesis. Cancer Res. 2007;67:6599–604.PubMed

56.

Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, et al. Germline MutY human homologue mutations and colorectal cancer: a multisite case–control study. Gastroenterology. 2009;136:1251–60.PubMedCentralPubMed

57.

Sampson JR, Dolwani S, Jones S, Eccles D, Ellis A, Evans DG, et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet. 2003;362:39–41.PubMed

58.

Gismondi V, Meta M, Bonelli L, Radice P, Sala P, Bertario L, et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int J Cancer. 2004;109:680–4.PubMed

59.

Venesio T, Molatore S, Cattaneo F, Arrigoni A, Risio M, Ranzani GN. High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis. Gastroenterology. 2004;126:1681–5.PubMed

60.

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.

61.

Yanaru-Fujisawa R, Matsumoto T, Ushijima Y, Esaki M, Hirahashi M, Gushima M, et al. Genomic and functional analyses of MUTYH in Japanese patients with adenomatous polyposis. Clin Genet. 2008;73:545–53.PubMed

62.

Ali M, Kim H, Cleary S, Cupples C, Gallinger S, Bristow R. Characterization of mutant MUTYH proteins associated with familial colorectal cancer. Gastroenterology. 2008;135:499–507.PubMedCentralPubMed

63.

Miyaki M, Iijima T, Yamaguchi T, Hishima T, Tamura K, Utsunomiya J, et al. Germline mutations of the MYH gene in Japanese patients with multiple colorectal adenomas. Mutat Res. 2005;578:430–3.PubMed

64.

Bai H, Jones S, Guan X, Wilson TM, Sampson JR, Cheadle JP, et al. Functional characterization of two human MutY homolog (hMYH) missense mutations (R227W and V232F) that lie within the putative hMSH6 binding domain and are associated with hMYH polyposis. Nucleic Acids Res. 2005;33:597–604.PubMedCentralPubMed

65.

Giraldez MD, Balaguer F, Caldes T, Sanchez-de-Abajo A, Gomez-Fernandez N, Ruiz-Ponte C, et al. Association of MUTYH and MSH6 germline mutations in colorectal cancer patients. Fam Cancer. 2009;8:525–31.PubMed

66.

Kim DW, Kim IJ, Kang HC, Jang SG, Kim K, Yoon HJ, et al. Germline mutations of the MYH gene in Korean patients with multiple colorectal adenomas. Int J Colorectal Dis. 2007;22:1173–8.PubMed

67.

Kim JC, Ka IH, Lee YM, Koo KH, Kim HC, Yu CS, et al. MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas. Virchows Arch. 2007;450:311–9.PubMed

68.

Goto M, Shinmura K, Nakabeppu Y, Tao H, Yamada H, Tsuneyoshi T, et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum Mutat. 2010;31:E1861–74.PubMedCentralPubMed

69.

Picelli S, Zajac P, Zhou XL, Edler D, Lenander C, Dalen J, et al. Common variants in human CRC genes as low-risk alleles. Eur J Cancer. 2010;46:1041–8.PubMed

70.

Kasahara M, Osawa K, Yoshida K, Miyaishi A, Osawa Y, Inoue N, et al. Association of MUTYH Gln324His and APEX1 Asp148Glu with colorectal cancer and smoking in a Japanese population. J Exp Clin Cancer Res. 2008;27:49.PubMedCentralPubMed

71.

Miyaishi A, Osawa K, Osawa Y, Inoue N, Yoshida K, Kasahara M, et al. MUTYH Gln324His gene polymorphism and genetic susceptibility for lung cancer in a Japanese population. J Exp Clin Cancer Res. 2009;28:10.PubMedCentralPubMed

72.

Kuno T, Matsubara N, Tsuda S, Kobayashi M, Hamanaka M, Yamagishi D, et al. Alterations of the base excision repair gene MUTYH in sporadic colorectal cancer. Oncol Rep. 2012;28:473–80.PubMed

73.

Raetz AG, Xie Y, Kundu S, Brinkmeyer MK, Chang C, David SS. Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. Carcinogenesis. 2012;33:2301–9.PubMedCentralPubMed

74.

Out AA, Wasielewski M, Huijts PE, van Minderhout IJ, Houwing-Duistermaat JJ, Tops CM, et al. MUTYH gene variants and breast cancer in a Dutch case–control study. Breast Cancer Res Treat. 2012;134:219–27.PubMedCentralPubMed

75.

Parker A, Gu Y, Mahoney W, Lee SH, Singh KK, Lu AL. Human homolog of the MutY repair protein (hMYH) physically interacts with proteins involved in long patch DNA base excision repair. J Biol Chem. 2001;276:5547–55.PubMed

76.

Hayashi H, Tominaga Y, Hirano S, McKenna AE, Nakabeppu Y, Matsumoto Y. Replication-associated repair of adenine:8-oxoguanine mispairs by MYH. Curr Biol. 2002;12:335–9.PubMed

77.

Jones N, Vogt S, Nielsen M, Christian D, Wark PA, Eccles D, et al. Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology. 2009;137:489–94.PubMed

78.

Win AK, Cleary SP, Dowty JG, Baron JA, Young JP, Buchanan DD, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011;129:2256–62.PubMedCentralPubMed

79.

Morak M, Laner A, Bacher U, Keiling C, Holinski-Feder E. MUTYH-associated 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.PubMed

80.

Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C, et al. Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res. 2003;63:7595–9.PubMed

81.

Nielsen M, Poley JW, Verhoef S, van Puijenbroek M, Weiss MM, Burger GT, et al. Duodenal carcinoma in MUTYH-associated polyposis. J Clin Pathol. 2006;59:1212–5.PubMedCentralPubMed

82.

Aretz S, Uhlhaas S, Goergens H, Siberg K, Vogel M, Pagenstecher C, et al. MUTYH-associated polyposis: 70 of 71 patients with biallelic mutations present with an attenuated or atypical phenotype. Int J Cancer. 2006;119:807–14.PubMed

83.

Nielsen M, Franken PF, Reinards TH, Weiss MM, Wagner A, van der Klift H, et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP). J Med Genet. 2005;42:e54.PubMedCentralPubMed

84.

Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Guidelines for the clinical management of familial adenomatous polyposis (FAP). Gut. 2008;57:704–13.PubMed

85.

Nieuwenhuis MH, Vogt S, Jones N, Nielsen M, Hes FJ, Sampson JR, et al. Evidence for accelerated colorectal adenoma–carcinoma progression in MUTYH-associated polyposis? Gut. 2012;61:734–8.PubMed

86.

Nielsen M, van Steenbergen LN, Jones N, Vogt S, Vasen HF, Morreau H, et al. Survival of MUTYH-associated polyposis patients with colorectal cancer and matched control colorectal cancer patients. J Natl Cancer Inst. 2010;102:1724–30.PubMedCentralPubMed

87.

Shinmura K, Goto M, Suzuki M, Tao H, Yamada H, Igarashi H, et al. Reduced expression of MUTYH with suppressive activity against mutations caused by 8-hydroxyguanine is a novel predictor of a poor prognosis in human gastric cancer. J Pathol. 2011;225:414–23.PubMed

88.

Tao H, Shinmura K, Suzuki M, Kono S, Mibu R, Tanaka M, et al. Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population. Cancer Sci. 2008;99:355–60.PubMed

89.

Halford SE, Rowan AJ, Lipton L, Sieber OM, Pack K, Thomas HJ, et al. Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. Am J Pathol. 2003;162:1545–8.PubMedCentralPubMed

90.

den Dunnen JT, Antonarakis SE. Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Hum Mutat. 2000;15:7–12.

91.

den Dunnen JT, Antonarakis SE. Nomenclature for the description of human sequence variations. Hum Genet. 2001;109:121–4.

Titel: MUTYH-associated colorectal cancer and adenomatous polyposis
verfasst von: Satoru Yamaguchi
Hideo Ogata
Daisuke Katsumata
Masanobu Nakajima
Takaaki Fujii
Soichi Tsutsumi
Takayuki Asao
Kinro Sasaki
Hiroyuki Kuwano
Hiroyuki Kato
Publikationsdatum: 01.04.2014
Verlag: Springer Japan
Erschienen in: Surgery Today / Ausgabe 4/2014
Print ISSN: 0941-1291
Elektronische ISSN: 1436-2813
DOI: https://doi.org/10.1007/s00595-013-0592-7

Leitlinien kompakt für die Allgemeinmedizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Facharzt-Training Allgemeinmedizin

Die ideale Vorbereitung zur anstehenden Prüfung mit den ersten 24 von 100 klinischen Fallbeispielen verschiedener Themenfelder

Mehr erfahren

Neu im Fachgebiet Allgemeinmedizin

25.04.2024 | Hypertonie | Nachrichten

Update Allgemeinmedizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

MUTYH-associated colorectal cancer and adenomatous polyposis

Abstract

Leitlinien kompakt für die Allgemeinmedizin

Facharzt-Training Allgemeinmedizin

Neu im Fachgebiet Allgemeinmedizin

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – Richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig

Update Allgemeinmedizin

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 4/2014

Initial experience with proximal ligation for profunda femoris artery aneurysms: report of three cases

Chyluria after ligation of the thoracic duct: a rare complication after thoracoscopic-assisted esophagectomy for esophageal cancer

Outcomes of emergency surgery for acute abdomen in dialysis patients: experience of a single community hospital

Analysis of treatment that includes both hepatic and pulmonary resections for colorectal metastases

Double common bile duct with choledochal cyst and cholelithiasis: report of a case

A single-center study of vascular access sites for intravenous ports

Leitlinien kompakt für die Allgemeinmedizin

Facharzt-Training Allgemeinmedizin

Neu im Fachgebiet Allgemeinmedizin

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Metformin rückt in den Hintergrund

Myokarditis nach Infekt – Richtig schwierig wird es bei Profisportlern

Thrombophiliescreening – Wenn, dann richtig

Update Allgemeinmedizin