Makoto Kagawa1, Satoru Kawakami2, Azusa Yamamoto3, Okihide Suzuki3,4, Nao Kamae4, Hidetaka Eguchi5, Yasushi Okazaki5, Gou Yamamoto6, Kiwamu Akagi6, Jun-Ichi Tamaru7, Tatsuro Yamaguchi8, Tomio Arai9, Hideyuki Ishida3,4. 1. Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan. 2. Department of Urology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan. kawakami@saitama-med.ac.jp. 3. Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 4. Department of Clinical Genetics, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 5. Diagnostics and Therapeutics of Intractable Diseases, Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan. 6. Division of Molecular Diagnosis and Cancer Prevention, Saitama Prefecture Cancer Center, Saitama, Japan. 7. Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan. 8. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan. 9. Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan.
Abstract
BACKGROUND: The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. METHODS: Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. RESULTS: Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63-79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. CONCLUSIONS: The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.
BACKGROUND: The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. METHODS: Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. RESULTS: Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63-79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. CONCLUSIONS: The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.
Authors: Christoph Engel; Markus Loeffler; Verena Steinke; Nils Rahner; Elke Holinski-Feder; Wolfgang Dietmaier; Hans K Schackert; Heike Goergens; Magnus von Knebel Doeberitz; Timm O Goecke; Wolff Schmiegel; Reinhard Buettner; Gabriela Moeslein; Tom G W Letteboer; Encarna Gómez García; Frederik J Hes; Nicoline Hoogerbrugge; Fred H Menko; Theo A M van Os; Rolf H Sijmons; Anja Wagner; Irma Kluijt; Peter Propping; Hans F A Vasen Journal: J Clin Oncol Date: 2012-10-22 Impact factor: 44.544
Authors: Sean C Skeldon; Kara Semotiuk; Melyssa Aronson; Spring Holter; Steven Gallinger; Aaron Pollett; Cynthia Kuk; Bas van Rhijn; Peter Bostrom; Zane Cohen; Neil E Fleshner; Michael A Jewett; Sally Hanna; Shahrokh F Shariat; Theodorus H Van Der Kwast; Andrew Evans; Jim Catto; Bharati Bapat; Alexandre R Zlotta Journal: Eur Urol Date: 2012-08-02 Impact factor: 20.096
Authors: Henry T Lynch; C Richard Boland; Gordon Gong; Trudy G Shaw; Patrick M Lynch; Riccardo Fodde; Jane F Lynch; Albert de la Chapelle Journal: Eur J Hum Genet Date: 2006-04 Impact factor: 4.246
Authors: K Ericson; B Halvarsson; J Nagel; E Rambech; M Planck; Z Piotrowska; H Olsson; M Nilbert Journal: Eur J Cancer Date: 2003-01 Impact factor: 9.162
Authors: H F A Vasen; G Möslein; A Alonso; I Bernstein; L Bertario; I Blanco; J Burn; G Capella; C Engel; I Frayling; W Friedl; F J Hes; S Hodgson; J-P Mecklin; P Møller; F Nagengast; Y Parc; L Renkonen-Sinisalo; J R Sampson; A Stormorken; J Wijnen Journal: J Med Genet Date: 2007-02-27 Impact factor: 6.318
Authors: R S van der Post; L A Kiemeney; M J L Ligtenberg; J A Witjes; C A Hulsbergen-van de Kaa; D Bodmer; L Schaap; C M Kets; J H J M van Krieken; N Hoogerbrugge Journal: J Med Genet Date: 2010-07 Impact factor: 6.318