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Multiplicity and Molecular Heterogeneity of Colorectal Carcinomas in Individuals With Serrated Polyposis

Rosty, Christophe MD, PhD, FRCPA*,†,‡; Walsh, Michael D. PhD*; Walters, Rhiannon J. BSc*; Clendenning, Mark PhD*; Pearson, Sally-Ann ADBLT*; Jenkins, Mark A. PhD§; Win, Aung Ko MBBS, MPH§; Hopper, John L. BA, MSc, PhD§; Sweet, Kevin MSc; Frankel, Wendy L. MD; Aronson, Melyssa MSc#; Gallinger, Steve MD, MSc#,**,††; Goldblatt, Jack MBChB, MD‡‡,§§; Tucker, Kathy MBBS∥∥; Greening, Sian BA¶¶; Gattas, Michael R. MBBS##; Woodall, Sonja PhD***; Arnold, Julie RN***; Walker, Neal I. MD; Parry, Susan MBChB***,†††; Young, Joanne P. PhD*; Buchanan, Daniel D. PhD*

The American Journal of Surgical Pathology: March 2013 - Volume 37 - Issue 3 - p 434–442
doi: 10.1097/PAS.0b013e318270f748
Original Articles

Serrated polyposis (SP) is a clinically defined syndrome characterized by the occurrence of multiple serrated polyps in the large intestine. Individuals with SP and their relatives are at increased risk of colorectal carcinoma (CRC). We aimed to determine the pathologic and molecular profiles of CRCs in individuals fulfilling World Health Organization criteria for SP. A total of 45 CRCs were obtained from 38 individuals with SP (27 female and 11 male patients; median age at CRC diagnosis, 58.5 y) attending genetics clinics. Tumor samples were pathologically reviewed, screened for somatic BRAF and KRAS mutations, and analyzed immunohistochemically for mismatch repair protein (MMR) expression. Tumors were spread throughout the large intestine, with 64% located in the proximal colon. Mutations in BRAF and KRAS and immunohistochemical evidence of MMR deficiency were found in 46%, 5%, and 38%, respectively. Nearly half of CRCs were BRAF/KRAS wild type, and these were associated with distal location (63%) and MMR proficiency (84%). Overexpression of p53 and/or evidence of β-catenin activation were identified in 13 CRCs. Ten patients (26%) had synchronous or metachronous CRCs. In conclusion, the majority of CRCs arising in individuals with SP do not harbor molecular hallmarks of serrated pathway CRCs but show a diverse range of molecular profiles. The high proportion of multiple CRCs suggests that individuals with SP would benefit from frequent colonoscopic surveillance and from a consideration of a more extensive colectomy at the time of CRC diagnosis.

*Cancer and Population Studies Group, Queensland Institute of Medical Research, Bancroft Centre

School of Medicine, University of Queensland

Envoi Pathology

##Queensland Clinical Genetics Service, Royal Childrens’ Hospital, Herston, Qld

§Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, School of Population Health, The University of Melbourne, Carlton, Vic., Australia

‡‡School of Paediatrics and Child Health, University of Western Australia, Nedlands

§§Genetic Services of Western Australia, Subiaco, WA

∥∥Hereditary Cancer Clinic, Prince of Wales Hospital, Randwick

¶¶Illawarra Cancer Centre, Wollongong Hospital, Wollongong, NSW, Australia

Department of Internal Medicine, Division of Human Genetics, Comprehensive Cancer Center

Department of Pathology, Ohio State University, Columbus, OH

#Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital

**Cancer Care Ontario

††Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada

***New Zealand Familial Gastrointestinal Cancer Registry, Auckland City Hospital

†††Department of Gastroenterology, Middlemore Hospital, Auckland, New Zealand

Conflicts of Interest and Source of Funding: Supported by National Cancer Institute, National Institutes of Health under 1R01CA123010 (Genetics of Serrated Neoplasia) and RFA # CA-95-011 and through cooperative agreements with the Australasian Colorectal Cancer Family Registry (U01 CA097735). During this work, J.P.Y. was a Cancer Council Queensland Senior Research Fellow. C.R. is a Jass Pathology Fellow. M.A.J. is an NHMRC Senior Research Fellow, and J.L.H. is an Australian fellow of the NHMRC. For the remaining authors none were declared.

Correspondence: Christophe Rosty, MD, PhD, FRCPA, Cancer and Population Studies Group, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Rd, Herston, Qld 4006, Australia (e-mail:

© 2013 Lippincott Williams & Wilkins, Inc.