Rona Yaeger1, Manish A Shah2, Vincent A Miller3, Judith R Kelsen4, Kai Wang5, Zachary J Heins6, Jeffrey S Ross3, Yuting He3, Eric Sanford3, Rhonda K Yantiss7, Sohail Balasubramanian3, Philip J Stephens3, Nikolaus Schultz8, Moshe Oren9, Laura Tang10, David Kelsen11. 1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. 2. Department of Medicine, Weill Cornell Medical College, New York, New York. 3. Foundation Medicine Inc, Cambridge, Massachusetts. 4. Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. 5. Foundation Medicine Inc, Cambridge, Massachusetts; Department of Pathology and Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China. 6. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. 7. Department of Pathology, Weill Cornell Medical College, New York, New York. 8. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York. 9. Department of Molecular Cell Biology, The Weizmann Institute, Israel. 10. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. 11. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York. Electronic address: kelsend@mskcc.org.
Abstract
BACKGROUND & AIMS: Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. METHODS: We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations. RESULTS: We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAF V600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. CONCLUSIONS: In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.
BACKGROUND & AIMS:Patients with inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are at increased risk for small bowel or colorectal cancers (colitis-associated cancers [CACs]). We compared the spectrum of genomic alterations in CACs with those of sporadic colorectal cancers (CRCs) and investigated differences between CACs from patients with CD vs UC. METHODS: We studied tumor tissues from patients with CACs treated at Memorial Sloan Kettering Cancer Center or Weill Cornell Medical College from 2003 through 2015. We performed hybrid capture-based next-generation sequencing analysis of >300 cancer-related genes to comprehensively characterize genomic alterations. RESULTS: We performed genomic analyses of 47 CACs (from 29 patients with UC and 18 with CD; 43 primary tumors and 4 metastases). Primary tumors developed in the ileum (n = 2), right colon (n = 18), left colon (n = 6), and rectosigmoid or rectum (n = 21). We found genomic alterations in TP53, IDH1, and MYC to be significantly more frequent, and mutations in APC to be significantly less frequent, than those reported in sporadic CRCs by The Cancer Genome Atlas or Foundation Medicine. We identified genomic alterations that might be targeted by a therapeutic agent in 17 of 47 (36%) CACs. These included the mutation encoding IDH1 R132; amplification of FGFR1, FGFR2, and ERBB2; and mutations encoding BRAFV600E and an EML4-ALK fusion protein. Alterations in IDH1 and APC were significantly more common in CACs from patients with CD than UC. CONCLUSIONS: In an analysis of CACs from 47 patients, we found significant differences in the spectrum of genomic alterations in CACs compared with sporadic CRCs. We observed a high frequency of IDH1 R132 mutations in patients with CD but not UC, as well as a high frequency of MYC amplification in CACs. Many genetic alterations observed in CACs could serve as therapeutic targets.
Authors: Douglas J Hartman; David Binion; Miguel Regueiro; Wolfgang Schraut; Nathan Bahary; Weijing Sun; Marina Nikiforova; Reetesh K Pai Journal: Am J Surg Pathol Date: 2014-08 Impact factor: 6.394
Authors: Christine Leowardi; Marie-Luise Schneider; Ulf Hinz; Jonathan M Harnoss; Ignazio Tarantino; Felix Lasitschka; Alexis Ulrich; Markus W Büchler; Martina Kadmon Journal: Ann Surg Oncol Date: 2015-10-14 Impact factor: 5.344
Authors: T A Brentnall; D A Crispin; P S Rabinovitch; R C Haggitt; C E Rubin; A C Stevens; G C Burmer Journal: Gastroenterology Date: 1994-08 Impact factor: 22.682
Authors: Donavan T Cheng; Talia N Mitchell; Ahmet Zehir; Ronak H Shah; Ryma Benayed; Aijazuddin Syed; Raghu Chandramohan; Zhen Yu Liu; Helen H Won; Sasinya N Scott; A Rose Brannon; Catherine O'Reilly; Justyna Sadowska; Jacklyn Casanova; Angela Yannes; Jaclyn F Hechtman; Jinjuan Yao; Wei Song; Dara S Ross; Alifya Oultache; Snjezana Dogan; Laetitia Borsu; Meera Hameed; Khedoudja Nafa; Maria E Arcila; Marc Ladanyi; Michael F Berger Journal: J Mol Diagn Date: 2015-03-20 Impact factor: 5.568
Authors: T C He; A B Sparks; C Rago; H Hermeking; L Zawel; L T da Costa; P J Morin; B Vogelstein; K W Kinzler Journal: Science Date: 1998-09-04 Impact factor: 47.728
Authors: B D Greenwald; N Harpaz; J Yin; Y Huang; Y Tong; V L Brown; T McDaniel; C Newkirk; J H Resau; S J Meltzer Journal: Cancer Res Date: 1992-02-01 Impact factor: 12.701
Authors: Andreas Gnirke; Alexandre Melnikov; Jared Maguire; Peter Rogov; Emily M LeProust; William Brockman; Timothy Fennell; Georgia Giannoukos; Sheila Fisher; Carsten Russ; Stacey Gabriel; David B Jaffe; Eric S Lander; Chad Nusbaum Journal: Nat Biotechnol Date: 2009-02-01 Impact factor: 54.908
Authors: Patricia A J Muller; Antonio G Trinidad; Patrick T Caswell; Jim C Norman; Karen H Vousden Journal: J Biol Chem Date: 2013-11-12 Impact factor: 5.157
Authors: Georg Schneditz; Joshua E Elias; Ester Pagano; M Zaeem Cader; Svetlana Saveljeva; Kathleen Long; Subhankar Mukhopadhyay; Maryam Arasteh; Trevor D Lawley; Gordon Dougan; Andrew Bassett; Tom H Karlsen; Arthur Kaser; Nicole C Kaneider Journal: Sci Signal Date: 2019-01-01 Impact factor: 8.192
Authors: P Chandrasinghe; B Cereser; M Moorghen; I Al Bakir; N Tabassum; A Hart; J Stebbing; J Warusavitarne Journal: Oncogene Date: 2017-09-04 Impact factor: 9.867