title: Retrospective review using targeted deep sequencing reveals mutational differences between gastroesophageal junction and gastric carcinomas.
abstract: BACKGROUND
  Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test.
  
  
  METHODS
  DNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data.
  
  
  RESULTS
  Gastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have ≥3 driver mutations detected (11% vs. 2%, p = 0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.
  
  
  CONCLUSIONS
  Panel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.
authors: University of British Columbia, Vancouver, Canada. hlichang@bccrc.ca.|Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 855 12 Ave W, Vancouver, BC, V5Z 1 M9, Canada. hlichang@bccrc.ca.|Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, Canada. hlichang@bccrc.ca.
authors: Hector H
authors: HH
authors: Li-Chang
authors: University of British Columbia, Vancouver, Canada. kkasaian@bcgsc.ca.|Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada. kkasaian@bcgsc.ca.
authors: Katayoon
authors: K
authors: Kasaian
authors: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada. yng@bccancer.bc.ca.
authors: Ying
authors: Y
authors: Ng
authors: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada. alum2@bccancer.bc.ca.
authors: Amy
authors: A
authors: Lum
authors: Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada. esther.kong@bccancer.bc.ca.
authors: Esther
authors: E
authors: Kong
authors: University of British Columbia, Vancouver, Canada. hlim@bccancer.bc.ca.|Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada. hlim@bccancer.bc.ca.
authors: Howard
authors: H
authors: Lim
authors: Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, Canada. sjones@bcgsc.ca.
authors: Steven Jm
authors: SJ
authors: Jones
authors: University of British Columbia, Vancouver, Canada. dhuntsma@bccancer.bc.ca.|Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 855 12 Ave W, Vancouver, BC, V5Z 1 M9, Canada. dhuntsma@bccancer.bc.ca.|Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, Canada. dhuntsma@bccancer.bc.ca.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada. dhuntsma@bccancer.bc.ca.
authors: David G
authors: DG
authors: Huntsman
authors: University of British Columbia, Vancouver, Canada. david.schaeffer@vch.ca.|Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 855 12 Ave W, Vancouver, BC, V5Z 1 M9, Canada. david.schaeffer@vch.ca.
authors: David F
authors: DF
authors: Schaeffer
authors: University of British Columbia, Vancouver, Canada. syip-02@bccancer.bc.ca.|Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Vancouver General Hospital, 855 12 Ave W, Vancouver, BC, V5Z 1 M9, Canada. syip-02@bccancer.bc.ca.|Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, Canada. syip-02@bccancer.bc.ca.
authors: Stephen
authors: S
authors: Yip
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004935:Esophageal Diseases / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*
references: Lancet. 2010 Aug 28;376(9742):687-97
references: 20728210
references: Nat Genet. 2013 May;45(5):478-86
references: 23525077
references: Gut. 2008 Mar;57(3):298-305
references: 17965056
references: Mol Cancer Ther. 2013 Sep;12(9):1738-48
references: 23825065
references: Lancet Oncol. 2013 Jan;14(1):38-47
references: 23200175
references: Ann Oncol. 2013 Mar;24(3):609-17
references: 22898040
references: Hum Pathol. 2011 Apr;42(4):594-601
references: 21146193
references: Nature. 2012 Jul 18;487(7407):330-7
references: 22810696
references: Nat Rev Cancer. 2001 Dec;1(3):233-40
references: 11902578
references: Mod Pathol. 2011 Jan;24(1):138-46
references: 20852593
references: Clin Cancer Res. 2008 Jun 15;14(12):3716-21
references: 18559588
references: Front Oncol. 2013 Apr 23;3:86
references: 23630663
references: Gastric Cancer. 2014;17(3):442-9
references: 24272205
references: Gut. 2010 Mar;59(3):282-4
references: 20207629
references: Br J Cancer. 2007 Feb 26;96(4):631-8
references: 17262083
references: Science. 2013 Mar 29;339(6127):1546-58
references: 23539594
references: Cancer Prev Res (Phila). 2008 Oct;1(5):329-38
references: 19138977
references: Int J Cancer. 2004 Aug 20;111(2):224-8
references: 15197775
references: Gut. 2000 Jan;46(1):9-13
references: 10601047
references: Methods Mol Biol. 2014;1102:461-80
references: 24258993
references: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references: 21296855
references: J Clin Endocrinol Metab. 2013 Nov;98(11):E1852-60
references: 23979959
references: PLoS One. 2013 Nov 13;8(11):e80478
references: 24236184
references: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
references: 15329413
references: Mol Cancer Ther. 2011 Jun;10(6):1028-35
references: 21482694
references: World J Gastroenterol. 2013 Sep 28;19(36):6098-107
references: 24106412
references: Mod Pathol. 2014 Feb;27(2):314-27
references: 23907151
references: Cancer Discov. 2012 Jul;2(7):591-7
references: 22705984
references: Nature. 2009 Dec 10;462(7274):739-44
references: 19935646
references: J Gastrointestin Liver Dis. 2013 Dec;22(4):413-8
references: 24369323
references: Methods Mol Biol. 2013;939:263-75
references: 23192552
references: PLoS Med. 2005 Jan;2(1):e17
references: 15696205
references: Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18281-9
references: 22988103
references: Blood. 2013 Oct 17;122(16):2877-87
references: 23954893
references: Ann Surg. 2000 Feb;231(2):179-87
references: 10674608
references: Cancer Res. 2013 Jan 1;73(1):276-84
references: 23066039
references: PLoS One. 2013;8(3):e54014
references: 23516391
references: Clin Cancer Res. 2011 May 1;17(9):2693-701
references: 21430069
references: Nat Rev Drug Discov. 2012 Nov;11(11):873-86
references: 23060265
references: Clin Chem Lab Med. 2014 May;52(5):707-14
references: 24334431
references: J Transl Med. 2011 Mar 30;9:33
references: 21450101
references: Leukemia. 2005 Aug;19(8):1345-9
references: 15959528
references: J Mol Diagn. 2013 Mar;15(2):234-47
references: 23321017
references: PLoS One. 2013 May 22;8(5):e63826
references: 23717493
references: J Mol Diagn. 2013 Nov;15(6):765-75
references: 23973117
references: J Mol Diagn. 2013 Mar;15(2):171-6
references: 23274167
references: Semin Diagn Pathol. 2005 Nov;22(4):256-65
references: 16939053
references: Nucleic Acids Res. 2000 Jan 1;28(1):27-30
references: 10592173
references: Leukemia. 2005 Mar;19(3):480-1
references: 15625552
references: Cancer Cell. 2006 Jul;10(1):65-75
references: 16843266
references: Semin Radiat Oncol. 2013 Jan;23(1):3-9
references: 23207041
references: Gut. 2007 Jul;56(7):918-25
references: 17317788
references: Nat Rev Clin Oncol. 2013 Nov;10(11):643-55
references: 24061039
references: Cancer Res. 2013 Aug 15;73(16):5195-205
references: 23786770
references: Mol Cancer Ther. 2012 Mar;11(3):690-9
references: 22238366
references: Mol Pathol. 1999 Oct;52(5):263-8
references: 10748875
references: J Mol Diagn. 2013 Sep;15(5):607-22
references: 23810757
references: J Clin Endocrinol Metab. 2013 May;98(5):E811-9
references: 23526464
references: Gut. 2009 May;58(5):636-42
references: 19136509
references: J Mol Diagn. 2010 Jan;12(1):43-50
references: 20007845
references: Clin Cancer Res. 2013 Jan 1;19(1):258-67
references: 23082002