Genetic mechanisms in interval colon cancers.
OBJECTIVE
The factors underlying the development of interval colon cancers are not well defined and are likely heterogeneous. We sought to determine whether there are distinct molecular properties associated with interval colon cancers.


METHODS
Colon cancers diagnosed within 5 years of a complete and well-prepped colonoscopic examination were identified over a 7-year period at a single institution. The clinical and pathological features of the tumors were defined. Analysis of DNA mismatch repair (MMR) and genotyping of a panel of oncogenes associated with colon cancer were performed.


RESULTS
Forty-two interval colon cancers were diagnosed at an average age of 70 years. 69 % of tumors were located in the right colon. 41 % of tumors exhibited DNA microsatellite instability (MSI). Loss of staining of DNA MMR proteins by immunohistochemistry (IHC) was confirmed in 82 % of the MSI-positive tumors. Among tumors with abnormal MSI and IHC, 54 % exhibited somatic methylation of the MLH1 promoter, but the remaining 43 % exhibited molecular features indicative of underlying Lynch syndrome (LS). The frequency of somatic mutations in the KRAS, BRAF, NRAS, and PIK3CA oncogenes was similar between interval cancer cases and controls.


CONCLUSIONS
Interval colon cancers are not distinguished by the activation of the KRAS, NRAS, BRAF, or PIK3CA oncogenic pathways. However, MSI pathway defects are present in a significant proportion of interval colon cancers. Underlying LS may explain nearly half of these MSI-positive cases, and the remaining cases appear to represent sporadic serrated pathway tumors.
GRJ 704, Gastrointestinal Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, MA, 02114, USA, jrichter@partners.org.
James M
JM
Richter
Maria Simona
MS
Pino
Thomas R
TR
Austin
Emily
E
Campbell
Jackie
J
Szymonifka
Andrea L
AL
Russo
Theodore S
TS
Hong
Darrell
D
Borger
A John
AJ
Iafrate
Daniel C
DC
Chung
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000236:Adenoma / Q000175:diagnosis*; D000251:Adenosine Triphosphatases / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002430:Cecal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D044682:Colon, Ascending / Q000473:pathology; D003110:Colonic Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D003111:Colonic Polyps / Q000175:diagnosis; D003113:Colonoscopy; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013997:Time Factors; D018631:ras Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C117307:KRAS protein, human; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D045643:DNA Repair Enzymes