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JMD 2005, Vol. 7, No. 4
Copyright © 2005 American Society for Investigative Pathology & Association for Molecular Pathology

Tumor Microsatellite Instability in Early Onset Gastric Cancer

Julinor Bacani*{dagger}{ddagger}, Rhonda Zwingerman*, Nando Di Nicola{dagger}, Samantha Spencer*, Trish Wegrynowski{dagger}, Kyle Mitchell*, Kazuko Hay*, Mark Redston§, Eric Holowaty, David Huntsman||**, Aaron Pollett{dagger}, Robert Riddell{dagger} and Steven Gallinger*{dagger}{dagger}

From the Center for Cancer Genetics-Samuel Lunenfeld Research Institute * and Departments of Pathology and Laboratory Medicine {dagger} and Surgery, {dagger}{dagger} Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Pathology and Laboratory Medicine, {ddagger} University of British Columbia, Vancouver British Columbia, Canada; Department of Pathology Brigham & Women’s Hospital, § Boston, Massachusetts; Ontario Cancer Registry, Cancer Care Ontario, Toronto, Ontario, Canada; Genetic Pathology Evaluation Center, || Vancouver General Hospital, Vancouver, British Columbia, Canada; Department of Pathology, British Columbia Cancer Agency, ** University of British Columbia, Vancouver, British Columbia, Canada

Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. Genetic factors are implicated, including DNA mismatch repair (MMR) deficiency manifested as tumor microsatellite instability (MSI). However, a standardized panel of markers and a definition of low-versus-high level MSI in GC are lacking. We examined a population-based cohort of early onset (≤50 yrs) gastric cancer. We identified 211 cases of early onset gastric cancer in Central-East Ontario from 1989 to 1993, with archival material available for 139 cases. Testing included a six-mononucleotide marker panel and a three-MMR immunohistochemical panel. Overall, 30% (41 of 139) of GC were MSI+, with allelic shifts at one to eight markers. An unexpected discordance between the BAT-25, BAT-26, and BAT-40 markers was observed in the MSI+ cases. Six cases showing multiple loci instability (≥3 markers MSI+/MSI-high) demonstrated MMR protein deficiency. Three novel hMLH1 mutations (two germline frameshift and one somatic nonsense) were also found. The only significant clinicopathological associations were increased tumor size in MSI+ cases (P = 0.04) and Lauren histotype (P = 0.006) and tumor grade (P = 0.007) in MSI-high cases. Tumor size, location, depth, nodal status, and Ming subtype were significant prognostic variables. Therefore, we propose a new definition of high-level MSI based on unifying characteristics of instability of more than or equal to three of six mononucleotide markers and loss of MMR protein expression.




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J T Bacani, M Soares, R Zwingerman, N di Nicola, J Senz, R Riddell, D G Huntsman, and S Gallinger
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Copyright © 2005 by the American Society for Investigative Pathology and the Association for Molecular Pathology.