Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study.
BACKGROUND
Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy.


OBJECTIVE
To determine whether or not gastric cancer is a true HNPCC spectrum malignancy.


METHODS
The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status.


RESULTS
This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS-mutations (p = 0.019) and frameshift mutations in repeat tracts of growth-regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI.


CONCLUSIONS
The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.
Gylling
A
A
Department of Medical Genetics, University of Helsinki, Biomedicum Helsinki, P O Box 63 (Haartmaninkatu 8), Helsinki 00014 Finland.
Abdel-Rahman
W M
WM
Juhola
M
M
Nuorva
K
K
Hautala
E
E
Järvinen
H J
HJ
Mecklin
J-P
JP
Aarnio
M
M
Peltomäki
P
P
D000368:Aged; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis / Q000379:methods; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009367:Neoplasm Staging; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins