Aberrant DNA methylation in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency.
OBJECTIVE
Approximately half of the families that fulfill Amsterdam criteria for Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) do not have evidence of the germline mismatch repair gene mutations that define this syndrome and result in microsatellite instability (MSI). The carcinogenic pathways and the best diagnostic approaches to detect microsatellite stable (MSS) HNPCC tumors are unclear. We investigated the contribution of epigenetic alterations to the development of MSS HNPCC tumors.


METHODS
Colorectal cancers were divided into 4 groups: (1) microsatellite stable, Amsterdam-positive (MSS HNPCC) (N = 22); (2) Lynch syndrome cancers (identified mismatch repair mutations) (N = 21); (3) sporadic MSS (N = 92); and (4) sporadic MSI (N = 46). Methylation status was evaluated for CACNAG1, SOCS1, RUNX3, NEUROG1, MLH1, and long interspersed nucleotide element-1 (LINE-1). KRAS and BRAF mutation status was analyzed.


RESULTS
MSS HNPCC tumors displayed a significantly lower degree of LINE-1 methylation, a marker for global methylation, than any other group. Although most MSS HNPCC tumors had some degree of CpG island methylation, none presented a high index of methylation. MSS HNPCC tumors had KRAS mutations exclusively in codon 12, but none harbored V600E BRAF mutations.


CONCLUSIONS
Tumors from Amsterdam-positive patients without mismatch repair deficiency (MSS HNPCC) have certain molecular features, including global hypomethylation, that distinguish them from all other colorectal cancers. These characteristics could have an important impact on tumor behavior or treatment response. Studies are underway to further assess the cause and effects of these features.
Goel
Ajay
A
Division of Gastroenterology, Department of Medicine, Baylor University, Medical Center, Dallas, Texas, USA.
Xicola
Rosa M
RM
Nguyen
Thuy-Phuong
TP
Doyle
Brian J
BJ
Sohn
Vanessa R
VR
Bandipalliam
Prathap
P
Rozek
Laura S
LS
Reyes
Josep
J
Cordero
Carmen
C
Balaguer
Francesc
F
Castells
Antoni
A
Jover
Rodrigo
R
Andreu
Montserrat
M
Syngal
Sapna
S
Boland
C Richard
CR
Llor
Xavier
X
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D013030:Spain; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014481:United States; D018631:ras Proteins / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D050677:Core Binding Factor Alpha 3 Subunit; D000070957:MutL Protein Homolog 1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018631:ras Proteins; C117307:KRAS protein, human; C501486:MLH1 protein, human; C105389:NEUROG1 protein, human; C493729:Runx3 protein, human; C108944:SOCS1 protein, human; C482119:BRAF protein, human