TY - JOUR
T1 - MLH1 constitutional and somatic methylation in patients with MLH1 negative tumors fulfilling the revised Bethesda criteria.
AU - Crucianelli, Francesca
AU - Genuardi, Maurizio
AU - Tricarico, Rossella
AU - Turchetti, Daniela
AU - Gorelli, Greta
AU - Gensini, Francesca
AU - Sestini, Roberta
AU - Giunti, Laura
AU - Pedroni, Monica
AU - De Leon, Maurizio Ponz
AU - Civitelli, Serenella
PY - 2014
Y1 - 2014
N2 - Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein. A novel case of constitutional MLH1 epimutation was identified. This patient was affected with multiple primary tumors, including breast cancer, diagnosed starting from the age of 55 y. Investigation of her offspring by allele specific expression revealed that the epimutation was not stable across generations. We also found MLH1 hypermethylation in cancer samples from 4 additional patients who did not have evidence of constitutional defects. These patients had some characteristics of LS, namely early age at onset and/or positive family history, raising the possibility of genetic influences in the establishment of somatic MLH1 methylation.
AB - Lynch syndrome (LS) is a tumor predisposing condition caused by constitutional defects in genes coding for components of the mismatch repair (MMR) apparatus. While hypermethylation of the promoter of the MMR gene MLH1 occurs in about 15% of colorectal cancer samples, it has also been observed as a constitutional alteration, in the absence of DNA sequence mutations, in a small number of LS patients. In order to obtain further insights on the phenotypic characteristics of MLH1 epimutation carriers, we investigated the somatic and constitutional MLH1 methylation status of 14 unrelated subjects with a suspicion of LS who were negative for MMR gene constitutional mutations and whose tumors did not express the MLH1 protein. A novel case of constitutional MLH1 epimutation was identified. This patient was affected with multiple primary tumors, including breast cancer, diagnosed starting from the age of 55 y. Investigation of her offspring by allele specific expression revealed that the epimutation was not stable across generations. We also found MLH1 hypermethylation in cancer samples from 4 additional patients who did not have evidence of constitutional defects. These patients had some characteristics of LS, namely early age at onset and/or positive family history, raising the possibility of genetic influences in the establishment of somatic MLH1 methylation.
KW - ASE, allele specific expression
KW - CRC, colorectal cancer
KW - DNA methylation
KW - LS, Lynch syndrome
KW - MMR, mismatch repair
KW - ASE, allele specific expression
KW - CRC, colorectal cancer
KW - DNA methylation
KW - LS, Lynch syndrome
KW - MMR, mismatch repair
UR - http://hdl.handle.net/10807/63710
U2 - 10.4161/15592294.2014.970080
DO - 10.4161/15592294.2014.970080
M3 - Article
SN - 1559-2294
VL - 9
SP - 1431
EP - 1438
JO - Epigenetics
JF - Epigenetics
ER -