Epigenetic variations in breast cancer progression to lymph node metastasis

URRUTIA GUILLERMO; LAURITO SERGIO; MARZESE DIEGO; GAGO FRANCISCO; OROZCO JAVIER; TELLO OLGA; BRANHAM MARIA T; CAMPOY, EMANUEL; ROQUÉ MARIA

CLINICAL & EXPERIMENTAL METASTASIS

SPRINGER

Lugar: Berlin; Año: 2015

0262-0898

Breast cancer is a heterogeneous disease characterizedby the accumulation of genetic and epigeneticalterations that contribute to the development of regionaland distant metastases. Lymph node metastasis (LNM)status is the single most important prognostic factor.Metastatic cancer cells share common molecular alterationswith those of the primary tumor, but in addition, theydevelop distinct changes that allow the cancer to progress.There is an urgent need for molecular studies which focuson identifying genomic and epigenomic markers that canpredict the progression to metastasis. The objective of thisstudy was to identify epigenetic similarities and differencesbetween paired primary breast tumor (PBT) and LNM. Weemployed Methylation-Specific-MLPA (Multiplex ligation-dependent probe amplification) to assess the methylationstatus of 33 cancer-related genes in a cohort of 50paired PBT and LNM specimens. We found that themethylation index, which represents the degree of aberrantlymethylated genes in a specimen, was maintained during the progression to LNM. However, some genespresented differential methylation profiles. Interestingly,PAX6 presented a significant negative correlation betweenpaired PBT and LNM (p = 0.03), which indicated a switchfrom methylated to unmethylated status in the progressionfrom PBT to LNM. We further identified that the methylationstatus of PAX6 on the identified CpG site functionallyaffected the expression of PAX6 at the mRNA level. Ourstudy unraveled significant epigenetic changes during theprogression from PBT to LNM, which may contribute toimproved prognosis, prediction and therapeutic managementof metastatic breast cancer patients.