Asymmetric Cancer Hallmarks in Breast Tumors on Different Sides of the Body

Abstract

During the last decades it has been established that breast cancer arises through the accumulation of genetic and epigenetic alterations in different cancer related genes. These alterations confer the tumor oncogenic abilities, which can be resumed as cancer hallmarks (CH). The purpose of this study was to establish the methylation profile of CpG sites located in cancer genes in breast tumors so as to infer their potential impact on 6 CH: i.e. sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, genome instability and invasion and metastasis. For 51 breast carcinomas, MS-MLPA derived-methylation profiles of 81 CpG sites were converted into 6 CH profiles. CH profiles distribution was tested by different statistical methods and correlated with clinical-pathological data. Unsupervised Hierarchical Cluster Analysis revealed that CH profiles segregate in two main groups (bootstrapping 90–100%), which correlate with breast laterality (p = 0.05). For validating these observations, gene expression data was obtained by RealTime-PCR in a different cohort of 25 tumors and converted into CH profiles. This analyses confirmed the same clustering and a tendency of association with breast laterality (p = 0.15). In silico analyses on gene expression data from TCGA Breast dataset from left and right breast tumors showed that they differed significantly when data was previously converted into CH profiles (p = 0.033). We show here for the first time, that breast carcinomas arising on different sides of the body present differential cancer traits inferred from methylation and expression profiles. Our results indicate that by converting methylation or expression profiles in terms of Cancer Hallmarks, it would allow to uncover veiled associations with clinical features. These results contribute with a new finding to the better understanding of breast tumor behavior, and can moreover serve as proof of principle for other bilateral cancers like lung, testes or kidney.

AGTR1 promoter hypermethylation in lung squamous cell carcinoma but not in lung adenocarcinoma

“…Besides, even though apparently symmetric, previous study showed that higher incidence of lung cancer was found on the right side (31), just as the breast cancer, which was about 5% more likely to be diagnosed in the left breast than the right (32). Breast cancer that arising on different sides of the body presented different cancer traits inferred from methylation and expression profiles (31), and this result contributed to serve as proof of principle for other bilateral cancers like the lung cancer. In our study, AGTR1 promoter methylation was shown likely to be not linked with gender, age, smoking history, clinical stage and tumor location.…”

When Left Does Not Seem Right: Epigenetic and Bioelectric Differences Between Left- and Right-Sided Breast Cancer

“…Based on this, specific aberrant DNA methylation patterns have been proposed as predictive and prognostic markers for several cancer types [16][17] [18] [19]. Specifically, in breast cancer, previous work of our group has identified that the DNA methylation profiles of tumor suppressor genes correlate with prognosis index [20] [21], with tumor subtypes [22], migration and metastasis capacity [23] [24], benign mammary lesions [25], and, more relevant for the topic of this study, with the laterality of the tumors [10]. In summary, tumor epigenome is influenceable by the microenvironment and can be associated with differential tumor behaviors.…”

“…From a previous work of our group [10], we counted with a database of 95 breast cancer female patients (mean age 54, range 31-86) who had previously signed an informed consent approved by the Ethics Committee of the Medical School of the National University of Cuyo, Mendoza,…”

“…Differences in L/R bilateral tumors have been reported for several cancer types, like breast [36], [37], colon [9], [38], [39], kidney [40], [41], brain [42], ovary [43], and eye [44]. Particularly in breast tumors, in addition to the largely known increased L-side incidence [45] [46], interesting differences in gene expression [8] [33], gland microbiota [47], mitochondria distribution [48] and methylation profiles [10] have been reported. It is reasonable to postulate that L/R adult glands conserve memories of their asymmetric embryogenic development, maintaining different L/R bioelectric patterns.…”

“…In particular, tumors in bilateral organs such as breast, colon, kidney or lung, show subtle but significant differences at morphological, genetic, molecular and incidence levels [8] [9]. Research data from our group and others (of diverse disciplines such as embryogenesis, development, molecular oncology, or cellular biology), have proposed that the asymmetric tumor microenvironment of bilateral organs could be part of the explanation for the L/R differences in cancer [10] [8] [3][4] [11] [12].…”