The PanCancer analysis of MAPK11 provides an overview of expression throughout the early and advanced stages of the disease as well as the genetic alterations of MAPK11 that contribute towards changes in expression. Focusing on female tissue-specific cancers (Fig. 2a), we outline a trend where MAPK11 expression in normal tissue is higher than that of early-stage BRCA, CESC, UCEC, and UCS cancer data sets. Unlike the other female cancers, MAPK11 expression in OV is primarily shown at the advanced stage of the disease which is often the stage of diagnosis due to the ambiguity of symptom presentation (Fig. 2d). The average expression of MAPK11 in OV (0.9 RSEM (log2(value + 1)), is relatively low compared to the other female cancers and is mirrored in the low expression alteration profile seen in Fig. 2b where shallow and deep deletion are the most frequent type of alteration.
Gene expression and methylation
It is generally considered that DNA methylation within the CpG island region of a gene’s promoter region is correlated with gene expression while DNA methylation within the gene body is also associated with chromosomal integrity [66]. To analyse the methylation status of MAPK11, 14 probes were chosen through the SMART database and studied within the female cancers: BRCA, CESC, and UCEC.
Here, we find a positive correlation of MAPK11 expression with methylation of the promoter region. Two of these CpG islands were found within the genomic region of MAPK11. The probe cg26790091 at the S-Shelf region showed lower methylation values compared to normal datasets and a positive correlation of expression and methylation was seen for all datasets with the exception of UCS (R=-0.04). The same pattern is observed with the N-Shore probe cg03717414, with lower methylation in all tested cancers compared to normal and a positive correlation between expression and methylation, again with exception to UCS (R=-0.0053). Following the genomic region of MAPK11, we found 10 locations on 2 islands with the first island having 4 methylation targets (CpG1: cg23755154, cg15036874, cg16054907, cg13577505) to present a strong positive correlation of expression-methylation for all 4 cancers (exception is probe cg15036874 in BRCA with an R=-0.095). Following the S-shore region, the next 6 locations located within the second island exhibit hypomethylation with a strong correlation between expression and methylation status (CpG2: cg19184963, cg08211722, cg15554007, cg00735239, cg00164898, cg00395632). Detailed results are located in Additional files 1, 2, and 3. Differences between the observed levels of expression and region-specific methylation are seen in Fig. 3 may influence the binding of transcriptional factors at the promoter region of the gene as well as the stability of the gene itself [67].
Gene expression and methylation analysis show that in BRCA, methylation at cg23755154 is significantly increased while the hypomethylated cg19184963 and cg00395632 are decreased within the tumour dataset (Additional file 1). In CESC, the dataset exhibits significant hypermethylation at cg15036874 and cg16054907 along with hypomethylation of the aggregated probes with tumour showing higher levels of methylation compared to normal tissue (Additional file 2). In UCEC, significant probe sites include the hypermethylation of cg23755154 and cg16054907 (Additional file 3). Information about the UCS and OV aggregation could not be obtained due to limitations of the SMART analysis tools (see Additional file 4).
We chose to group the methylated probes by region separating those that are located at CpG island 1 and those at CpG island 2 to analyse the separate promoter binding regions. A Spearman correlation analysis between the expression of MAPK11 and DNA methylation (M value) of MAPK11 in three of the female cancers indicates that expression is significantly positively associated with the methylation of region 1, a phenomenon that does not align with the normal paradigm of gene expression (cg23755154, cg15036874, cg16054907,cg13577505). Negative correlation however was seen with the following 6 probes that are localised to the second CpG island: cg19184963, cg08211722, cg15554007, cg00735239, cg00164898, cg00395632 (Fig. 4, see Additional file 1, 2, and 3).
Average aggregation of probes indicates that the gene is hypermethylated within the region of the first CpG island region yet hypomethylated in the second for both cancer data and normal, there is little significant difference between the levels of expression and methylation for the aggregated probes of BRCA with CESC and UCEC only exhibiting slight variation. Further analysis of the collection of probes aligning at the CpG island regions of the gene MAPK11 in wildtype and cancer data sets can be seen in Additional Fig. 5.
Complementary methylation analysis using MEXPRESS, indicates that there is no significant difference in the expression of the MAPK11 between the stages of each cancer data set studied (Fig. 5, Additional file 5). Moreover, no significant changes were observed for the BRCA oestrogen and BRCA progesterone receptor status, HER2/neu receptor, or menopause status of the cancers (data not shown here).