Table 7 Top three modules/maps given by Metacore.

1

DNA damage_ATM/ATR regulation of G1/S checkpoint: It is the highest scoring map (i.e., the map with the lowest p value). ATM/ATR regulates both the checkpoints of the G1/S and S/G2. DNA damage checkpoints pathways arrest or delay the progression of cell cycle in response to the DNA damage. Eukaryotic cell cycle have four phases, G1 (G indicating gap), S (Synthesis), G2 (Gap 2), and M (Mitosis), and one outside, G0 (Gap 0).

CDK2, p53, Ubiquitin, BRCA1, c-Myc, PCNA, MDM2

2

Transcription_P53 signaling pathway: It is the second highest scoring map (i.e., the map with the second lowest p-value). The Tumor protein p53, also known as p53 ortransformation-related protein 53 (TRP53), plays a significant role in shielding the genome integrity. While being activated, p53 will bind to the enhancer/promoter regions of downstream target genes. And then it regulates the transcription of these genes, through which it initiates cellular processes that responsible for lots of its tumor-suppressor related functions. It is not surprising that core network of 4 cancers are related to the p53 signaling pathway.

CDK2, p53, CBP, p300, Rb protein, MDM2, Beta-catenin

3

DNA damage_BRCA1 as a transcription regulator: It is the third highest scoring map (i.e., the map with the third lowest p-value). Activation of breast cancer susceptibility gene 1 (BRCA1) by DNA damage occurs via activating the ataxia telangiectasia mutated serine/threonine protein kinase (ATM) or serine/threonine-protein kinase ATR (ataxia telangiectasia and Rad3 related protein kinase). These protein kinases can either directly or indirectly phosphorylate BRCA1 (by cell cycle checkpoint kinase 2 (Chk2)). BRCA1 acts a significant role in the DNA repair process by expediting cellular response upon DNA repair. There are numerous DNA repair pathways (see map 427 Role of BRCA1 and BRCA2 in DNA repair). We know that DNA repair is highly related to various cancers.

p53, ESR1 (nuclear), BRCA1, c-Myc, PCNA, Rb protein