RB1 and neoplasm: Activating mutations in oncogenes (such as CCND1, EGFR, PIK3CA, KRAS, BRAF) and inactivating changes in tumor suppressor genes—like RB1, APC, and WNT signaling pathway components (CHK1 and CHK2-BRCA1)—can dramatically enhance cell proliferation and increase the replication stress levels, causing double-strand breaks in the DNA, with consequent genomic instability that affects tumor progression (57).