DNA damage appears to be the primary underlying cause of cancer. If accurate DNA repair is deficient, DNA damages tend to accumulate. Unrepaired DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis. DNA damage can also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms). Investigation of epigenetic down- or upregulation of repaired DNA genes as possibly central to progression of cancer has been regularly undertaken since 2000.
As described in Regulation of transcription in cancer, epigenetic downregulation of the DNA repair gene MGMT occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40&ndash;90% of colorectal cancers and 50% of brain cancers. Similarly, epigenetic downregulation of LIG4 occurs in 82% of colorectal cancers and epigenetic downregulation of NEIL1 occurs in 62% of head and neck cancers and in 42% of non-small-cell lung cancers.
Epigenetic upregulation of the DNA repair genes PARP1 and FEN1 occurs in numerous cancers (see Regulation of transcription in cancer). PARP1 and FEN1 are essential genes in the error-prone and mutagenic DNA repair pathway microhomology-mediated end joining.  If this pathway is upregulated, the excess mutations it causes can lead to cancer.  PARP1 is over-expressed in tyrosine kinase-activated leukemias, in neuroblastoma, in testicular and other germ cell tumors, and in Ewing's sarcoma. FEN1 is upregulated in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung.