Genetic Mutations and Epigenetic Modifications: Driving Cancer and Informing Precision Medicine

Table 1

Selected list of precisely targeted molecular alterations in cancer.

Gene symbol	Gene name	Effect of alteration	Major associations with specific tumor types	Implicated therapy
Protooncogenes and oncogenes
BCR-ABL	Breakpoint cluster region, Abelson murine leukemia viral oncogene homolog fusion protein	Compromises fidelity of DNA repair, deregulates proliferation, impairs apoptosis and differentiation	Chronic myelogenous leukemia	Imatinib, dasatinib,
HRAS/KRAS	Harvey/Kristen rat sarcoma viral oncogene homolog	Constitutively activates MEK/ERK progrowth signaling	Non-small cell lung cancer	Salirasib
BRAF	v-Raf murine sarcoma viral oncogene homolog B	Constitutively activates MEK/ERK progrowth signaling	Melanoma, V600E or V600K mutations	Vemurafenib, dabrafenib
BCL2	B-cell lymphoma/leukemia-2	Impairs apoptosis	Leukemia, lymphoma, melanoma	Venetoclax
Tumor suppressor genes
BRCA1/2	Breast cancer 1/2	Impaired DNA repair	Breast and ovarian cancers	PARP inhibitor (via synthetic lethality)
Epigenetic modifying genes
IDH1/2	Isocitrate dehydrogenase	DNA hypermethylation, disrupts differentiation	Acute myeloid leukemia (AML)	AG120, AG221, AG881
EZH2	Enhancer of zeste 2 polycomb repressive complex 2 subunit	Inhibits apoptosis, silences by H3K27 trimethylation	Lymphoma	Tazemetostat
DOT1L	DOT1-like histone H3K79 methyltransferase	Inhibits differentiation and apoptosis	Mixed-lineage leukemia	Pinometostat
DNMT	DNA methyltransferase	Disrupts normal patterns of DNA methylation	Breast and colon cancers, glioma, AML	Azacytidine,; decitabine
HDAC	Histone deacetylases	Disrupts normal patterns of histone acetylation	Gastric, breast, colorectal cancers	Vorinostat, romidepsin
Other targets
ER	Estrogen receptor	Sustains proliferative growth signals	Breast and ovarian cancers	Tamoxifen
CD20	B-lymphocyte antigen, cluster of differentiation (CD) 20	Supports B-cell activation and cell cycle progression	B-cell lymphomas	Rituximab
ERBB2 (HER2/neu)	Human epidermal growth factor receptor 2	Sustains proliferative growth signals	Breast, ovarian, uterine, and lung cancers	Trastuzumab
PD1	Programmed cell death protein 1 (CD279)	Prevents activation of T-cells	Potentially targets all solid tumors	Nivolumab
CTLA4	Cytotoxic T-lymphocyte associated protein 4	Prevents activation of T-cells	Potentially targets all solid tumors	Ipilimumab
AP-1	Activating protein 1	Regulates gene expression controlling differentiation, proliferation, and apoptosis	Colorectal cancer; case study	Irbesartan (angiotensin II receptor antagonist)
PML-RAR	Promyelocytic leukemia, retinoic acid receptor alpha fusion gene	Inhibits granulocytic differentiation	Acute promyelocytic leukemia	Retinoic acid
Biomarkers for clinical agents
APAF1	Apoptotic protease activating factor 1	Prevents apoptosis	Melanoma	Doxorubicin
MGMT	O^6-methylguanine-DNA methyltransferase	Reverses DNA damage	Glioma	Alkylating agents

Although IDH1/2 are not epigenetic modifying genes, alterations in these genes can have profound effects on the epigenome.