Proto-Oncogenes and Tumor Suppressor Genes

1. RAS Oncogene Mutations: Mutations in the RAS family of genes (KRAS, HRAS, NRAS) are common in various cancers. These mutations lead to the continuous activation of the RAS protein, which in turn continuously signals downstream pathways like the MAPK/ERK pathway, promoting uncontrolled cell proliferation.

2. PIK3CA Mutations: Mutations in the PIK3CA gene, which encodes the p110α catalytic subunit of PI3K, are found in several cancers, including breast cancer. These mutations result in the activation of the PI3K/AKT/mTOR pathway, leading to increased cell growth and survival.

3. BRAF Mutations: The BRAF gene encodes a protein involved in the MAPK/ERK signaling pathway. Mutations in BRAF, particularly the V600E mutation, are common in melanoma and other cancers1. This mutation leads to the constitutive activation of the BRAF protein, driving cell proliferation and survival.

4. TP53 Mutations: The TP53 gene encodes the p53 tumor suppressor protein, which plays a crucial role in cell cycle regulation and apoptosis. Inherited mutations in TP53 can lead to Li-Fraumeni syndrome, a condition that significantly increases the risk of developing various cancers1. These mutations lead to the downregulation in p53 activity, allowing cells with DNA damage to continue dividing unchecked.

5. RET Proto-Oncogene Mutations: Mutations in the RET gene are associated with multiple endocrine neoplasia type 2 (MEN2), a hereditary cancer syndrome. These mutations lead to the activation of the RET tyrosine kinase receptor, which in turn activates downstream signaling pathways like the RAS/RAF/MEK/ERK pathway, promoting tumorigenesis.

6. KIT Mutations: Mutations in the KIT gene, which encodes a receptor tyrosine kinase, are associated with gastrointestinal stromal tumors (GISTs). These mutations lead to the constitutive activation of the KIT protein, promoting cell proliferation and survival.

7. PTEN Mutations: The PTEN gene encodes a tumor suppressor protein that negatively regulates the PI3K/AKT pathway. Inherited mutations in PTEN can lead to Cowden syndrome, a condition that increases the risk of breast, thyroid, and other cancers. Loss of PTEN function results in uncontrolled activation of the PI3K/AKT pathway.

8. SMAD4 Mutations: The SMAD4 gene is involved in the TGF-β signaling pathway, which regulates cell growth and differentiation. Mutations in SMAD4 are associated with juvenile polyposis syndrome, a condition that increases the risk of colorectal cancer. Loss of SMAD4 function disrupts TGF-β signaling, leading to increased cell proliferation.

9. NF1 Mutations: The NF1 gene encodes neurofibromin, a protein that negatively regulates the RAS/MAPK pathway. Inherited mutations in NF1 can lead to neurofibromatosis type 1, a condition that increases the risk of benign and malignant tumors. Loss of NF1 function results in the continuous activation of the RAS/MAPK pathway.

10. ALK Mutations: The ALK gene encodes a receptor tyrosine kinase that is involved in the regulation of cell growth and differentiation. Inherited mutations in ALK are associated with familial lung cancer. These mutations lead to the constitutive activation of the ALK protein, promoting cell proliferation and survival.

11. RB1 Mutations: The RB1 gene encodes the retinoblastoma protein (pRB), a crucial regulator of the cell cycle. Inherited mutations in RB1 can lead to hereditary retinoblastoma, a type of eye cancer. Loss of pRB function results in the disruption of cell cycle regulation, allowing unchecked cell division.

12. CDKN2A Mutations: The CDKN2A gene encodes two tumor suppressor proteins, p16INK4a and p14ARF, which are involved in cell cycle regulation. Inherited mutations in CDKN2A are associated with familial melanoma. These mutations disrupt the function of p16INK4a and p14ARF, leading to uncontrolled cell proliferation.

13. MET Mutations: The MET gene encodes a receptor tyrosine kinase that is involved in cell growth and differentiation. Inherited mutations in MET are associated with hereditary papillary renal cell carcinoma. These mutations lead to the activation of the MET protein, promoting tumorigenesis.

14. STK11 Mutations: The STK11 gene encodes a serine/threonine kinase involved in regulating cell growth and metabolism. Inherited mutations in STK11 can lead to Peutz-Jeghers syndrome, a condition that increases the risk of gastrointestinal and other cancers. Loss of STK11 function results in dysregulated cell growth.

15. BRCA1 and BRCA2 Mutations: The BRCA1 and BRCA2 genes encode proteins involved in DNA repair. Inherited mutations in these genes significantly increase the risk of breast and ovarian cancers. Loss of BRCA1 or BRCA2 function leads to genomic instability and increased tumorigenesis.

16. APC Mutations: The APC gene encodes a tumor suppressor protein that regulates the Wnt signaling pathway. Inherited mutations in APC lead to familial adenomatous polyposis (FAP), a condition that greatly increases the risk of colorectal cancer. Loss of APC function results in dysregulated cell growth and differentiation.

17. VHL Mutations: The VHL gene encodes a protein involved in the regulation of hypoxia-inducible factors (HIFs). Inherited mutations in VHL lead to von Hippel-Lindau syndrome, a condition that increases the risk of various tumors. Loss of pVHL function results in the accumulation of HIFs and promotes tumorigenesis.

18. MLH1 Mutations: The MLH1 gene is involved in the DNA mismatch repair pathway. Inherited mutations in MLH1 can lead to Lynch syndrome (hereditary nonpolyposis colorectal cancer, or HNPCC), which increases the risk of colorectal and other types of cancer. Loss of MLH1 function results in increased mutation rates and genomic instability.

19. TSC1/TSC2 Mutations: The TSC1 and TSC2 genes encode proteins hamartin and tuberin that form a complex involved in the regulation of the mTOR pathway. Inherited mutations in these genes cause tuberous sclerosis complex, a condition that increases the risk of benign tumors and, occasionally, malignant tumors. Loss of hamartin or tuberin function leads to dysregulated mTOR signaling and abnormal cell growth.

20. WT1 Mutations: The WT1 gene encodes a transcription factor involved in kidney and gonadal development. Inherited mutations in WT1 can lead to Wilms tumor, a type of kidney cancer in children. Loss of WT1 function disrupts normal cell differentiation and proliferation.

Tumor suppressor genes can generally be categorized based on their primary functions in maintaining cellular homeostasis and preventing tumorigenesis. Here are some broad categories for the action of tumor suppressors:

1. Gatekeepers: These tumor suppressors directly regulate the cell cycle and prevent the propagation of damaged cells by inducing cell cycle arrest or apoptosis. Examples include:

   • RB1 (retinoblastoma protein): Regulates the G1/S transition of the cell cycle.

   • TP53 (p53): Induces cell cycle arrest and apoptosis in response to DNA damage.

2. Caretakers: These genes are involved in maintaining genomic stability by repairing DNA damage and preventing mutations. Examples include:

   • BRCA1 and BRCA2: Involved in the repair of double-strand breaks through homologous recombination.

   • MLH1: Part of the DNA mismatch repair pathway.

3. Landscapers: These tumor suppressors regulate the microenvironment around cells to maintain tissue architecture and inhibit tumor invasion and metastasis. Examples include:

   • APC: Regulates the Wnt signaling pathway and is involved in maintaining cell adhesion and suppressing tumor formation in the colon.

4. Metabolic Regulators: These genes help control cellular metabolism and energy homeostasis, preventing abnormal cell growth. Examples include:

   • STK11 (LKB1): Regulates cell growth and metabolism.

5. Signal Transduction Regulators: These tumor suppressors modulate key signaling pathways that control cell growth, differentiation, and survival. Examples include:

   • PTEN: Negatively regulates the PI3K/AKT pathway.

   • NF1: Negatively regulates the RAS/MAPK pathway.