What is the molecular basis of cancer?
Cancer is fundamentally a disease of genes. The molecular basis of cancer involves changes in the DNA sequence of genes that regulate cell growth and division. These changes can lead to the uncontrolled proliferation of cells, which forms the basis of tumor development. The primary molecular changes include mutations, chromosomal rearrangements, and epigenetic modifications.
What are oncogenes and tumor suppressor genes?
Oncogenes are mutated forms of normal genes, called proto-oncogenes, which promote cell growth and division. When these genes are mutated, they can become hyperactive, leading to uncontrolled cell proliferation. Examples include
RAS,
MYC, and
HER2. Tumor suppressor genes, on the other hand, are genes that inhibit cell growth and division. When these genes are inactivated or lost, cells can grow uncontrollably. Prominent examples include
TP53,
RB1, and
BRCA1/2.
How do mutations contribute to cancer?
Mutations can arise from various sources, such as exposure to carcinogens, radiation, or can be inherited. These mutations can activate oncogenes or inactivate tumor suppressor genes. For instance, a point mutation in the
RAS gene can create a protein that is constantly active, promoting continuous cell division. Similarly, a mutation in the
TP53 gene can lead to a defective p53 protein, which normally acts as the "guardian of the genome" and helps repair DNA damage or induce apoptosis in damaged cells.
What role do chromosomal rearrangements play in cancer?
Chromosomal rearrangements, such as translocations, inversions, and deletions, can also contribute to cancer. A well-known example is the
Philadelphia chromosome in chronic myeloid leukemia (CML), resulting from a translocation between chromosomes 9 and 22. This translocation creates a fusion gene,
BCR-ABL, that produces an abnormal protein with tyrosine kinase activity, driving the proliferation of leukemic cells.
What are epigenetic modifications and their role in cancer?
Epigenetic modifications involve changes in gene expression without altering the DNA sequence. These modifications include
DNA methylation,
histone modification, and
non-coding RNA regulation. Aberrant DNA methylation patterns, such as hypermethylation of tumor suppressor gene promoters, can silence these genes, contributing to cancer development. For example, hypermethylation of the
CDKN2A gene promoter can inactivate the p16INK4a protein, leading to uncontrolled cell cycle progression.
How do signaling pathways contribute to cancer?
Cancer cells often have dysregulated signaling pathways that promote growth, survival, and metastasis. Key pathways involved include the
PI3K/AKT/mTOR pathway, the
MAPK/ERK pathway, and the
WNT pathway. Mutations in components of these pathways can lead to their constant activation. For instance, mutations in the
PIK3CA gene, encoding the p110α subunit of PI3K, can lead to hyperactivation of the PI3K/AKT/mTOR pathway, promoting cellular survival and growth.
What are the emerging molecular targets for cancer therapy?
Advances in understanding the molecular basis of cancer have led to the development of targeted therapies. These therapies specifically inhibit the function of mutated proteins or dysregulated pathways in cancer cells. Examples include
tyrosine kinase inhibitors like
imatinib for BCR-ABL in CML,
HER2 inhibitors like trastuzumab for HER2-positive breast cancer, and
immune checkpoint inhibitors targeting
PD-1 or
CTLA-4 in various cancers.
How do cancer cells evade the immune system?
Cancer cells can evade the immune system through various mechanisms. They may downregulate the expression of
antigens, produce immunosuppressive cytokines, or express immune checkpoint proteins like
PD-L1, which bind to PD-1 on T cells and inhibit their activity. Additionally, the tumor microenvironment can be altered to support immune evasion and tumor growth.
Conclusion
Understanding the molecular basis of cancer is crucial for developing effective treatments. Mutations, chromosomal rearrangements, and epigenetic modifications play significant roles in cancer development and progression. Advances in molecular biology have led to targeted therapies that inhibit specific molecular abnormalities, offering hope for more effective and personalized cancer treatments in the future.
