Genetic and Epigenetic Alterations in Cancer
Summary of Key Points
• A root cause of cancer is the accumulation of genetic and epigenetic defects in key cellular pathways regulating proliferation, differentiation, and death. The defects in cancer cells are of two types: gain-of-function alterations affecting oncogenes and loss-of-function alterations affecting tumor suppressor genes. Regardless of whether the defects are genetic or epigenetic in nature, a common net consequence is dysregulation of gene expression in cancer cells.
• Clinical and pathological studies indicate that many cancers arise from preexisting benign lesions, and numerous cooperating genetic and epigenetic defects affecting multiple independent signaling pathways are likely needed for development of most clinically recognizable cancers.
• A process termed clonal selection has a key role in determining the particular constellation of genetic and epigenetic defects present in a cancer cell. Clonal selection is essentially an evolutionary process that promotes outgrowth of precancerous and cancerous cells carrying those mutations and gene expression changes that confer the most potent proliferative and survival properties upon the cancer cells in a given context.
• Although a sizeable and diverse array of mutations and gene expression changes have been implicated in cancer pathogenesis, the defects appear to affect a more limited number of conserved signaling pathways or networks. A relatively small collection of oncogenes and tumor suppressor genes is recurrently deranged in cancer cells of various types and includes the RAS, PIK3CA, EGFR, RAF, β-catenin, and MYC oncogene proteins and the p53, p16Ink4a, ARF, RB1, PTEN, APC, and NF1 tumor suppressor proteins. The proteins that are recurrently targeted by mutations in cancer likely represent particularly critical hubs in the cell’s regulatory circuitry.
• Although cancer represents a very heterogeneous collection of diseases, the development of all cancers, regardless of type, appears to be critically dependent on the acquisition of certain traits that allow the cancer cells to grow in an unchecked fashion in their tissue of origin and to grow as metastatic lesions in distant sites in the body. Signature traits that are likely to be inherent in the majority, if not all, cancers include the following: (1) an increased tendency to manifest a stem cell or progenitor-like phenotype; (2) an enhanced response to growth-promoting signals; (3) a relative resistance to growth inhibitory cues; (4) an increased mutation rate to allow for the rapid generation of new variant daughter cells; (5) the ability to attract and support a new blood supply (angiogenesis); (6) the capacity to minimize an immune response and/or evade destruction by immune effector cells; (7) the capacity for essentially limitless cell division; (8) a failure to respect tissue boundaries, allowing for invasion into adjacent tissues and organs, as well as blood vessels and lymphatics; and (9) the ability to grow in organ sites with microenvironments that are markedly different from the one where the cancer cells arose.
• Certain gene defects in cancer cells may contribute to a few or perhaps even only one of the signature traits. However, many of the gene defects and expression changes might have been selected for in large part because they exert pleiotropic effects on the cancer cell phenotype.
• Despite the fact that some gene defects may arise early in the development of certain cancer types, advanced cancer cells might still be critically dependent on the “early gene defects” for continued growth and survival. Such findings imply that agents that specifically target key signaling pathways and proteins could have utility in advanced cancers even if the signaling pathway defect arose very early in cancer development.
• Future studies will further clarify the role of the diverse array of genetic and epigenetic defects in cancer phenotypes, allowing more definitive and more specific strategies for cancer detection and diagnosis and therapeutic targeting of cancer cells.
• Genomic characterization of organ site cancer—breast cancer, for example—identifies a number of subtypes with different prognoses and therapeutic relevance.
1. Which of the following represent mechanisms of oncogene mutational activation in human cancer?
A Gene amplification of the HER2 gene in breast cancer
B Chromosomal translocations, such as those involving the immunoglobulin heavy chain gene and the c-MYC gene in Burkitt lymphoma
C Nonsense and frameshift mutations that lead to premature truncation of protein synthesis together with mRNA instability for the PTEN gene in prostate cancer
D Point mutation at codon 12 of the KRAS gene that interferes with the ability of KRAS to hydrolyze guanosine triphosphate in pancreatic cancer
2. Which of the following statements is true?
A Proteins functioning in the pRb (RB1) and p53 tumor suppressor pathways are frequently targeted by somatic mutations in human cancer. The pathway alterations include mutations inactivating the pRb and p53 tumor suppressor proteins, as well as oncogene alterations, such as somatic mutations leading to increased cyclin D1 or CDK4 expression and/or function, and even other tumor suppressor alterations, such as those affecting the p16INK4a or ARF proteins.
B The adenomatous polyposis coli (APC) tumor suppressor protein functions in the so-called Hedgehog tumor suppressor pathway, as a secreted antagonist for Hedgehog ligands.
C In families affected by the BRCA1, BRCA2, or hereditary nonpolyposis cancer (HNPCC) syndromes, cancer development occurs in essentially all gene mutation carriers by age 35 to 40 years.
D The inherited genetic basis of colon and other cancers in patients affected by HNPCC syndromes and that also links the inherited HNPCC cases to about 10% to 12% of apparently sporadic colorectal cancers are gain-of-function mutations in histone modifiers, particularly the histone lysine methyltransferases.
3. Which of the following does not describe a potential direct contribution of a specific gene defects to the epigenetic changes seen in cancer?
A Isocitrate dehydrogenase 1 (IDH1) mutations in glioblastoma and the DNA hypermethylation phenotypes observed
B Inactivation of the BRG1 chromatin remodeling protein in lung cancer and gene expression patterns reflecting an undifferentiated state in the cancer cells
C Activation of the BCL2 mitochondrial antiapoptotic factor by translocation in follicular lymphoma (FL) and the epigenetic inactivation of the pRb and p16Ink4a tumor suppressors seen in subsets of FL cases
D Inactivation of the TET2 methylcytosine dioxygenase protein in acute myeloid leukemia and the DNA hypermethylation phenotypes observed
1. Answer: C. The PTEN gene is a tumor suppressor gene affected by loss-of-function mutations in human cancer. Nonsense and frameshift mutations lead to abrogation of full-length functional PTEN protein and premature truncation codings in messenger RNAs (mRNAs) that encode proteins, often leading to nonsense-mediated degradation effects on the mutant mRNAs. The other three answers represent mutational activation of oncogenes in representative human cancers.
2. Answer: A. The description of some of the factors and mechanisms that can disrupt the function of the pRb and p53 tumor suppressor pathways is accurate. The other three answers are not true. Among other functions, the APC tumor suppressor functions in the cytoplasm and perhaps the nucleus to regulate the levels of β-catenin in the canonical Wnt signaling pathway. Germline mutations in the BRCA1, BRCA2, and MSH2/MLH1/MSH6 genes strongly predisposes to cancer, but the lifetime risk of cancer is well less than 100% and the age at onset is variable, often arising in the sixth or seventh decade of life. The HNPCC syndromes arise as a result of inactivating mutations in one allele of a mismatch repair gene (e.g., MSH2, MLH1, and MSH6) and about 10% to 12% of apparently sporadic colorectal cancers have somatic gene silencing of the MLH1 gene, due perhaps in part to hypermethylation of the DNA sequences in the promoter region of the MLH1 gene.
3. Answer: C. The BCL2 protein is believed to function in the mitochondria as an antiapoptotic factor, and there is no obvious basis for a direct link of BCL2 function to epigenetic silencing of pRb and p16Ink4a. The other three answers describe potential direct connections between specific gene defects and epigenetic changes in cancer.
