Cellular Pathology V Molecular Genetics

1. Cellular Pathology V • Molecular Genetics

2. There are lots of social controls (adhesion signals, cytokines) on cells and tissues needed for growth and survival. • The normal mutational load that occurs is handled by limiting the number of divisions in germ cells (normally there’s a quite high rate of mutation) and innate resistance mechanisms to tumorigenesis. Most malignancy requires multiple mutations.

3. Over generations subclones may accumulate mutations and compete. Those with a reproductive or survival advantage can dominate over time. • Initial mutations often don’t do much, but as they accumulate the effects can be big, especially when a mutation increases the rate of subsequent mutations.

4. Clonal selection theory: • neoplasia requires multiple steps. Some mutations lead to a selective advantage, and clonal changes reflect the key selected events. • So tumors are homogeneous for early changes, but may be heterogeneous for later changes

5. Types of mutations include oncogenes (gain of function, usually dominant), tumor suppressor genes (loss of function, usually recessive), genome maintenance genes (loss of function, usually recessive), and genes that affect telomeres.

6. There are also lots of passenger mutations, which are very common and don’t have an effect on the neoplasm. • They may predate the neoplastic changes and make identifying causal genes difficult

7. To test if a cancer is caused by an oncogene or tumor suppressor, fuse a neoplastic cell with a normal cell. • If oncogenic, the result will be neoplastic. • If tumor suppressor, it’ll be normal.

8. Mutation types include translocation, amplification (creates double minutes of extra DNA representing the amplified region), point mutations, and deletions. • Telomeres are shorter than normal in neoplasia, but they survive. • So the senescence mechanism is somehow turned off.

9. When two chromosomes fuse, you can get multiple centromeres that result in abnormal mitoses and breaks in chromosomes or changes in chromosomal number. • To find oncogenes, they added transforming DNA to cells, implanted them in mice and got tumors. • So, the mutated genes must have been oncogenes.

10. Oncogene functions include growth factor receptors, signal transduction mutations, changes in nuclear oncoproteins that affect gene expression, anti-apoptotic factors and tumor-suppressor antagonists.

11. Tumor suppressor gene functions include adhesion molecules, cytoskeletal components, signal transduction or cell cycle regulators, apoptotic factors, and chromatin structural molecules.

12. Many viral proteins inhibit the same regulatory proteins to promote replication, in an example of convergent evolution. • You may have cascades of tumor suppressor and oncogene products that inhibit influence one another.

13. Dominant oncogenes are rarely inherited since they usually result in developmental defects. Genome maintenance genes are commonly inherited, as are tumor suppressor genes.

14. Syndromes resulting from inheritance of one mutant copy of a tumor suppressor gene show autosomal dominant pedigree patterns, though their histology looks recessive with only a few neoplastic cells.

15. Syndromes like this include retinoblastoma, Li-Fraumeni syndrome, Adenomatous polyposis coli, von Hippel-Lindau, and neurofibromatosis.

16. Syndromes resulting from defective genome maintenance genes include xeroderma pigmentosa (need to be homozygous), HNPCC-Lynch syndrome (shows up if heterozygous), and for one mutation fanconi anemia (homozygous) or breast/ovary/pancreatic cancer (heterozygous).

17. Rational therapy for cancer may seek to kill cells based on a cancer-cell specific biochemistry, or alter gene function/expression or immune response to a specific target. • Mutation based drug resistance can occur, in which changes alter the drug binding pocket so the drug no longer works