Carcinogenesis: Activation of growth promoting oncogenes

1. Mutations may cause

   1. changes in structure of gene—resulting in synthesis of abnormal protein

      1. cannot do normal function

   2. changes in regulation of a normal protein

      1. enhanced/inappropriate production of structurally normal growth promoting protein

2. Point mutations

   1. ras

      1. mutations affect domain critical to GAP-induced hydrolysis of GTP

      2. mutant ras proteins have  ability to hydrolyze GTP

      3. result: cell stimulated to proliferate

         1. stimulated to continue from G1 to S phase

      4. common in pancreatic, COLON, and thyroid cancers

3. Chromosomal translocations

   1. result

      1. over-expression of protooncogene

      2. gene may undergo structural changes

   2. Burkitt’s lymphoma

      1. all tumors have 1/3 translocations each involving 8:14

      2. most common:

         1. c-myc (norm location #8) translocated to #14 band 32

         2. placed adjacent to heavy chain Ig gene that has high transcriptional activity

         3. result: over-expression of c-myc

   3. Follicular B-cell lymphoma

      1. bcl-2 gene involved

      2. moved from normal location (8q21) to #14 near Ig heavy chain gene

         1. results in over-expression (same mechanism as above)

   4. Philadelphia chromosome

      1. illustrates genetic damage due to translocation

      2. involves 9:22 translocation to produce bcr-c-abl gene

4. Gene amplification

   1. caused by reduplication and manifold amplification

   2. may produce several hundred copies of protooncogene in tumor cell

   3. ex.

      1. N-myc in neuroblastoma

      2. c-erb B2 in breast cancer

      3. both associated with poor prognosis

Category: Pathology Notes