Carcinogenes is is the process by which cancer develops. By the time the cancer has been detected, it contains billions of cells, often including many normal cells like fibroblasts in the supporting connective tissue associated with the carcinoma. These normal connective cells of a tumor (neoplastic mass) are sometimes referred to as the stroma whereas the neoplastic cells of the tumor are called the parenchyma. However, There is evidence that cancers originate from a single abnormal cell. While most malignant tumors are monoclonal in origin, this does not mean that a singe mutation is by itself enough to . In fact, evidence indicates the the genesis of a cancer typically requires several independent rare accidents that occur in the lineage of one cell.
Cancers seem to arise by a process in which an initial population of slightly abnormal cells which are descendants of a single mutant ancestor, evolve from bad to worse through successive cycles of mutation. Such evidence comes from epidemiological studies of the incidence of cancer as a function of age. If a single mutation were responsible, occurring with a fixed probability per year, the chance of developing cancer in any given year should be independent of age. In fact, for most types of cancer the incidence rises steeply with age as would be expected if cancer is caused by a slow accumulation of numerous random mutations in a single line of cells.
Animal models also confirm that a single genetic alteration is insufficient to cause cancer but rather that multiple mutations are required in many genes (perhaps ten or more). For those cancers that have a discernible external cause, cancer also does not usually become apparent until long after exposure to the causal agent. The incidence of lung cancer, for example, does not begin to rise steeply until 1-2- after heavy smoking. The incidence of luekemias from radiation similarly do not show a marked rise until about 5 years after exposure.
Other factors which are important for the development of cancer cells and how they evade host immune response are covered in a separate disease mechanisms section (see right hand panel).
Cancer Mutations
All cancers are believed to be due to mutations. (Albitar, US 10,227,657)
Myeloid differentiation primary response gene 88 (MYD88): has significant therapeutic and diagnostic value in a range of cancer types, including Waldenstrom’s Macroglobulinemia (WM), diffuse alrge B-cell lymphoma (DLBCL), monoclonal gammopathy of unknown significance (MGUS), and spenic marginal zone lymphoma (SMZL). MYD88 is an adaptor molecule in a TLR and interleukin-1 receptor signaling pathway. Mutation in MYD88 results in over-activation of Toll-interleukin-receptor pathways, subsequent phosphorylation of IRAK1/4, and release of nuclear factor factor kappa B (NF-kB) drive cell survival and proliferation. It has been demonstrated in DLBCL and WM that inbhibition of MYD88 signaling resutls in decreased NF-kB activity and reduced cell survival. (Albitar, US 10,227,657)5P positive cells. However, inherent limtiations in this methodology prohibit AS-PCR from detecting variants other than those previously described or specifically designed for this purpose. Wild-type blocking PCR (WTB-PCR) using locked nucleic acid (LNA) has demonstrated high sensitivity and versatility in the detection of low percentage mutant populations. By adding an LNA oligo (10-12NT), complementary to the region of the hotspot, amplifcaiton of the WT allele is inhibited, leading to experimentally driven positive selection for mutant alleltes. This is accomplished by designing the LnA oligo so that it anneals to the template strand during the primer annealing step of PCR and melts form mutant template DNA, but not WT DNA, during extension. Becasue a single nucleotide mistmatch in the LnA-DNA hybrid greatly decreases its melting temeprature, only mutant template DNA is free to complete its extension. Albitar, US 10,227,657)
Most mutations in MYD88 occur at condom L265, converting leucine to proline; however, mutations at M232, P258, L103 and Q143 have also beenr eported. Allele-specific polymerase chain reaction (PCR) based assay have been developed for MYD88 L265P and dmonstrated the ability to detect minute fractions of L26