III. [ Mathematical Models of Clonal Disease ]
Developing biologically based mathematical models of clonal diseases for analyses of historical age-specific mortality data for cohorts defined
by gender and general ethnicity.
This section contains PDF copies of our several papers attemting to model age-specific cancer mortality risk complete with all their warts and worse blemishes. We include PDF copies of the seminal works of Nordling, Armitage and Doll and Moolgavkar upon which foundation our models are constructed.
The page features the current effort of Mr. Lohith Kini an MIT graduate student in Computer Science and Engineering working with Profs. W.G.Thilly (MIT), Stephan Morgenthaler and Dr. Pablo Herrero-Jimenez
to update the model to account for the discoveries (in lung) that:
- mutations found in adult tissue appear to have occurred in stem cells a limited part of
the fetal-juvenile period and not as widely believed in adult tissues
- mutation rates (lung) in the fetal-juvenile period distribute almost rectangularly such that
the gene-inactivation rate of the upper and lower deciles vary by approximately 7.5 fold.
Key observations to date are:
- that the high and declining rates of cancer deaths in years 0-4 can be accounted
by deaths occurring in the first year arising from tumor initiation and promotion events of several
the earliest metakaryotic mutator stem cells in proto-organs whereas deaths in later pediatric years
can be accounted as tumors in which promotion occurred in postnatal initiated stem cells.
- the marked deceleration of cancer mortality rates between the age interval 15-19 and 20-24 may be
accounted for deaths up to maturity arising from a large number of independent pathways of initation and promotion that
give rise to a first neoplastic stem cell before physical maturity.
- subsequent deaths (>20 yrs) arise primarily from a set of initiation/promotion events in
which genetic and/or environmental factors lead to slow but inexorable growth and oncomutation of preneoplastic stem cells
that leads to a first subsequently lethal neoplastic stem cell.
- the maximum and subsequent decline in age-specific cancer death rates after
correction for coincident forms of death can be accounted simply by the earlier deaths of persons with
the higher fetal-juvenile mutation rates
Other stratification factors may also contribute but the variation among adult lungs
analyzed suggests that the distribution of fetal-juvenile mutation rates is sufficient to account for the
observed maxima and decline for most tumor sites.
