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Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia

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Biologically-Based Risk Estimation for Radiation-Induced Chronic Myeloid Leukemia

Radiation Carcinogenesis: Applying Basic Science to Epidemiological Estimates of Low-Dose Risks

- Bayesian methods and CML
- Linear-Quadratic-Exponential model
- Likelihood and prior data sets
- Baseline LQE estimate of CML risk
- Improved risk estimates based on BCR-to-ABL distances and CML target cell numbers
- Net lifetime CML risk: Can it have a U-shaped low dose response?

- Priors+ likelihood estimates posteriors
- Posterior information equals prior plus likelihood information
- Posterior means are information-weighted averages of prior and likelihood means
- Posteriors are normal if the prior and likelihood estimates are normal
- Priors act as soft constraints on the parameters
- Priors and structures come from the same data

- CML is homogeneous, prevalent, radiation-induced, and caused by BCR-ABL
- The a2 intron of ABL is unusually large
- Leukemic endpoints have rapid kinetics
- White blood cells need fewer stages
- Linear CML risk is not biologically-based
- Linear-quadratic-exponential CML risk does have a biological basis

Using the BCR-ABL to CML

waiting time density

and the linear model

we maximized

the log-likelihood

The LQE model is

where

Di and Dni are the gamma and neutron doses in gray

N is the number of CML target cells per adult

P(ba|T)is the probability of BCR-ABL given a translocation

This is a one-stage model of carcinogenesis.

- CML is practically absent in Nagasaki
- High dose HF waiting times are too long
- HM data is consistent with prior expectations

aage at diagnosis

bO = observed cases (E = expected background cases based on U.S. incidence rates)

ctsx = average of the times since exposure for the cases

- C1 and k: SEER data
- kt : Patients irradiated for BGD
- k, k and kn : CAFC and MRA assays
- / and n/: Lymphocyte dicentric yields
- C2 : Depends on , kt, N, and P(ba|T)
- N: SEER and translocation age structure data
- P(ba|T): BCR and ABL intron sizes, the genome size

- Linear model
- R = 0.0075 Gy-1 and Q = 0.0158 Gy-1

- LQE posterior model
- R = 0.0022 Gy-1 and Q = 0.0042 Gy-1

The lifetime excess CML risk in the limit of low -ray doses

yields

- A comparison of age responses for CML and total translocations suggests a CML target cell number of 2x108
- 1012 nucleated marrow cells per adult and one LTC-IC per 105 marrow cells suggests 107 CML target cells
- P(ba|T) = 2TablTbcr/2 may not hold

BCR-to-ABL 2D distances in lymphocytes

Kozubek et al. (1999) Chromosoma 108: 426-435

- P(ba|D)= probability of a BCR-ABL translocation per G0/G1 cell given a dose D
- tD(r)dr = expected energy at r given an ionization event at the origin
- = intra-track component + inter-track component
- Sba(r) = the BCR-to-ABL distance probability density
- g(r) = probability that two DSBs misrejoin if they are created r units apart
- Y = 0.0058 DSBs per Mb per Gy; = mass density
- TBCR = 5.8 kbp; TABL = 300 kbp

din [.01, .025], dx in [.04, .05], d in [.05, .06]

G=35 DSB/Gy per cell

6.25 kev/um3 = 1 Gy

R = 3.7 um r0 = 0.24 m, p0 = 0.06

- Transplant doses of 10, 100, and 1000 CRU => CRU levels 1-20% or 15-60% normal Blood (1996) 88: 2852-2858
- Broad variation in human HSC levels Stem Cells (1995) 13: 512-516
- Low levels of HSCs in BMT patients Blood (1998) 91: 1959-1965

Figure 3: Hypersensitivity ratios in the literature (left panel) and the log-survival dose response for T98G human glioma cells (right panel). Figures from Joiner, M.C., Marples, B., Lambin, P., Short, S.C. and Turesson, I., Low-dose hypersensitivity: current status and possible mechanisms. Int J Radiat Oncol Biol Phys (2001) 49: 379-389.

The net lifetime excess risk of CML is

Letting Dn = 0 while D 0

We solved R0 = 0 for ks as a function of exposure age x.

- Bayesian methods provide a natural framework for biologically based risk estimation
- BCR-to-ABL distance data and knowledge of CML target cell numbers can be useful in a biologically based approach to CML risk estimation
- Low dose hypersensitivity to killing might lead to a U-shaped low dose response if there is a dead-band in the control of target cell numbers

- Rainer Sachs
- David Hoel
- NIH and DOE