Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in alpha-particle irradiated mice

Abstract

Osteosarcoma is the most frequent secondary malignancy following radiotherapy of patients with bilateral retinoblastoma. This suggests that the Rb1 tumour suppressor gene might confer genetic susceptibility towards radiation-induced osteosarcoma. To define the contribution of the Rb1 pathway in the multistep process of radiation carcinogenesis, we evaluated somatic allelic changes affecting the Rb1 gene itself as well as its upstream regulator p16 in murine osteosarcoma induced by (227)Th incorporation. To distinguish between the contribution of germline predisposition and the effect of a 2-hit allelic loss, two mouse models harbouring heterozygote germline Rb1 and p16 defects were tested for the incidence and latency of osteosarcoma following irradiation. We could show that all tumours arising in BALB/c×CBA/CA hybrid mice (wild-type for Rb1 and for p16) carried a somatic allelic loss of either the Rb1 gene (76.5%) or the p16 gene (59%). In none of the tumours, we found concordant retention of heterozygosity at both loci. Heterozygote knock-out mice for Rb1 exhibit a significant increase in the incidence of osteosarcoma following (227)Th incorporation (11/24 [corrected] in Rb1+/- vs. 2/18 in Rb1+/+, p=4×10(-5)), without affecting tumour latency. In contrast, heterozygote knock-out mice for p16 had no significant change in tumour incidence, but a pronounced reduction of latency (LT(50%) =355 days in p16+/- vs. 445 days in p16+/+, p=8×10(-3)). These data suggest that Rb1 germline defects influence early steps of radiation osteosarcomagenesis, whereas alterations in p16 mainly affect later stages of tumour promotion and growth.

Rb1 Haploinsufficiency Promotes Telomere Attrition and Radiation-Induced Genomic Instability

“…The increase in sensitivity to radiation-induced osteosarcoma is reiterated in a mouse model upon conditional inactivation of the Rb1 gene in the osteoblastic lineage (6). We now show that loss of only one Rb1 allele in nontransformed primary osteoblast cell cultures is accompanied by a number of hallmarks of genomic instability.…”

“…This sequence of events is consistent with the existence of a mutator phenotype originally proposed by Loeb (28) to explain the appearance of mutations in tumor cells at a rate above that predicted from the sporadic mutation rate alone. The duality of action (cell cycle and telomere length) that we ascribe to Rb1 can explain the increases susceptibility to both sporadic and radiation-induced osteosarcoma that is associated with retinoblastoma gene mutations (4,6). This may also give an explanation for the high levels of chromosomal rearrangements that is frequently observed in osteosarcoma, and more recently in retinoma before the loss of the second RB1 allele (12).…”

“…Germline mutation of the RB1 tumor suppressor gene increases sensitivity to both sporadic and radiation-induced osteosarcoma (5)(6)(7). A study of the genetic determinants that predispose inbred mouse strains to radiation-induced osteosarcoma after injection of bone-seeking 227 Th revealed a major modifying gene mapping to the Rb1 locus (8).…”

“…Analysis of the increased susceptibility to radiation that is associated with Rb1 is hindered by the high sporadic rate of cancer in animals engineered to lack one copy of Rb1 in the germline (9). However, the increased sensitivity to radiation could be reiterated in mice that had been rendered Rb1 haploinsufficient through the conditional deletion of one Rb1 allele in the osteoblastic lineage (6).…”

Prostatic Tissue Levels of 43 Trace Elements in Patients with Prostate Adenocarcinoma

“…On the other hand, findings of this study documented fact that the adenocarcinoma of human prostate accumulates high levels of many trace elements including Al, B, Be, Bi, Cr, Fe, Hg, Ni, Sn, Th, and Zr. Genotoxicity and carcinogenicity of these elements are well known (Anghileri et al, 2000;Gordon & Bowser, 2003;Crespo-López et al, 2009;Bian et al, 2011;Gonzalez-Vasconcellos et al, 2011;Müezzinoğlu et al, 2011;Sappino et al, 2012;Helmig et al, 2013;Adámik et al, 2015;Farasani & Darbre, 2015). On the other hand, compared to human body soft tissues, the normal prostate of young adults has higher levels of many trace elements, including Zn (V. Zaichick & S. Zaichick, 2013, 2013a, 2013b, 2013c, 2014d.…”