Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma

Toguchida, Junya; Ishizaki, Kanji; Sasaki, Masao S.; Nakamura, Yusuke; Ikenaga, Mituo; Kato, Mitsuo; Sugimot, Masayuki; Kotoura, Yoshihiko; Yamamuro, Takao

doi:10.1038/338156a0

Cited by 197 publications

(70 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This observation is different from the example of genome imprinting that has been seen in several types ofhuman pediatric tumors. A tumor-suppressor gene, the Wilms tumor gene, was inactivated exclusively in the father during spermatogenesis (17)(18)(19)(20). In the present study, the Ki-ras allele of the A/J mouse was activated to an Proc.…”

Section: Discussionmentioning

confidence: 99%

Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids.

You

Wang

Stoner

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A mouse strain with low lung tumor susceptibility (C3H) and a strain with high lung tumor susceptibilit (A/J) were reciprocally crossed to produce C3A and AC3 F1 hybrid mice. Ki-ras oncogenes were detected in spontaneous and chemically induced lung tumors obtained from the C3Aand AC3 mice. To further explore the genetics of the Ki-ras gene in mouse lung tumor susceptibility, the parental origin of Ki-ras oncogenes detected in lung tumors from the F1 hybrids was determined by a strategy based on a 37-base-pair deletion in the second intron of the A/J Ki-ras allele. (ii) Spontaneously occurring and chemically induced lung tumors from the A/J mouse were found to have a high frequency (88-100%o) of activated Ki-ras protooncogenes (7, 8). Ki-ras oncogenes have also been detected in spontaneous and chemically induced lung tumors from C3H mice; the tumors induced in C3H mice after repeated carcinogen administration, however, were smaller in size at the time of sacrifice, the tumor multiplicity was lower, and the latency period for tumor development was much longer than in the sensitive A/J mice (9). These data suggest that spontaneous and chemically induced lung tumors from the C3H x A/J (C3A) and A/J x C3H (AC3) F1 hybrids should contain Ki-ras oncogenes. To further understand the genetics of the Ki-ras gene in mouse lung tumor susceptibility, we examined the parental origin of the activated Ki-ras protooncogenes detected in lung tumors from C3A and AC3 hybrid mice.MATERIALS AND METHODS Lung Tumor Induction. The C3H/HeJ and A/J parents of the C3A and AC3 F1 hybrids originated from mice purchased from The Jackson Laboratory. Spontaneous lung tumors were collected from untreated 2-year-old C3A mice. Six-to 8-week-old C3A or AC3 mice were given i.p. injections of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK, 50 mg/kg), dissolved in phosphate-buffered saline, three times per week for 8 weeks. Controls were given i.p. injections of saline solution. Vinyl carbamate (VC) was administered to 7-week-old C3A or AC3 mice in a single injection (either 60 or 20 mg/kg). Tumors were harvested from chemically treated animals between 6 and 14 months of age. This time frame oftumor collection enabled us to obtain both adenomas and adenocarcinomas. Lung tumors were collected, frozen in liquid nitrogen, and then stored at -80°C. Before freezing, a representative portion of each tumor was fixed in neutral buffered 10%o formalin for histopathological examination.Polymerase Chain Reaction (PCR). The primer-directed enzymatic amplification of specific Ki-ras DNA sequences was carried out as described (10) with Taq DNA polymerase. Reactions were carried out in a 100-,l mixture that contained 2 ,ug of DNA, 50 mM KCl, 10 mM Tris (pH 8.4), 2.5 mM MgCl2, 200 ,uM dNTPs, gelatin at 200 ,ug/ml, 2 units of Taq DNA polymerase (Perkin-Elmer/Cetus), and two primers. Samples were subjected to 25 cycles of amplification in a thermal cycler (DNA denaturation at 94°C for 1 min, primer annealing at 45°C for 2 min, and extension at 72°C for 2 ...

show abstract

Section: Discussionmentioning

confidence: 99%

Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids.

You

Wang

Stoner

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The retinoblastoma tumor suppressor gene (RB1) is inactivated in 20% to 40% of sporadic osteosarcomas and is linked to poor disease outcome (2). RB1 was first identified as the gene mutated in human retinoblastoma (3).…”

Section: Introductionmentioning

confidence: 99%

Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation

Kansara¹,

Leong²,

Lin³

et al. 2013

J. Clin. Invest.

View full text Add to dashboard Cite

Ionizing radiation (IR) and germline mutations in the retinoblastoma tumor suppressor gene (RB1) are the strongest risk factors for developing osteosarcoma. Recapitulating the human predisposition, we found that Rb1 +/-mice exhibited accelerated development of IR-induced osteosarcoma, with a latency of 39 weeks. Initial exposure of osteoblasts to carcinogenic doses of IR in vitro and in vivo induced RB1-dependent senescence and the expression of a panel of proteins known as senescence-associated secretory phenotype (SASP), dominated by IL-6. RB1 expression closely correlated with that of the SASP cassette in human osteosarcomas, and low expression of both RB1 and the SASP genes was associated with poor prognosis. In vivo, IL-6 was required for IR-induced senescence, which elicited NKT cell infiltration and a host inflammatory response. Mice lacking IL-6 or NKT cells had accelerated development of IR-induced osteosarcomas. These data elucidate an important link between senescence, which is a cell-autonomous tumor suppressor response, and the activation of host-dependent cancer immunosurveillance. Our findings indicate that overcoming the immune response to senescence is a rate-limiting step in the formation of IR-induced osteosarcoma.

show abstract

“…One such region is the 17p12-17p13.3 area, which has shown frequent losses of heterozygosity in glioma, colon carcinoma, small cell lung carcinoma, breast carcinoma, and osteosarcoma (12)(13)(14)(15)(16). The gene for p53, a protein that has been implicated in tumorigenesis in mice and transformation in vitro (reviewed in ref.…”

mentioning

confidence: 99%

Mechanisms of p53 loss in human sarcomas.

Mulligan

Matlashewski

Scrable

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

227

101

View full text Add to dashboard Cite

An important role for the p53 gene in neoplastic transformation in vitro and in vivo has been imputed by functional studies and identification of tumor-acquired gene defects or alterations in its expression. To study the generality and mechanisms of p53 alteration in human cancer, we examined 241 tumors of several ypes for structural aberrations of the locus. Alterations ofthe gene or its RNA or protein products consistent with loss of function by either recessive or dominant mechanisms were identified among this set uniquely in rhabdomyosarcomas and osteosarcomas. The alterations of p53 in rhabdomyosarcoma tumors included cases with complete deletion of both p53 alleles, complete deletions of one allele with or without point mutation of the remaining allele, and absence ofdetectable RNA. Similarly, we detected homozygous deletion and lack of expression of p53 RNA or aberrant expression of p53 protein in osteosarcomas. These observations provide strong support for the inclusion of the p53 locus in the group of loci whose functional inactivation by either dominant or recessive modes plays a significant role in human cancer.

show abstract

Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma

Cited by 197 publications

References 22 publications

Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids.

Parental bias of Ki-ras oncogenes detected in lung tumors from mouse hybrids.

Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation

Mechanisms of p53 loss in human sarcomas.

Contact Info

Product

Resources

About