Li-Fraumeni syndrome – a molecular and clinical review

Varley, Jennifer; Evans, D. Gareth; Birch, Jillian M

doi:10.1038/bjc.1997.328

Cited by 318 publications

(202 citation statements)

References 99 publications

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“…Thereafter, we use the general term Li-Fraumeni (LF) to include both LFS and LFL strains. Skin biopsies were obtained with informed consent from cancer-affected patients and their blood relatives of LF families documented previously (Varley et al, 1997a and b and references in Table 1) and from normal control individuals including one spouse (strain 22MA) from LFS family 83 (Table 2A). The biopsies were chopped into fragments approximately 1 mm3 and allowed to attach to the surface of a plastic Petri dish or T30 flask (Costar) for 15 min before addition of minimal essential medium with Earles' salts and 15% fetal calf serum (Gibco) (LF medium), which was renewed twice weekly.…”

Section: Materials and Methods Establishment Of Culturesmentioning

confidence: 99%

Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Boyle

Mitchell²,

Greaves³

et al. 1998

Br J Cancer

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Summary Previous work has indicated a role for p53 in cell cycle control, genomic stability and cellular responses to DNA-damaging agents.However, few data are available for human fibroblasts heterozygous for defined germline mutations in TP53. We report studies on 25 strains derived from 12 families with Li-Fraumeni syndrome (LFS) and 18 strains from normal volunteers. The families include three that are classical LFS families, but in whom no TP53 mutation has been found. In the families with mutations, increased longevity and resistance to low-doserate ionizing radiation showed a statistically significant association with the presence of TP53 mutations. However, not all heterozygotes had increased longevity or were radioresistant, and fibroblasts from cancer-affected members of LFS families without TP53 mutations showed no significant increase in either of these end points. In contrast, all mutation-carrying strains showed evidence of genomic instability, expressed as aneuploidy, and accumulated structural chromosome aberrations in up to 100% of cells, usually accompanied by loss of the wild-type TP53 allele, immediately before senescence. Levels of aneuploidy higher than in normal cells were also observed in fibroblasts from families without TP53 mutations, suggesting that chromosome instability is a major factor in determining the cancer proneness of these families.

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Section: Materials and Methods Establishment Of Culturesmentioning

confidence: 99%

Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Boyle

Mitchell²,

Greaves³

et al. 1998

Br J Cancer

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“…20 For mouse strains, there is no apparent correlation between susceptibility to carcinogenesis in different organs, suggesting that genetic susceptibility and resistance to cancer are organ-and tissue-specific. 21 On the other hand, our results suggest that some loci provide genetic resistance to cancer of different organs (lung, skin) and of different histotypes.…”

Section: Skin and Lung Cancer Modifiersmentioning

confidence: 99%

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

Saran

Zaffaroni

Pazzaglia

et al. 2001

Intl Journal of Cancer

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The Car-R outbred mouse line was phenotypically selected for high resistance to two-stage skin tumorigenesis. In the present study we tested the hypothesis that a subset of genetic loci responsible for resistance to skin tumorigenesis of Car-R mice might also inhibit lung tumorigenesis. Skin and lung tumorigenesis were induced in groups of Car-R, SWR/J, (SWR/JxCar-R)F1 and SWR/Jx(SWR/JxCar-R) backcross mice by i.p. urethane initiation and skin TPA promotion. Car-R mice showed a much lower susceptibility to both skin and lung tumorigenesis as compared to SWR/J mice, which are susceptible to both lung and skin tumorigenesis. The Car-R-inherited genome significantly inhibited both skin and lung cancer development in the F1 progeny of Car-R with SWR/J mice. In the backcross population, skin and lung tumor phenotypes showed a statistically significant correlation, indicating that a subset of the cancer resistance alleles, which segregated in the Car-R line during selection for resistance to skin carcinogenesis, provides resistance to both skin and lung tumorigenesis. © 2002 Wiley-Liss, Inc. Key words: cancer modifiers; genetic susceptibility; inherited predisposition; Kras2 linkage disequilibrium; lung neoplasm; Pthlh Non-inbred carcinogenesis-resistant (Car-R) and carcinogensusceptible (Car-S) mouse lines were generated by phenotypic selection for resistance and susceptibility, respectively, to 2-stage skin carcinogenesis, starting from a cross of 8 inbred strains (A, BALB/c, C57BL/6, CBA, DBA/2, P, SJL and SWR). 1,2 The Car mice interline difference in susceptibility is Ͼ100-fold. 3 Tumor susceptibility and resistance in the Car lines were initially considered skin tissue-specific, because there was no interline difference in sarcoma induction by subcutaneous injection of chemical carcinogens. 4 In our present study, we tested the hypothesis that Car-R mice carry cancer resistance loci that inhibit susceptibility to both skin and lung tumorigenesis. Tumors were initiated in SWR/J mice, which are highly susceptible to both lung and skin cancer 3 and in Car-R and (SWR/JxCar-R)F1 mice using urethane, a multi-organ carcinogen that can initiate both lung and skin tumorigenesis. 5,6 Analysis of urethane-initiated and TPA-promoted Car-R, SWR/J and (SWR/JxCar-R)F1 mice revealed resistance to both skin and lung carcinogenesis in the Car-R line and F1 hybrids, showing that the genetic resistance of Car-R mice to both tumor types is dominant over the susceptibility of the SWR/J strain. Linkage disequilibrium (LD) and haplotype analyses showed that Car-R mice carry the Pulmonary adenoma susceptibility 1 (Pas1 s ) allele despite their resistance to lung tumorigenesis. The Pas1 s allele is carried by A/J and SWR/J mice and is dominant in crosses between A/J and C3H/He or C57BL/6 mice. 7,8 Resistance alleles, however, carried by some mouse strains (e.g., M. spretus, BALB/c, SM/J) at pulmonary adenoma resistance (Par) loci inhibit Pas1-mediated susceptibility to lung tumorigenesis in a dominant or co-dominant way. 9 -11 Skin an...

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“…There appear to be no universally agreed rules for managing LFS but there are some published guidelines. 22 Clinical genetic counseling for families with germline TP53 mutations is obviously important. Patients and at-risk family members should also be monitored to identify tumors early.…”

Section: Introductionmentioning

confidence: 99%

p53 and disease: when the guardian angel fails

2006

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The p53 tumor suppressor gene (TP53) is mutated more often in human cancers than any other gene yet reported. Of importance, it is mutated frequently in the common human malignancies of the breast and colorectum and also, but less frequently, in other significant human cancers such as glioblastomas. There is also one inherited cancer predisposing syndrome called Li-Fraumeni that is caused by TP53 mutations. In this review, we discuss the significance of p53 mutations in some of the above tumors with a view to outlining how p53 contributes to malignant progression. We also discuss the usefulness of TP53 status as a prognostic marker and its role as a predictor of response to therapy. Finally, we outline some evidence that abnormalities in p53 function contribute to the etiology of other non-neoplastic diseases.

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Li-Fraumeni syndrome – a molecular and clinical review

Cited by 318 publications

References 99 publications

Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Chromosome instability is a predominant trait of fibroblasts from Li-Fraumeni families

Inhibition of both skin and lung tumorigenesis by Car‐R mouse‐derived cancer modifier loci

p53 and disease: when the guardian angel fails

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