Analysis revealed a nonsense variant of TP53 which has been previously reported in families with sarcomas and other typical Li Fraumeni syndrome-associated cancers but never in a familial leukemia kindred.
(2) Coincidental p53 allele mutation and PML loss shifts the tumor profile toward sarcoma formation, which is paralleled in human leiomyosarcomas (indicated by immunohistochemistry; IHC).
Accelerated carcinoma and sarcoma tumour formation in p53(+/-) females with bi-allelic Igf2 expression was associated with reductions in p53 loss of heterozygosity and apoptosis.
Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers.
This suggests that selective up-regulation of p21 in cancer cells could be a successful therapeutic intervention for sarcomas and tumors with lower resistance to mitochondrial oxidative damage, regardless of p53 status.
The p53 and phosphoinositide-3-kinase, catalytic, alpha polypeptide/v-akt murine thymoma viral oncogene homolog/mechanistic target of rapamycin (PIK3CA/AKT/mTOR) pathways frequently are altered in sarcoma with complex genomics, such as leiomyosarcoma (LMS) or undifferentiated pleomorphic sarcoma (UPS).
On the other hand, p53 is a well-characterized tumor suppressor gene and p53 heterozygous mice develop sarcoma and other tumors starting from 12 months of age.
We propose, therefore, that MDM2 markers along with TP53 sequencing should be considered as patient biomarkers in clinical trials of sarcomas using MDM2 antagonists.
The ESPL1 hypomorphic, p53 heterozygous transgenic mice (ESPL1(+/hyp), p53(+/-)) also show a significantly reduced life span with an altered tumor spectrum of carcinomas and sarcomas compared to p53(+/-) mice alone.
Using irradiation chimeras generated by transplanting bone marrow cells from mice carrying either the Rosa26StoploxPLacZ or the Z/EG reporter, as well as the floxed p53 and Rb genes, into irradiated p53loxP/loxPRbloxP/loxP mice, it was determined that sarcomas do not originate from bone marrow-derived cells, such as macrophages, but arise from the local resident cells.
We have previously developed a line of primary mesenchymal stem cells (MSC, the putative origin of various types of sarcoma) in which five oncogenic steps toward a fully transformed state are sequentially introduced including: human telomerase, inactivation of p53 and pRb tumor suppressor genes and activation of the oncogenes c-Myc and H-Ras.