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TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

Ribi S, Baumhoer D, Lee K - Oncotarget (2015)

Bottom Line: Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription.We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere.Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss.

View Article: PubMed Central - PubMed

Affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.

ABSTRACT
Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

No MeSH data available.


Related in: MedlinePlus

Tumors of LFS family show impaired TP53 transcriptionRNA was extracted from blood from one unrelated control individual, TP53 intron 1 rearrangement carriers of the LFS family H2 and P13, OS lung metastasis of H2 and a lung adenocarcinoma derived cell line of P13. qRT-PCRs targeting all twelve TP53 isoforms (TP53) and short transcripts encoding for the N-terminus lacking isoforms Δ133p53 and Δ160p53 (TP53 delta) were performed in triplicates. Quantification cycle values (Cq) were normalized to GAPDH expression and are shown as fold change relative to control (y-axis). Error bars represent standard deviations. One representative of two experiments.
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Figure 5: Tumors of LFS family show impaired TP53 transcriptionRNA was extracted from blood from one unrelated control individual, TP53 intron 1 rearrangement carriers of the LFS family H2 and P13, OS lung metastasis of H2 and a lung adenocarcinoma derived cell line of P13. qRT-PCRs targeting all twelve TP53 isoforms (TP53) and short transcripts encoding for the N-terminus lacking isoforms Δ133p53 and Δ160p53 (TP53 delta) were performed in triplicates. Quantification cycle values (Cq) were normalized to GAPDH expression and are shown as fold change relative to control (y-axis). Error bars represent standard deviations. One representative of two experiments.

Mentions: We performed quantitative reverse transcription polymerase chain reactions (qRT-PCRs) targeting transcripts encoding for the twelve described p53 isoforms and for isoforms Δ133α, −β, −γ and Δ160α, −β, −γ (TP53 delta), respectively, and found a reduction of transcripts by 23–53% for the blood of H2 and P13 where the rearrangement was in a heterozygous state, and a reduction by 89–100% for the OS lung metastasis of H2 and a cell line derived from the lung adenocarcinoma of P13 (Figure 5). This implies that the rearrangements result in a loss of TP53 transcription and function rather than a switch to reported transcripts lacking exon 1.


TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome.

Ribi S, Baumhoer D, Lee K - Oncotarget (2015)

Tumors of LFS family show impaired TP53 transcriptionRNA was extracted from blood from one unrelated control individual, TP53 intron 1 rearrangement carriers of the LFS family H2 and P13, OS lung metastasis of H2 and a lung adenocarcinoma derived cell line of P13. qRT-PCRs targeting all twelve TP53 isoforms (TP53) and short transcripts encoding for the N-terminus lacking isoforms Δ133p53 and Δ160p53 (TP53 delta) were performed in triplicates. Quantification cycle values (Cq) were normalized to GAPDH expression and are shown as fold change relative to control (y-axis). Error bars represent standard deviations. One representative of two experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480712&req=5

Figure 5: Tumors of LFS family show impaired TP53 transcriptionRNA was extracted from blood from one unrelated control individual, TP53 intron 1 rearrangement carriers of the LFS family H2 and P13, OS lung metastasis of H2 and a lung adenocarcinoma derived cell line of P13. qRT-PCRs targeting all twelve TP53 isoforms (TP53) and short transcripts encoding for the N-terminus lacking isoforms Δ133p53 and Δ160p53 (TP53 delta) were performed in triplicates. Quantification cycle values (Cq) were normalized to GAPDH expression and are shown as fold change relative to control (y-axis). Error bars represent standard deviations. One representative of two experiments.
Mentions: We performed quantitative reverse transcription polymerase chain reactions (qRT-PCRs) targeting transcripts encoding for the twelve described p53 isoforms and for isoforms Δ133α, −β, −γ and Δ160α, −β, −γ (TP53 delta), respectively, and found a reduction of transcripts by 23–53% for the blood of H2 and P13 where the rearrangement was in a heterozygous state, and a reduction by 89–100% for the OS lung metastasis of H2 and a cell line derived from the lung adenocarcinoma of P13 (Figure 5). This implies that the rearrangements result in a loss of TP53 transcription and function rather than a switch to reported transcripts lacking exon 1.

Bottom Line: Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription.We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere.Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss.

View Article: PubMed Central - PubMed

Affiliation: Cancer Therapeutics & Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.

ABSTRACT
Somatic mutations of TP53 are among the most common in cancer and germline mutations of TP53 (usually missense) can cause Li-Fraumeni syndrome (LFS). Recently, recurrent genomic rearrangements in intron 1 of TP53 have been described in osteosarcoma (OS), a highly malignant neoplasm of bone belonging to the spectrum of LFS tumors. Using whole-genome sequencing of OS, we found features of TP53 intron 1 rearrangements suggesting a unique mechanism correlated with transcription. Screening of 288 OS and 1,090 tumors of other types revealed evidence for TP53 rearrangements in 46 (16%) OS, while none were detected in other tumor types, indicating this rearrangement to be highly specific to OS. We revisited a four-generation LFS family where no TP53 mutation had been identified and found a 445 kb inversion spanning from the TP53 intron 1 towards the centromere. The inversion segregated with tumors in the LFS family. Cancers in this family had loss of heterozygosity, retaining the rearranged allele and resulting in TP53 expression loss. In conclusion, intron 1 rearrangements cause p53-driven malignancies by both germline and somatic mechanisms and provide an important mechanism of TP53 inactivation in LFS, which might in part explain the diagnostic gap of formerly classified "TP53 wild-type" LFS.

No MeSH data available.


Related in: MedlinePlus