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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 LOH at the TP53 locus(A) OncoScan array derived copy number and allele frequency plots of the TP53 locus of OS lung metastasis of H2 show copy number neutral LOH. Chromosome 17 at 7.544 Mb to 7.618 Mb is shown with gene track (top), copy number (middle) and allele frequency (bottom). Y-axis of copy number is copy number ratio compared to reference (normal); y-axis of allele frequency shows homozygous allele calls for all single nucleotide polymorphisms in the window with values close to 0 and 1, respectively. (B) Semi quantitative PCR of LFS-BP2 (a), the wild type allele at the BP2 locus (b) and RNA polymerase II (positive control, c) of H2 germline DNA (30 PCR cycles) and H2 OS lung metastasis (28 PCR cycles) is shown. L, ladder.
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Figure 6: Tumors of LFS family show LOH at the TP53 locus(A) OncoScan array derived copy number and allele frequency plots of the TP53 locus of OS lung metastasis of H2 show copy number neutral LOH. Chromosome 17 at 7.544 Mb to 7.618 Mb is shown with gene track (top), copy number (middle) and allele frequency (bottom). Y-axis of copy number is copy number ratio compared to reference (normal); y-axis of allele frequency shows homozygous allele calls for all single nucleotide polymorphisms in the window with values close to 0 and 1, respectively. (B) Semi quantitative PCR of LFS-BP2 (a), the wild type allele at the BP2 locus (b) and RNA polymerase II (positive control, c) of H2 germline DNA (30 PCR cycles) and H2 OS lung metastasis (28 PCR cycles) is shown. L, ladder.

Mentions: To test for deletions of the second allele in tumors, copy number analysis using OncoScan FFPE Express (Affymetrix, Inc.) were performed on tumor samples of H2 (two OS lung metastases that developed six months apart), P1 (undifferentiated pleomorphic sarcoma) and P13 (lung adenocarcinoma and meningioma). Loss of heterozygosity (LOH) at the TP53 locus occurred in all five investigated tumors (Figure 6A and Supplementary Figures S14 and S15). Semi quantitative genomic PCR for LFS-BP2 showed a stronger signal for the LFS breakpoint than for the non-rearranged allele suggesting a duplication of the rearranged allele and loss of the non-rearranged allele with the weak PCR signal derived from stroma contamination (Figure 6B). Our findings suggest LOH as a frequent mechanism for TP53 inactivation after an initial intron 1 rearrangement.


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 LOH at the TP53 locus(A) OncoScan array derived copy number and allele frequency plots of the TP53 locus of OS lung metastasis of H2 show copy number neutral LOH. Chromosome 17 at 7.544 Mb to 7.618 Mb is shown with gene track (top), copy number (middle) and allele frequency (bottom). Y-axis of copy number is copy number ratio compared to reference (normal); y-axis of allele frequency shows homozygous allele calls for all single nucleotide polymorphisms in the window with values close to 0 and 1, respectively. (B) Semi quantitative PCR of LFS-BP2 (a), the wild type allele at the BP2 locus (b) and RNA polymerase II (positive control, c) of H2 germline DNA (30 PCR cycles) and H2 OS lung metastasis (28 PCR cycles) is shown. L, ladder.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4480712&req=5

Figure 6: Tumors of LFS family show LOH at the TP53 locus(A) OncoScan array derived copy number and allele frequency plots of the TP53 locus of OS lung metastasis of H2 show copy number neutral LOH. Chromosome 17 at 7.544 Mb to 7.618 Mb is shown with gene track (top), copy number (middle) and allele frequency (bottom). Y-axis of copy number is copy number ratio compared to reference (normal); y-axis of allele frequency shows homozygous allele calls for all single nucleotide polymorphisms in the window with values close to 0 and 1, respectively. (B) Semi quantitative PCR of LFS-BP2 (a), the wild type allele at the BP2 locus (b) and RNA polymerase II (positive control, c) of H2 germline DNA (30 PCR cycles) and H2 OS lung metastasis (28 PCR cycles) is shown. L, ladder.
Mentions: To test for deletions of the second allele in tumors, copy number analysis using OncoScan FFPE Express (Affymetrix, Inc.) were performed on tumor samples of H2 (two OS lung metastases that developed six months apart), P1 (undifferentiated pleomorphic sarcoma) and P13 (lung adenocarcinoma and meningioma). Loss of heterozygosity (LOH) at the TP53 locus occurred in all five investigated tumors (Figure 6A and Supplementary Figures S14 and S15). Semi quantitative genomic PCR for LFS-BP2 showed a stronger signal for the LFS breakpoint than for the non-rearranged allele suggesting a duplication of the rearranged allele and loss of the non-rearranged allele with the weak PCR signal derived from stroma contamination (Figure 6B). Our findings suggest LOH as a frequent mechanism for TP53 inactivation after an initial intron 1 rearrangement.

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