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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

Translocation hotspot in intron 1 of TP53 in OS samples(A) Genes derived from the UCSC known genes database [43] (top) and copy number information derived from DNA-PET sequencing data of four OS samples (blue tracks, bottom) are shown in the Genome Browser. Genes transcribed from the plus strand are represented in gold, genes transcribed from the minus strand are represented in green. Boxes indicate exons, barbed lines indicate introns. The TP53 locus for patients PZP, KRD, and YZH has a copy number of two while patient AJF shows loss of one copy. (B) Enlargement of gene (top) and breakpoint (bottom) view of the TP53 locus. GENCODE transcripts with unresolved problems have been excluded. Note that TP53 is transcribed on the minus strand (from right to left). Mapping regions of DNA-PET sequence tags which represent a rearrangement are shown as dark red (5′-tags) and pink (3′-tags) arrow heads with the predicted breakpoint being located at the tip of the dark red and the base of the pink arrow heads (dashed lines). SV identifiers are in red letters, predicted breakpoint locations and connections are indicated for each rearrangement in black letters. Numbers in squared brackets indicate number of PETs which connect the two genomic regions of a SV (dPET cluster size). Shaded in gray are stretches of identical sequences for both breakpoint sides.
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Figure 1: Translocation hotspot in intron 1 of TP53 in OS samples(A) Genes derived from the UCSC known genes database [43] (top) and copy number information derived from DNA-PET sequencing data of four OS samples (blue tracks, bottom) are shown in the Genome Browser. Genes transcribed from the plus strand are represented in gold, genes transcribed from the minus strand are represented in green. Boxes indicate exons, barbed lines indicate introns. The TP53 locus for patients PZP, KRD, and YZH has a copy number of two while patient AJF shows loss of one copy. (B) Enlargement of gene (top) and breakpoint (bottom) view of the TP53 locus. GENCODE transcripts with unresolved problems have been excluded. Note that TP53 is transcribed on the minus strand (from right to left). Mapping regions of DNA-PET sequence tags which represent a rearrangement are shown as dark red (5′-tags) and pink (3′-tags) arrow heads with the predicted breakpoint being located at the tip of the dark red and the base of the pink arrow heads (dashed lines). SV identifiers are in red letters, predicted breakpoint locations and connections are indicated for each rearrangement in black letters. Numbers in squared brackets indicate number of PETs which connect the two genomic regions of a SV (dPET cluster size). Shaded in gray are stretches of identical sequences for both breakpoint sides.

Mentions: We analyzed the genome structures of four pre-therapeutic OS using DNA paired-end tag sequencing (DNA-PET), a genome-wide mate-pair sequencing approach [13–15] and predicted 434, 289, 348 and 420 SVs, respectively, to be somatically acquired (Supplementary Tables S1–S6, Figures S1A and S1B, S2 and S3A, S3B and S3C). We identified seven breakpoints within a small region of intron 1 of TP53 in three OS tumors (Figure 1, Figure S4 and Supplementary Table S7) and the fourth (AJF) had a 94 kb deletion that included the entire TP53 gene as well as neighboring genes (Figure 1A and 1B). Tumor YZH showed a balanced translocation between TP53 intron 1 and chromosome 1. The sequence of the breakpoints showed the presence of the same 555 bp and 293 bp of the TP53 and chromosome 1 loci, respectively, on both sides of the translocations (Supplementary Figure S5A and S5B). Tumor PZP had a 12.5 kb inverted insertion originating from chromosome 6 containing ENPP1 exons 19 to 25 including the stop codon (Supplementary Figure S6A and S6B). In addition, the TP53 intronic sequences on both sides of the insertion overlapped by 59 bp suggesting that a similar mechanism was responsible for the translocations in both YZH and PZP. Tumor KRD had complex inter-chromosomal translocations with the three different partner chromosomes 1, 5 and 6 (Figure 1B) implying that these are three independent events. At least one event had to be non-clonal meaning that two or three independent clones with structural rearrangements in TP53 intron 1 underlie this tumor. The translocation breakpoints in intron 1 of TP53 with chromosomes 1 and 6 were only 45 bp apart with an overlap of 46 bp of the intron 1 sequence. The overlap and orientations were compatible with one event of similar mechanism as for tumors YZH and PZP. In contrast, the DNA-PET mapping regions of the chromosome 5 translocation suggest that this rearrangement occurred on the other allele of TP53 or in an independent clone (Figure 1B).


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

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

Translocation hotspot in intron 1 of TP53 in OS samples(A) Genes derived from the UCSC known genes database [43] (top) and copy number information derived from DNA-PET sequencing data of four OS samples (blue tracks, bottom) are shown in the Genome Browser. Genes transcribed from the plus strand are represented in gold, genes transcribed from the minus strand are represented in green. Boxes indicate exons, barbed lines indicate introns. The TP53 locus for patients PZP, KRD, and YZH has a copy number of two while patient AJF shows loss of one copy. (B) Enlargement of gene (top) and breakpoint (bottom) view of the TP53 locus. GENCODE transcripts with unresolved problems have been excluded. Note that TP53 is transcribed on the minus strand (from right to left). Mapping regions of DNA-PET sequence tags which represent a rearrangement are shown as dark red (5′-tags) and pink (3′-tags) arrow heads with the predicted breakpoint being located at the tip of the dark red and the base of the pink arrow heads (dashed lines). SV identifiers are in red letters, predicted breakpoint locations and connections are indicated for each rearrangement in black letters. Numbers in squared brackets indicate number of PETs which connect the two genomic regions of a SV (dPET cluster size). Shaded in gray are stretches of identical sequences for both breakpoint sides.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Translocation hotspot in intron 1 of TP53 in OS samples(A) Genes derived from the UCSC known genes database [43] (top) and copy number information derived from DNA-PET sequencing data of four OS samples (blue tracks, bottom) are shown in the Genome Browser. Genes transcribed from the plus strand are represented in gold, genes transcribed from the minus strand are represented in green. Boxes indicate exons, barbed lines indicate introns. The TP53 locus for patients PZP, KRD, and YZH has a copy number of two while patient AJF shows loss of one copy. (B) Enlargement of gene (top) and breakpoint (bottom) view of the TP53 locus. GENCODE transcripts with unresolved problems have been excluded. Note that TP53 is transcribed on the minus strand (from right to left). Mapping regions of DNA-PET sequence tags which represent a rearrangement are shown as dark red (5′-tags) and pink (3′-tags) arrow heads with the predicted breakpoint being located at the tip of the dark red and the base of the pink arrow heads (dashed lines). SV identifiers are in red letters, predicted breakpoint locations and connections are indicated for each rearrangement in black letters. Numbers in squared brackets indicate number of PETs which connect the two genomic regions of a SV (dPET cluster size). Shaded in gray are stretches of identical sequences for both breakpoint sides.
Mentions: We analyzed the genome structures of four pre-therapeutic OS using DNA paired-end tag sequencing (DNA-PET), a genome-wide mate-pair sequencing approach [13–15] and predicted 434, 289, 348 and 420 SVs, respectively, to be somatically acquired (Supplementary Tables S1–S6, Figures S1A and S1B, S2 and S3A, S3B and S3C). We identified seven breakpoints within a small region of intron 1 of TP53 in three OS tumors (Figure 1, Figure S4 and Supplementary Table S7) and the fourth (AJF) had a 94 kb deletion that included the entire TP53 gene as well as neighboring genes (Figure 1A and 1B). Tumor YZH showed a balanced translocation between TP53 intron 1 and chromosome 1. The sequence of the breakpoints showed the presence of the same 555 bp and 293 bp of the TP53 and chromosome 1 loci, respectively, on both sides of the translocations (Supplementary Figure S5A and S5B). Tumor PZP had a 12.5 kb inverted insertion originating from chromosome 6 containing ENPP1 exons 19 to 25 including the stop codon (Supplementary Figure S6A and S6B). In addition, the TP53 intronic sequences on both sides of the insertion overlapped by 59 bp suggesting that a similar mechanism was responsible for the translocations in both YZH and PZP. Tumor KRD had complex inter-chromosomal translocations with the three different partner chromosomes 1, 5 and 6 (Figure 1B) implying that these are three independent events. At least one event had to be non-clonal meaning that two or three independent clones with structural rearrangements in TP53 intron 1 underlie this tumor. The translocation breakpoints in intron 1 of TP53 with chromosomes 1 and 6 were only 45 bp apart with an overlap of 46 bp of the intron 1 sequence. The overlap and orientations were compatible with one event of similar mechanism as for tumors YZH and PZP. In contrast, the DNA-PET mapping regions of the chromosome 5 translocation suggest that this rearrangement occurred on the other allele of TP53 or in an independent clone (Figure 1B).

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