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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) Location of BAC clones which have been selected for FISH relative to TP53 and immediate neighbouring genes. Other genes of the track have been deleted for clarity. Color code matches fluorophore of FISH analysis shown in B. (B) Examples of a negative and positive break-apart signal of two color FISH which has been used to screen 267 formalin fixed and paraffin embedded (FFPE) OS samples and 141 other bone-forming tumors. (C) Copy number overview of 73 OS tumors at the TP53 locus based on CytoScan array analysis. Top panel shows the cumulative copy number across all samples with red indicating loss and blue gain in copy number. Lower panel shows the copy number gains and losses for each of the 73 OS tumors individually. Note the changes in copy number within intron 1 of TP53 detectable in 23 cases (yellow box).
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Figure 2: Translocation hotspot in intron 1 of TP53 in OS samples(A) Location of BAC clones which have been selected for FISH relative to TP53 and immediate neighbouring genes. Other genes of the track have been deleted for clarity. Color code matches fluorophore of FISH analysis shown in B. (B) Examples of a negative and positive break-apart signal of two color FISH which has been used to screen 267 formalin fixed and paraffin embedded (FFPE) OS samples and 141 other bone-forming tumors. (C) Copy number overview of 73 OS tumors at the TP53 locus based on CytoScan array analysis. Top panel shows the cumulative copy number across all samples with red indicating loss and blue gain in copy number. Lower panel shows the copy number gains and losses for each of the 73 OS tumors individually. Note the changes in copy number within intron 1 of TP53 detectable in 23 cases (yellow box).

Mentions: We designed a break-apart FISH test using probes flanking the TP53 gene (Figure 2A) and investigated a series of 215 pre-therapeutic OS samples arranged on a tissue microarray (TMA). We found 11% (23 out of 215) of the cases to have rearrangements at the TP53 locus (FISH break-apart positive; Figure 2B). Of note, in all 23 FISH positive cases, both alleles showed the break-apart signal. However, FISH positive patients did not differ from negative patients in terms of overall-survival (p = 0.6), event-free survival (p = 0.7), occurrence of metastases, or response to neoadjuvant chemotherapy (Table 1 and Supplementary Tables S8 and S9). Rearrangements at this locus nevertheless appear to be a recurrent finding in OS. To test whether the TP53 rearrangement also occurred in other bone-forming tumors that sometimes can be difficult to distinguish histologically from OS in small biopsies, we analyzed another series of 124 bone-forming tumors and tumor-like lesions using our FISH assay. None of these cases showed evidence of TP53 rearrangement. To further exclude TP53 intron 1 rearrangements in other tumor types we used our FISH assay to analyze an additional 966 tumors on a TMA (Supplementary Tables S10 and S11). None of the 966 tumors showed a break-apart signal suggesting the somatic TP53 intron 1 rearrangements represent a specific finding in OS.


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) Location of BAC clones which have been selected for FISH relative to TP53 and immediate neighbouring genes. Other genes of the track have been deleted for clarity. Color code matches fluorophore of FISH analysis shown in B. (B) Examples of a negative and positive break-apart signal of two color FISH which has been used to screen 267 formalin fixed and paraffin embedded (FFPE) OS samples and 141 other bone-forming tumors. (C) Copy number overview of 73 OS tumors at the TP53 locus based on CytoScan array analysis. Top panel shows the cumulative copy number across all samples with red indicating loss and blue gain in copy number. Lower panel shows the copy number gains and losses for each of the 73 OS tumors individually. Note the changes in copy number within intron 1 of TP53 detectable in 23 cases (yellow box).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Translocation hotspot in intron 1 of TP53 in OS samples(A) Location of BAC clones which have been selected for FISH relative to TP53 and immediate neighbouring genes. Other genes of the track have been deleted for clarity. Color code matches fluorophore of FISH analysis shown in B. (B) Examples of a negative and positive break-apart signal of two color FISH which has been used to screen 267 formalin fixed and paraffin embedded (FFPE) OS samples and 141 other bone-forming tumors. (C) Copy number overview of 73 OS tumors at the TP53 locus based on CytoScan array analysis. Top panel shows the cumulative copy number across all samples with red indicating loss and blue gain in copy number. Lower panel shows the copy number gains and losses for each of the 73 OS tumors individually. Note the changes in copy number within intron 1 of TP53 detectable in 23 cases (yellow box).
Mentions: We designed a break-apart FISH test using probes flanking the TP53 gene (Figure 2A) and investigated a series of 215 pre-therapeutic OS samples arranged on a tissue microarray (TMA). We found 11% (23 out of 215) of the cases to have rearrangements at the TP53 locus (FISH break-apart positive; Figure 2B). Of note, in all 23 FISH positive cases, both alleles showed the break-apart signal. However, FISH positive patients did not differ from negative patients in terms of overall-survival (p = 0.6), event-free survival (p = 0.7), occurrence of metastases, or response to neoadjuvant chemotherapy (Table 1 and Supplementary Tables S8 and S9). Rearrangements at this locus nevertheless appear to be a recurrent finding in OS. To test whether the TP53 rearrangement also occurred in other bone-forming tumors that sometimes can be difficult to distinguish histologically from OS in small biopsies, we analyzed another series of 124 bone-forming tumors and tumor-like lesions using our FISH assay. None of these cases showed evidence of TP53 rearrangement. To further exclude TP53 intron 1 rearrangements in other tumor types we used our FISH assay to analyze an additional 966 tumors on a TMA (Supplementary Tables S10 and S11). None of the 966 tumors showed a break-apart signal suggesting the somatic TP53 intron 1 rearrangements represent a specific finding in OS.

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