Somatic and Germline <i>TP53</i> Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors

Sherborne, Amy L.; Lavergne, Vincent; Yu, Katharine; Lee, Leah; Davidson, Philip R.; Mazor, Tali; Smirnoff, Ivan V.; Horvai, Andrew E.; Loh, Mignon L.; DuBois, Steven G.; Goldsby, Robert E.; Neglia, Joseph P.; Hammond, Sue; Robison, Leslie L.; Wustrack, Rosanna; Costello, J; Nakamura, Alice; Shannon, Kevin; Bhatia, Smita; Nakamura, Jean L.

doi:10.1158/1078-0432.ccr-16-0610

Cited by 31 publications

(27 citation statements)

References 51 publications

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“…In the human-only NMF analysis, we included tumor samples initiated by either IR or UV. Two IR-induced malignancies from patients were analyzed by whole exome sequencing (a single tumor sample from one patient, Patient 1, and 2 anatomically separate tissue samples of the same tumor from the other, Patient 2), revealing a total of 194 single nucleotide variants (SNVs) for Patient 1, and a total of 361 SNVs for Patient 2 (202 in sample A and 159 in sample B) 10 . The third clinical case was a UV-associated squamous cell carcinoma of the scalp (Patient 3).…”

Section: Resultsmentioning

confidence: 99%

“…Focally irradiated mice develop IR-induced malignancies that resemble clinical IR-induced malignancies both anatomically and histologically 9 . Similar to the clinically-based radiation protocols utilized in our mouse model, the two human IR-induced malignancies included in this analysis were induced by focal fractionated radiation 10 . As a result, the mouse and human IR-induced malignancies shared key similarities in mutagenic exposure with the previously analyzed WES data from the IR-induced malignancies arising within our mouse model 4 .…”

Section: Introductionmentioning

confidence: 99%

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A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies

Davidson

Sherborne

Taylor

et al. 2017

Sci Rep

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Single nucleotide variants (SNVs) identified in cancer genomes can be de-convolved using non-negative matrix factorization (NMF) into discrete trinucleotide-based mutational signatures indicative of specific cancer-causing processes. The stability of NMF-generated mutational signatures depends upon the numbers of variants available for analysis. In this work, we sought to assess whether data from well-controlled mouse models can compensate for scarce human data for some cancer types. High quality sequencing data from radiotherapy-induced cancers is particularly scarce and the mutational processes defining ionizing radiation (IR)-induced mutagenesis in vivo are poorly defined. Here, we combine sequencing data from mouse models of IR-induced malignancies and human IR-induced malignancies. To determine whether the signatures identified from IR-exposed subjects can be differentiated from other mutagenic signatures, we included data from an ultraviolet radiation (UV)-induced human skin cancer and from a mouse model of urethane-induced cancers. NMF distinguished all three mutagens and in the pooled analysis IR was associated with mutational signatures common to both species. These findings illustrate the utility of pooled analysis of mouse and human sequencing data.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies

Davidson

Sherborne

Taylor

et al. 2017

Sci Rep

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“…The cleaned and trimmed reads were aligned to the reference human sequence (GRCh37/hg19) using TopHat (v1.4.0), a fast splice junction mapping software that uses Bowtie alignment to align reads 30 – 34 . The mapped reads were assembled using Cufflinks (v2.0.0) software, and the transcripts across all samples were merged using Cuffmerge program.…”

Section: Methodsmentioning

confidence: 99%

Chronic sun exposure-related fusion oncogenes EGFR-PPARGC1A in cutaneous squamous cell carcinoma

Egashira

Jinnin

Ajino

et al. 2017

Sci Rep

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Cutaneous squamous cell carcinoma (cSCC) differs from SCC of other organs in its strong association with chronic sun exposure. However, the specific driver mutations in cSCC remain unknown. Fusion genes in established cSCC cell lines (A431 and DJM-1) were predicted by transcriptome sequence, and validated by Sanger sequence, fluorescence in situ hybridization and G-banding. By transcriptome sequencing, we identified fusion gene EGFR-PPARGC1A in A431, which were expressed in 31 of 102 cSCCs. The lesions harboring the fusion gene tended to be located in sun-exposed areas. In vivo cutaneous implantation of EGFR-PPARGC1A-expressing NIH3T3 induced tumors resembling human cSCC, indicating its potent tumorigenicity. NIH3T3 transfected with EGFR-PPARGC1A as well as A431 showed increased cell proliferation activity. With regard to underlying mechanism, EGFR-PPARGC1A protein causes constitutive tyrosine phosphorylation, and induces the phosphorylation of wild-type full-length epidermal growth factor receptor (EGFR) by dimerization. Conversely, the RNAi-mediated attenuation of EGFR or CRISPR/Cas9-mediated knockdown of the fusion gene in A431 led to a decrease in the cell number, and may have therapeutic value. Our findings advance the knowledge concerning genetic causes of cSCC and the function of EGFR, with potential implications for new diagnostic and therapeutic approaches.

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“…We did not address the implications of the underlying disorder for therapy of tumors that develop, or for second cancers and subsequent surveillance. This will likely be very syndrome specific, e.g., a greater risk of therapy-related cancers in Li-Fraumeni Syndrome, retinoblastoma predisposition or DNA instability syndromes, etc., and less so in individuals with certain other syndromes (14–16). The recommendations will likely need substantial personalization, as the surveillance recommendations will depend on the child’s risk of a second tumor, while taking into account their risk of recurrence, the therapy that they received, and the biological nature of the predisposition syndrome.…”

Section: Importance Of Consensus Protocolsmentioning

confidence: 99%

Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr

Brodeur

Nichols

Plon

et al. 2017

Clinical Cancer Research

148

110

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The prevalence of childhood cancer attributable to genetic predisposition was generally considered very low. However, recent reports suggest that at least 10% of pediatric cancer patients harbor a germline mutation in a cancer predisposition gene. Although some of these children will have a family history suggestive of a cancer predisposition syndrome, many others will not. Evidence from recent pediatric studies suggests that surveillance and early detection of cancer in individuals carrying a germline cancer predisposing mutation may result in improved outcomes. However, there is a lack of consistency in the design of cancer surveillance regimens across centers nationally and internationally. To standardize approaches, the Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) convened a workshop, during which consensus screening recommendations for children with the most common cancer predisposition syndromes were developed. In general, we considered a 5% or greater chance of developing a childhood cancer to be a reasonable threshold to recommend screening. Conditions for which the cancer risk was between 1 to 5% were addressed individually. In a series of manuscripts accompanying this article, we provide recommendations for surveillance, focusing on when to initiate and/or discontinue specific screening measures, which modalities to use, and the frequency of screening. Points of controversy are also reviewed. We present the outcome of our deliberations for consensus screening recommendations for specific disorders in 18 position papers as Open Access publications and available on an AACR-managed web site.

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Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors

Cited by 31 publications

References 51 publications

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies

Chronic sun exposure-related fusion oncogenes EGFR-PPARGC1A in cutaneous squamous cell carcinoma

Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr

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