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Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing.

ABSTRACT: Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma. DFSP often reveals a specific chromosome translocation, t(17;22)(q22;q13), which results in the fusion of collagen 1 alpha 1 (COL1A1) gene and platelet-derived growth factor-B (PDGFB) gene. The COL1A1-PDGFB fusion protein activates the PDGFB receptor and resultant constitutive activation of PDGFR receptor is essential in the pathogenesis of DFSP. Thus, blocking PDGFR receptor activation with imatinib has shown promising activity in the treatment of advanced and metastatic DFSP. Despite the success with targeted agents in cancers, acquired drug resistance eventually occurs. Here, we tried to identify potential drug resistance mechanisms against imatinib in a 46-year old female with DFSP who initially responded well to imatinib but suffered rapid disease progression. We performed whole-genome sequencing of both pre-treatment and post-treatment tumor tissue to identify the mutational events associated with imatinib resistance. No significant copy number alterations, insertion, and deletions were identified during imatinib treatment. Of note, we identified newly emerged 8 non-synonymous somatic mutations of the genes (ACAP2, CARD10, KIAA0556, PAAQR7, PPP1R39, SAFB2, STARD9, and ZFYVE9) in the imatinib-resistant tumor tissue. This study revealed diverse possible candidate mechanisms by which imatinib resistance to PDGFRB inhibition may arise in DFSP, and highlights the usefulness of whole-genome sequencing in identifying drug resistance mechanisms and in pursuing genome-directed, personalized anti-cancer therapy.

SUBMITTER: Hong JY

PROVIDER: S-EPMC3726773 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing.

Hong Jung Yong JY Liu Xiao X Mao Mao M Li Miao M Choi Dong Il DI Kang Shin Woo SW Lee Jeeyun J La Choi Yoon Y

PloS one 20130729 7

Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma. DFSP often reveals a specific chromosome translocation, t(17;22)(q22;q13), which results in the fusion of collagen 1 alpha 1 (COL1A1) gene and platelet-derived growth factor-B (PDGFB) gene. The COL1A1-PDGFB fusion protein activates the PDGFB receptor and resultant constitutive activation of PDGFR receptor is essential in the pathogenesis of DFSP. Thus, blocking PDGFR receptor activation with imatinib has shown promising a ...[more]

PMID: 23922791

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Project description:BackgroundDermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous tumor in children. Most published articles are sporadic or small series and lack systematically molecular analyses. The aim of our study is to better understand the clinicopathologic and genetic features of these rare lesions.MethodsAll patients diagnosed with DFSP aged ≤ 18 years were retrospectively reviewed from January 2006 to May 2022.ResultsA total of 66 cases (32 male and 34 female patients) were identified, with ages ranging from 0.3 to 18 years (median, 13 years). Tumor locations predominantly occurred on the trunk (38/66, 57.6%), followed by the extremities (20/66, 30.3%) and head/neck (8/66, 12.1%). Histological findings revealed classic (41/66, 62.1%), myxoid (4/66, 6.1%), pigmented (6/66, 9.1%), plaque-like (3/66, 4.5%), giant cell fibroblastoma (GCF; 6/66, 9.1%), and fibrosarcomatous (6/66, 9.1%) variants of DFSP. Immunochemistry revealed minority tumors (9/66, 13.6%) showing patchy or negative staining for CD34. Fluorescence in situ hybridization (FISH) indicated that 49 of 53 tested cases including all detected biopsy specimens (11/11) contained COL1A1-PDGFB fusion, in which the average copy number gain of COL1A1-PDGFB was 0.68. There were four cases negative for COL1A1-PDGFB rearrangement, one of which was found to harbor a novel COL3A1-PDGFB fusion by next-generation sequencing (NGS). Treatment for 63 patients comprised 40 marginal excisions and 23 wide local excisions (WLEs), including 1 with imatinib therapy. Follow-up information was available on 49 patients with a duration of 12-161 months (median, 60 months). Fourteen patients developed tumor recurrence, all with initial marginal excisions. The others survived with no evidence of disease.ConclusionsThis study of pediatric DFSP indicates certain discrepancies in clinicopathologic characteristics between children and adults. The majority of pediatric DFSPs contain COL1A1-PDGFB fusion, the same as their adult counterparts. The COL3A1-PDGFB chimerism might be associated with the special morphology of GCF, which needs further investigation. FISH is valuable in biopsy tissues and cases with atypical CD34 immunostaining, while supplementary NGS could be helpful to identify the cytogenetically cryptic DFSP. Overall, an urgent accurate diagnosis is needed to formulate an optimal therapeutic strategy in the pediatric population.

Dataset Information

Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing.

Publications

Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing.

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