Characterization of genetic lesions in rhabdomyosarcoma using a high‐density single nucleotide polymorphism array

Abstract

Rhabdomyosarcoma (RMS) is a common solid tumor in childhood divided into two histological subtypes, embryonal (ERMS) and alveolar (ARMS). The ARMS subtype shows aggressive clinical behavior with poor prognosis, while the ERMS subtype has a more favorable outcome. Because of the rarity, diagnostic diversity and heterogeneity of this tumor, its etiology remains to be completely elucidated. Thus, to identify genetic alterations associated with RMS development, we performed single nucleotide polymorphism array analyses of 55 RMS samples including eight RMS-derived cell lines. The ERMS subtype was characterized by hyperploidy, significantly associated with gains of chromosomes 2, 8 and 12, whereas the majority of ARMS cases exhibited neardiploid copy number profiles. Loss of heterozygosity of 15q was detected in 45.5% of ARMS that had been unrecognized in RMS to date. Novel amplifications were also detected, including IRS2 locus in two fusion-positive tumors, and KRAS or NRAS loci in three ERMS cases. Of note, gain of 13q was significantly associated with good patient outcome in ERMS. We also identified possible application of an ALK inhibitor to RMS, as ALK amplification and frequent expression of ALK were detected in our RMS cohort. These findings enhance our understanding of the genetic mechanisms underlying RMS pathogenesis and support further studies for therapeutic development of RMS. (Cancer Sci 2013; 104: 856-864) R habdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Two major histological subtypes are recognized: alveolar (ARMS) and embryonal (ERMS). The ERMS subtype (approximately 60% of all RMS cases) is usually a localized disease with a favorable prognosis, typically occurring in younger children.(1) It presents mostly as a disease of the head, neck or genitourinary tract.(1) In contrast, the ARMS subtype, which accounts for approximately 20% of RMS, commonly involves the extremities in older children, exhibiting aggressive clinical behavior with frequent metastatic diseases.(1) Approximately 75% of ARMS exhibit characteristic chromosomal translocations, t(2;13)(q35:q14) and t(1;13)(p36: q14), which generate aberrant fusion transcription factors PAX3-FOXO1 and PAX7-FOXO1, respectively.(2,3) Loss of heterozygosity (LOH) at 11p15.5 is a common chromosomal aberration in ERMS as well as other pediatric tumors, for example, Wilms tumor and hepatoblastoma.(4) According to previous reports using array-based comparative genomic hybridization, numerical changes primarily involving gains of chromosomes 2, 8 and 12 are generally associated with ERMS, and ARMS are typically characterized by genomic amplifications (5)(6)(7)(8) including co-amplifications of PAX3 ⁄ 7 and FOXO1 loci in fusion-positive tumors. (5,(7)(8)(9) Although these genetic findings suggest that the two subtypes represent discrete clinicopathological entities, their molecular basis has not been completely elucidated.In the present study, we performed high-density single nucleotide polymorphism (SNP) array analysis of 55 RM...

Rhabdomyosarcomas in children with neurofibromatosis type I: A national historical cohort

“…On a genetic point of view, the whole genome profiling performed in six cases reveals whole chromosome rearrangement not so different from those reported in sporadic cases: polysomy 2 and 8 are indeed the most frequent aberration in ERMS; [28,32] likewise, the 11p LOH found in 5/6 tumours in our series has been also widely encountered in sporadic ERMS. [33] Interestingly, we have observed some specific gene alterations that may synergize with the RAS pathway. The inactivation of p16 is encountered in sporadic RMS, [27,28] which emphasized that targeting the cell cycle might be of interest together with inhibiting the RAS transduction.…”

The role of anaplastic lymphoma kinase in pediatric cancers

“…Alveolar rhabdomyosarcoma shows an aggressive phenotype, whereas embryonal has a more favorable prognosis . We previously found that ALK inhibitors were effective in select rhabdomyosarcoma cell lines with high ALK expression levels, suggesting a possible therapeutic target for ALK inhibitors in rhabdomyosarcoma . Compared with TAE684 and 2,4‐pyrimidinediamine derivative (2,4‐PDD), the different pharmacological behavior of crizotinib may be related to MET inhibition, the specific activity of crizotinib, because the rhabdomyosarcoma cell lines examined also express MET to varying degrees .…”

“…We previously found that ALK inhibitors were effective in select rhabdomyosarcoma cell lines with high ALK expression levels, suggesting a possible therapeutic target for ALK inhibitors in rhabdomyosarcoma . Compared with TAE684 and 2,4‐pyrimidinediamine derivative (2,4‐PDD), the different pharmacological behavior of crizotinib may be related to MET inhibition, the specific activity of crizotinib, because the rhabdomyosarcoma cell lines examined also express MET to varying degrees . Given that ALK amplification or copy number gain is predominantly detected in ARMS (6–17%), rhabdomyosarcoma cases with a poor prognosis may benefit from ALK inhibitors.…”

“…(63) We previously found that ALK inhibitors were effective in select rhabdomyosarcoma cell lines with high ALK expression levels, suggesting a possible therapeutic target for ALK inhibitors in rhabdomyosarcoma. (64) Compared with TAE684 and 2,4-pyrimidinediamine derivative (2,4-PDD), the…”

“…Cancer type Normalized expression value different pharmacological behavior of crizotinib may be related to MET inhibition, the specific activity of crizotinib, because the rhabdomyosarcoma cell lines examined also express MET to varying degrees. (64) Given that ALK amplification or copy number gain is predominantly detected in ARMS (6-17%), (64,65) rhabdomyosarcoma cases with a poor prognosis may benefit from ALK inhibitors.…”