A novel aberration of COL1A1-PDGFB fusion as an insertion in chromosome 15 in one case of dermatofibrosarcoma protuberans involving a rare location.

Dermatofibrosarcoma protuberans (DFSP) is a rare sarcoma of the skin arising from the dermis. Its location is most commonly presented on the trunk of middle-aged adults and rarely on the face. The characteristic genetic aberration in the form of a reciprocal translocation t(17;22)(q21;q13) or a ring fusing the COL1A1 and PDGFB genes is found in 90% of DFSP. We present a case of a 42-year-old man who presented with a DFSP on the left cheek with foci of myxoid-fibrosarcomatous transformation. A conventional chromosomal analysis revealed a complex karyotype without a supernumerary ring chromosome or a linear translocation t(17;22). Comparative genome hybridization and fluorescence in-situ hybridization revealed the fusion of COL1A1 and PDGFB probes inserted in chromosome 15. This is a unique case of DFSP characterized by a rare body location, unique histopathological features, and novel chromosome COL1A1-PDGFB insertion, and may help guide future diagnostic and patient care modalities.

Narrowing down the Common Cytogenetic Deletion 14q to a 5.6-Mb Critical Region in 1p/19q Codeletion Oligodendroglioma-Relapsed Patients Points to Two Potential Relapse-Related Genes: SEL1L and STON2.

Based on a literature review and our database, we report on the smallest 14q deletion identified in a brain tumor characterized by 1p/19q codeletion low-grade oligodendroglioma. In 2013, array-comparative genomic hybridization of the brain tumor revealed 1p/19q codeletion as a sole abnormality. In 2019, the patient relapsed showing additional abnormalities including a 14q deletion of 16.5 Mb at 14q24.2q31.3. This region overlaps with 2 previously identified minimal regions, 14q21.2q24.3 and 14q31.3q32.1, based on 142 cases of glioma. The authors reported no correlation between these 2 regions and survival. By extracting these 2 regions from our patient's deletion and comparing it to 12 other cases of 1p/19q codeletion oligodendrogliomas reported in the literature, we narrowed down the 14q loss possible critical region to 5.6 Mb mapping at 14q31.1q31.2. This region contains 2 potential relapse-related genes: SEL1L and STON2.

A novel translocation t(10;17)(p13;q11.2) harboring two cryptic deletions identified by array-CGH and characterized by SUZ12 overexpression in a patient with chronic thrombocytosis.

No specific translocation is associated with myeloproliferative neoplasms (MPNs). However, an interstitial deletion involving subband 17q11.2 which includes the NF1 gene, although rare, is a recurrent aberration in several myeloid disorders including MPNs. For the first time, we report an acquired novel translocation involving 10p13 and 17q11.2 in a 62-year-old Caucasian female which was referred for investigation of chronic and persistent unexplained thrombocytosis. The patient had no history of hematological sequelae and genomic testing for JAK2, CALR, and MPL mutations were negative. She was subsequently diagnosed with a triple negative essential thrombocythemia. Array-CGH analysis noted that the translocation harbored two cryptic deletions, one of which involved 17q11.2 encompassing the NF1 gene. One of the junction breakpoints involved the SUZ12 gene. Immunohistochemical assessment of the marrow trephine showed increased megakaryocytic expression of the SUZ12 protein, as well as EZH2 and Ki67; biochemical abnormalities suggestive of excess megakaryocytic hyperplasia. This novel translocation may affect the expression of SUZ12 and its downstream targets, and may represent a unique pathogenomic etiology which drives chronic thrombocytosis in essential thrombocythemia.

A Novel t(10;22) Translocation Harboring an IGL Gene Deletion in a CLL Patient Transforming to B-PLL with 1q Gain.

OBJECTIVES: We report on a rare case of B-cell prolymphocytic leukemia (B-PLL) in a patient with a history of chronic lymphocytic leukemia (CLL) that showed a novel translocation t(10;22)(q21;q11.22) and an interstitial deletion of 11q14.1-q23.3 in 2017. The chromosome microarray analysis (CMA) confirmed the 11q22 deletion and revealed a small interstitial deletion of IGL gene. In 2018, the patient presented with worsening lymphocytosis, anemia and thrombocytopenia. The peripheral blood smear revealed an increased prolymphocyte population, which comprised 60.4% of lymphoid cells, establishing a diagnosis of B-cell prolymphocytic leukemia. The CMA and G-banded chromosome analysis showed one additional aberration in the form of 1q gain translocated onto the other homologue 22. These findings suggested clonal evolution of CLL to B-PLL. The most common translocation involving immunoglobulin lambda chain (IGL) in CLL is the t(18;22), followed by t(8;22) and (11;22). An evolution to B-PLL occurs in most cases without gaining additional aberrations. Here, we report for the first time a novel translocation involving IGL with chromosome 10q21 and one 1q gain occurring in a patient with CLL that transformed to B-PLL. Based on the disease progression and this newly developed cytogenetic aberration, our case supports the progressive nature of CLL in the presence of IGL deletion and suggests the pathological role of 1q gain in CLL transformation.

A Novel Variant Rearrangement of the Rare Aberration dic(17;20)(p11.2;q11.2) Characterized by Array-CGH as an Insertion in a Patient with Myelodysplastic Syndrome of Multilineage Dysplasia (MDS-MLD).

We report on a novel variant of the dicentric chromosome 17;20 (dic (17;20)(p11.2;q11.2) in a patient with de novo myelodysplastic syndrome (MDS). Based on FISH and array-CGH, the variant turns out to be an insertion of chromosome 17 (17p11.2-telomere 17) into chromosome 20 with breakpoints at 20q11.22 and 20q13.33. Based on conventional chromosome analysis and G-banding patterns, the region 17p11.2-17q25 was directly inserted between 20q11.22 and 20q13.33. The breakpoint junctions occurred within KCNJ12 (17p11.2), UQCC1 (20q11.2), and CDH4 (20q13.3), leading to 5' deletions of all the genes and positioning the 3' of UQCC1 next to KCNJ12 at 17p11.2 and CDH4 next to an unknown gene at 17q25-20q13.3. In addition, the centromere of chromosome 17 was not active, transforming the primary constriction to a flat band. Therefore, the novel insertion variant is a pseudo dicentric derivative chromosome with one functional centromere: 45,XX,der(17;20)del(20)(q11.22q13.33)ins(20;17)(q11.2;p11.2q25). A review of the literature of all dic(17;20) cases is presented. For the first time, we report an array-CGH characterization of such rare variant that revealed to be an insertion.

Three Novel Aberrations Involving PLAG1 Leading to Lipoblastoma in Three Different Patients: High Amplification, Partial Deletion, and a Unique Complex Rearrangement.

Lipoblastoma is a rare benign neoplasm with overlapping histology with other lipomatous tumors. Genetic aberrations including translocations of 8q and splitting of the PLAG1 probe leading to "promoter swapping" and gains of chromosome 8 or PLAG1 foci have been described in lipoblastoma. Here, we report 3 lipoblastomas revealing novel genetic aberrations involving PLAG1: a high level of PLAG1 amplification up to 50 copies in a 4-year-old girl with recurrence of a right flank mass, a partial deletion of PLAG1 with the flanking junction breakpoints involving the 3'PLAG1 and 5'HAS2 genes in a 17-month-old boy with a retroperitoneal mass, and an insertion of 2q31 into 8q11.2 and translocation of 8q to 2q with the latter translocated onto 12q leading to separation of the PLAG1 FISH probe in a 5-year-old girl with a left back mass. Our novel cytogenetic findings further expand the mechanisms of PLAG1 transcriptional upregulation in lipoblastoma pathogenesis.

Novel TLE4-NTRK2 fusion in a ganglioglioma identified by array-CGH and confirmed by NGS: Potential for a gene targeted therapy.

Gangliogliomas are rare neoplasms of the central nervous system that mostly originate in the temporal lobe and are associated with seizures. Literature mentions that BRAF mutations are most commonly associated with gangliogliomas. We discuss a unique case of ganglioglioma originating in the posterior fossa that showed multiple losses and a unique interstitial deletion at 9q21 by an array-comparative genome hybridization (array-CGH). The deletion led to a novel molecular fusion (TLE4-NTRK2) which was confirmed by next generation sequencing and provides a potential for a gene-targeted therapy.

Subcutaneous melanocytoma mimicking a lipoma: a rare presentation of a rare neoplasm with histological, immunohistochemical, cytogenetic and molecular characterization.

Melanocytoma are the melanocytic tumors originating from leptomeningeal melanocytes. Melanocytomas are commonly seen in the central nervous system (CNS) and are often associated with neurocutaneous melanosis (NCM). However, simultaneous presentation of intra-axial and extracranial melanocytoma is a very rare event. Here, we report a unique case of 21-year-old male with intermediate-grade subcutaneous (SC) melanocytoma, mimicking lipoma, occurred synchronously with an intracranial melanocytoma, not associated with NCM. A 21-year-old Caucasian male presented to the emergency department (ED) with severe vertigo and vomiting. A magnetic resonance imaging (MRI) of the brain was performed at the ED, which revealed an SC mass in the right occipital scalp and a right cerebellopontine angle (CPA) mass. Excision of the SC mass revealed a well-circumscribed highly pigmented melanocytic tumor. The SC mass tumor cells were positive for melanocytic lineage markers. The histopathological features were between benign melanocytomas and malignant melanomas. The Ki67 and PHH3 IHCs confirm the intermediate grade of the tumors. An array-CGH (comparative genome hybridization) and next-generation sequencing analysis of the tumor DNA extracted from the formalin-fixed paraffin-embedded tissue reveals chromosome 6p gain and p.Q209P mutation in the GNAQ gene, respectively, consistent with the diagnosis of intermediate-grade melanocytoma.

Cryptic insertion of 3'FOXO1 into inverted chromosome arm 2q in the presence of two normal chromosome 13s and 13 small interstitial duplications in a patient with alveolar rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) is a pediatric soft tissue neoplasm with a characteristic translocation, t(2;13)(q35;q14), which is detected in 70-80% of cases. This well-described translocation produces the gene fusion product PAX3-FOXO1. Cryptic rearrangements of this fusion have never before been reported in ARMS. Here we describe a patient with ARMS that showed, by fluorescence in situ hybridization and G-banded chromosomes, a cryptic insertion of 3'FOXO1 into inverted chromosome 2q. The inversion breakpoints were depicted by array comparative genomic hybridization as two small interstitial duplications, one of which involved the PAX3 gene. In addition, the array comparative genomic hybridization results revealed 1q gain, 16q loss, and 11 more small duplications, with one of them involving the FOXO1 gene. Although the pathogenesis in classic ARMS cases is thought to be driven by the 5'PAX3-3'FOXO1 fusion on derivative chromosome 13, here we report a novel cryptic insertion of 3'FOXO1 resulting in a pathogenic fusion with 5'PAX3 on inverted chromosome 2q.

Papillary thyroid cancer in struma testis with malignant transformation in the lung associated with trisomy 17 successfully treated with total thyroidectomy and radioiodine ablation.

BACKGROUND: Struma testis is a rare entity, and there are only few reports on the malignant transformation of a testicular teratoma to papillary thyroid carcinoma in the literature. In this report, we describe the malignant transformation of struma testis with distant lung metastasis associated with trisomy 17 and a coexisting papillary microcarcinoma in the thyroid. CASE REPORT: A 56-year-old man presented after a left orchiectomy for an undescended left testicle. Pathologic examination identified a monodermal teratoma composed of thyroid parenchyma and associated with a 1.7-cm papillary thyroid carcinoma. Further evaluation showed a pulmonary mass on a chest CT scan. Total thyroidectomy revealed a 0.5-mm focus of papillary thyroid cancer, and removal of the lung mass confirmed metastatic papillary thyroid cancer. Array-comparative genomic hybridization of both tumors showed trisomy 17 in the struma testes and the lung metastasis. The patient responded well to radioactive iodine ablation and has no evidence of cancer 3 years later. CONCLUSION: To our knowledge, this is the first case of papillary thyroid cancer in struma testes metastatic to the lung. It highlights the difficulties in treating these patients. Surgery to remove cancer foci, followed by radioactive iodine ablation, resulted in an excellent response in our patient. Interestingly, trisomy 17, which has so far been observed only in noninvasive thyroid nodules, was associated with pulmonary metastasis in our patient.

ABL1 gene involvement within a complex three-way translocation (2;9;4) in perineurioma characterized by molecular cytogenetic methods.

Perineuriomas are rare peripheral nerve sheath tumors with one or few chromosomal rearrangements or numerical changes. Two main types and three subtypes have been defined but with few specific genetic associations. Chromosome 10 aberrations have been found in three cases of the sclerosing perineurioma subtype. Chromosome 22 abnormalities have been described in different types of perineurioma. None of these aberrations has been described at the molecular level. We report on a complex rearrangement characterized by fluorescence in situ hybridization and array-comparative genome hybridization, which revealed submicroscopic deletions at 2p23 and 9q34 that involved the ABL1 gene in a soft tissue perineurioma case.

Malignant transformation of a desmoplastic infantile ganglioglioma in an infant carrier of a nonsynonymous TP53 mutation.

INTRODUCTION: Desmoplastic infantile ganglioglioma is a rare intracranial neoplasm classified as World Health Organization grade I tumor under neuronal and mixed neuronal-glial tumors (2007 World Health Organization brain tumor classification). It is usually a good prognosis, but 40% of patients require further medical, radiation, and/or surgical intervention, and 15% develop leptomeningeal spread or die from desmoplastic infantile ganglioglioma. Transformation to malignant glioblastoma occurs, but the genetic alterations associated with the transformation are generally unknown. METHODS: We describe a desmoplastic infantile ganglioglioma in a 2-month-old boy, which showed aggressive behavior, requiring debulking at 2.5 months of age and chemotherapy at 10 months of age after tumor progression. At 8.5 years of age he developed malignant transformation to glioblastoma. Chromosome microarray analysis using oligo array and genomic sequencing was performed on the biopsy specimen from 2 months of age and on the subsequent transformed malignant glioblastoma. RESULTS: After being clinically stable for 7.5-years, transformation to glioblastoma transformation occurred. He did well for 1 year but subsequently died from tumor progression. Chromosome microarray analysis using oligo array performed on the biopsy specimen obtained at 2 months of age did not reveal significant abnormalities; but there were significant genomic deletions and duplications associated with the glioblastoma. These included multiple genomic losses involving 4q and Y, gains of 5q, and amplification of 12q14. Genomic sequencing revealed a single nucleotide variant, p.R248Q in exon 7 of TP53, in the primary desmoplastic infantile ganglioglioma and the glioblastoma multiforme. CONCLUSIONS: The nonsynonymous variant (p.R248Q in exon 7) of the TP53 gene is predicted to alter the structure of the L2/L3 motif of the DNA binding domain of p53 protein. It was detected in the primary desmoplastic infantile ganglioglioma and glioblastoma multiforme. This child illustrates the rare recurrence of desmoplastic infantile ganglioglioma with malignant transformation to glioblastoma caused by a nonsynonymous TP53 mutation, providing explanation for other rare benign tumor transformations. The TP53 gene is a known primary site of genetic alteration that predisposes to malignant tumors, and this case indicates that it might also be involved in the behavior and outcome of desmoplastic infantile ganglioglioma. Therefore more genetic testing is recommended on desmoplastic infantile ganglioglioma tumors, which may provide biologic prognostic markers.

Masked hypodiploidy in anaplastic meningiomas by duplication of the original clone found in atypical meningiomas: illustration of the evolution of genetic alterations.

Meningiomas are common, usually benign neoplasms of the central nervous system. Atypical and anaplastic meningiomas can be aggressive, show more rapid growth, and a greater propensity to recur following resection. General consensus believes that genetic abnormalities leading to anaplastic transformation are present at initial tumor presentation; however, this has not been demonstrated by array-comparative genome hybridization. We confirm the hypothesis by showing the evolution of genetic alterations in the transformation of an atypical meningioma to an anaplastic meningioma. Additionally, we provide potential genes responsible for malignant transformation of meningiomas, which, with further research, may provide diagnostic and therapeutic implications.

Narrowing down the common deleted region of 5q to 6.0 Mb in blastic plasmacytoid dendritic cell neoplasms.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy. Simple and complex recurrent cytogenetic abnormalities have been reported, which demonstrate predominantly genomic losses, of which deletions of 5q are the most frequent aberrations in BPDCN with or without cutaneous manifestation; however, the gene responsible for the disease remains unknown. Using microarray-based molecular characterization, a recent study on several cases of BPDCN with the 5q deletion identified a large, common deleted region (CDR) of 29 Mb that contains several possible candidate genes. We report on a 67-year-old female patient who presented with leukemic BPDCN without skin involvement and had a deletion of 5q and a t(6;8)(p21;q24). By oligo-array-comparative genome hybridization (a-CGH) method, the genomic coordinations of the 5q deletion demonstrated unique breakpoints reported for the first time. Through mapping with those published cases using the same a-CGH method, the CDR was reduced from 29 Mb to 6 Mb, which excluded the previous candidate genes and highlighted an excellent biological gene: the HINT1 gene. Moreover, a molecular cytogenetic characterization of the translocation t(6;8) was performed in search for a novel gene fusion that could be associated with tumor progression.

Oculo-auriculo-vertebral spectrum, cat eye, and distal 22q11 microdeletion syndromes: a unique double rearrangement.

An array-CGH on 19-year-old male showed a proximal 1.11 Mb duplication and a distal 1.7 Mb deletion of 22q11.2 regions flanking the Velocardiofacial/DiGeorge syndrome region that remained intact. FISH analyses revealed both abnormalities to be on the same homolog 22. This double rearrangement lead to the co-existence of two syndromes: Cat eye and distal 22q11.2 microdeletion syndromes with a rare associated phenotype of oculo-auriculo-vertebral spectrum (OAVS). A review of the literature indicates that this is the second report of a proximal duplication and the fifth report of a distal deletion and OAVS suggestive of a possible OAVS candidate gene in this region.

Modified array-based comparative genomic hybridization detects cryptic and variant PML-RARA rearrangements in acute promyelocytic leukemia lacking classic translocations.

Acute promyelocytic leukemia (APL) is typically defined at the molecular level by a reciprocal translocation of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes. An accurate diagnosis of APL is critical for appropriate choice of therapy and prognostic assessment. Cryptic and variant rearrangements in APL are discoverable by a variety of molecular methods including fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction, or gene sequencing. Rare reports of FISH-negative APL harboring cryptic rearrangements of PML-RARA detected by reverse transcriptase polymerase chain reaction or sequencing have been described. Here, we describe the detection of cryptic or variant PML-RARA rearrangements by translocation-based comparative genomic hybridization (tCGH), a recently described modification of traditional CGH technology that facilitates the detection of balanced translocations by means of the linear amplification of a potential translocation breakpoint region(s), in 2 unusual cases of APL. One tumor lacked detectable t(15;17) by karyotype and FISH, and the other tumor lacked the typical morphologic and immunophenotypic features of APL and had a variant 3-way translocation involving PML and RARA. PML-RARA translocations were identified by tCGH in both cases providing confirmation of the diagnosis of APL. These data emphasize the benefit of using complementary molecular methods including tCGH for detecting cryptic and variant PML-RARA translocations in unusual cases of APL.

Deceptively benign low-grade fibromyxoid sarcoma: array-comparative genomic hybridization decodes the diagnosis.

Low-grade fibromyxoid sarcoma (previously known as Evans tumor) is a rare soft tissue neoplasm characterized by a deceptively bland appearance despite the potential for late metastasis or recurrence. We describe a 13-year-old patient with a popliteal fossa mass initially thought to be benign that, because of array-comparative genomic hybridization findings and subsequent immunohistochemistry, was diagnosed as low-grade fibromyxoid sarcoma. The array-comparative genomic hybridization demonstrated a loss of 11p11.2p15.5 and a gain of 16p11.2p13.3 with breakpoints involving the CREB3L1 (cAMP responsive element-binding protein 3-like 1) and FUS (fused in sarcoma) genes, respectively. Subsequent fluorescence in situ hybridization analysis of a dual-labeled break-apart FUS probe on interphase cells was positive. Our case highlights the importance of using genetic information obtained via array-comparative genomic hybridization to classify accurately pediatric soft tissue tumors.

Cryptic deletion of EGR1 in association with a novel balanced t(5;22)(q31;q11.2) in a patient with myelodysplastic syndrome.

Loss of chromosome 5 or deletion of 5q is commonly seen in patients with myelodysplastic syndrome (MDS). Loss of EGR1, located on 5q31, has been postulated as contributing to the pathology of MDS in patients with -5/del(5q). We report on the first case of a patient with a novel apparent balanced translocation between chromosomes 5 and 22 at breakpoints 5q31 and 22q11.2. Fluorescence in situ hybridization using a probe of EGR1 detected a cryptic deletion masked by the translocation.

Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with inv(16)(p13q22) as a sole genetic abnormality.

Inversion of chromosome 16, inv(16)(p13q22), juxtaposes the core binding factor beta (CBFB) and myosin heavy chain 11 (MYH11) genes, resulting in a myeloid leukemic disease phenotype characterized by increased bone marrow and peripheral blood blasts with myelomonocytic antigen expression and an accompanying eosinophilia. This cytogenetic abnormality has been reported in a variety of other neoplasms, in which it generally occurs as part of a complex karyotype, including rare B-lineage non-Hodgkin lymphomas. We report a case of clinically, morphologically, and immunologically typical lymphoplasmacytic lymphoma/Waldenström macroglobulinemia in which a majority of the malignant cells had an inv(16)(p13q22) as a sole abnormality. We review the literature and discuss the possible role of this genetic lesion in B-cell neoplasia.