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Kaposi sarcoma (KS) is a human herpesvirus 8 (HHV8)-associated vascular proliferation that most often involves the skin. Rarely, KS shows marked nuclear atypia or pleomorphism; such examples are known as "anaplastic" KS. This poorly characterized variant often pursues an aggressive course; little is known of its genetic landscape. This study evaluated the clinicopathologic and genomic features of anaplastic KS. We identified 9 anaplastic KS cases from 7 patients and 8 conventional KS cases, including a matched conventional KS and primary metastasis anaplastic KS pair from a single patient (anaplastic KS diagnosed 9 years after conventional KS). All patients with anaplastic KS were men, aged 51 to 82 years, who had locally aggressive tumors predominantly affecting the soft tissue and bone of the lower extremities (5/7 patients). Four patients were known to be HIV positive (all on antiretrovirals), 2 were HIV negative, and 1 was of unknown HIV status. The tumors showed angiosarcoma-like or pleomorphic spindle cell sarcoma morphology. Plasma cell-rich chronic inflammation and hemosiderin deposition were commonly present. Single-nucleotide polymorphism-based chromosomal microarray analysis showed the anaplastic KS cohort to demonstrate highly recurrent whole chromosome (chr) gains of chr 7, 11, 19, and 21, which primarily affected olfactory and G protein-coupled receptor signaling and losses of chr6_q and chrY. Compared with conventional KS, anaplastic KS cases showed significantly more total copy number alterations and more frequent gains of chr7 and chr11_q13.1 (MARK2, RELA, and ESRRA, including high copy number gain in 1 case). Pathway analysis demonstrated that these gains preferentially affected genes that facilitate cyclin-dependent cell signaling. Furthermore, anaplastic KS cases were phylogenetically distinct from conventional KS cases, including the patient-matched primary metastasis anaplastic KS pair and conventional KS. Our study is the first to demonstrate that a more complex genome and distinct copy number alterations distinguish anaplastic KS from conventional KS. Gains of chr7 and chr11_q13.1 appear central to biological transformation., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Genome-wide copy number profiling by single-nucleotide polymorphism (SNP) array is increasingly employed in the clinical diagnostic workup of melanocytic tumors. We present our SNP array results on 675 melanocytic tumors, including 615 histologically ambiguous tumors evaluated by our institution's dermatopathology consultation service and a separate validation cohort of 26 known benign nevi and 34 known malignant melanomas. The total number of somatic copy number abnormalities, sub-chromosomal copy number abnormalities, regions of homozygosity, and abnormalities at disease-associated regions was significantly associated with a diagnosis of malignancy across disease categories. In our study, the number of copy number abnormalities was the factor that best discriminated between benign versus malignant diagnoses, confirming recent published research. Histologically ambiguous tumors had a range and spectrum of abnormalities, including recurrent 11p gains, copy state transitions over kinase genes, and 3p deletions overlapping BAP1 in neoplasms with Spitzoid morphology. Our data suggest that histologically ambiguous melanocytic neoplasms and early primary melanomas have a range of abnormalities that is intermediate between unambiguous benign or malignant melanocytic neoplasms. Careful technical review and an integrated diagnostic approach are essential for the accurate interpretation of SNP array results on histologically ambiguous melanocytic tumors., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Nodular hidradenoma is a cutaneous adnexal tumor of sweat gland origin, characterized by its diverse but overlapping histomorphologic features with other skin tumors. In addition, distinction of benign hidradenoma and its malignant counterpart hidradenocarcinoma can be challenging, especially in prognostic prediction. We retrospectively reviewed pathological features of 29 cases, including benign nodular hidradenoma (n = 17) and hidradenocarcinoma (n = 12), with clinical follow-up ranging from 18 to 216 months. Genomic copy number variation (CNV) was studied in selected cases (n = 18) by single nucleotide polymorphism microarray. None of the benign hidradenomas (0/17) or low-grade hidradenocarcinomas (0/6) had recurrence or metastasis after complete excision, whereas all 6 high-grade hidradenocarcinomas (6/6) showed locally destructive disease, recurrence, or local metastases. In benign hidradenomas, CNV abnormality was absent in all clear cell hidradenomas (0/5) but was detected in a considerable portion of poroid hidradenoma (3/5), with number of abnormalities ranging 2, 4, and 9. In malignant cases, regardless of morphological classification, both low-grade hidradenocarcinomas demonstrated limited CNV abnormalities in 2 areas (2/2), whereas all high-grade hidradenocarcinomas contained 8 or more CNV abnormalities (6/6). No disease-associated death was recorded in the cohort except one case was lost to follow-up after the development of metastatic disease. Overall, the findings support that genomic CNV abnormalities may serve as a sensitive but less specific tool in detecting malignancy in these tumors, and potentially have a role in predicting clinical behavior particularly in the tumors of nonporoid morphology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Myxopapillary ependymomas (MPEs) have an indolent clinical course, corresponding to World Health Organization Grade I. A total of 13 pediatric MPEs have been reported in the literature with "anaplastic features," including elevated proliferative activity (≥5 mitoses/10 high-power fields), necrosis, and microvascular proliferation. No consensus exists regarding the prognostic significance of such features. A retrospective clinicopathologic review of pediatric MPEs diagnosed between 1996 and 2018 at Mayo Clinic was performed. Totally, 8 pediatric MPEs (6 male; age: 7.52 to 16.88 y) were identified. Totally, 3 had disseminated disease at presentation. All patients underwent surgical resection (7 gross total; 1 subtotal). Totally, 5 cases harbored ≥5 mitoses/10 high-power fields (range: 5 to 9), 3 of which showed necrosis (2 with disseminated disease). Postsurgery, 2 patients received radiation; one with disseminated disease and another with increased mitotic activity/necrosis; neither has recurred (follow-up: 1.18 and 3.19 y). In all, 2 patients with disseminated disease, elevated mitotic activity, and necrosis had new metastatic disease/progression of nonresected metastatic foci (2.6 and 26.8 mo), received radiation therapy, and remain progression free (3.01 and 9.34 y). All patients are alive (median follow-up 1.31 y, range: 0.66 to 11.75). Among pediatric MPEs, the concurrent presence of elevated mitotic activity and necrosis may be associated with an aggressive clinical course, warranting closer surveillance and consideration of adjuvant therapies., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Testing the products of conception (POCs) provides information about the cause of fetal loss and helps determine the recurrence risk of future losses and chromosome abnormalities in subsequent pregnancies. Historically, the Mayo Clinic Cytogenetics Laboratory performed targeted fluorescent in situ hybridization (FISH) testing to identify aneuploidy of only certain chromosomes in formalin-fixed, paraffin-embedded (FFPE) POC samples. Chromosomal microarray studies using the Affymetrix OncoScan FFPE Assay can detect copy number changes across the genome. We validated the utility of the OncoScan assay using 25 archival FFPE POC specimens with previous FISH results (five normal, 12 trisomy, six triploidy, two monosomy). Of the five normal samples, four had no clinically relevant findings, and one sample was found to have trisomy 9, which is not detectable by the FISH test. For the 20 samples with abnormal FISH results, the OncoScan assay identified all reported abnormalities along with additional findings. A sample with trisomy 22 was also found to have trisomy 7. Another sample reported as triploidy was found to have four copies of chromosome 16. In conclusion, we verified the performance characteristics of OncoScan on FFPE POC specimens and found it acceptable for clinical use. Additional information was identified in 3 of 25 cases (12%) that would explain the pregnancy loss or provide recurrence risk for the family., (Copyright © 2017 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care., Methods: A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions., Results: Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic., Conclusion: Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.

Meckel syndrome (MKS) is an embryonic lethal, autosomal recessive disorder characterized by polycystic kidney disease, central nervous system defects, polydactyly and liver fibrosis. This disorder is thought to be associated with defects in primary cilia; therefore, it is classed as a ciliopathy. To date, six genes have been commonly associated with MKS (MKS1, TMEM67, TMEM216, CEP290, CC2D2A and RPGRIP1L). However, mutation screening of these genes revealed two mutated alleles in only just over half of our MKS cohort (46 families), suggesting an even greater level of genetic heterogeneity. To explore the full genetic complexity of MKS, we performed exon-enriched next-generation sequencing of 31 ciliopathy genes in 12 MKS pedigrees using RainDance microdroplet-PCR enrichment and IlluminaGAIIx next-generation sequencing. In family M456, we detected a splice-donor site change in a novel MKS gene, B9D1. The B9D1 protein is structurally similar to MKS1 and has been shown to be of importance for ciliogenesis in Caenorhabditis elegans. Reverse transcriptase-PCR analysis of fetal RNA revealed, hemizygously, a single smaller mRNA product with a frameshifting exclusion of B9D1 exon 4. ArrayCGH showed that the second mutation was a 1.713 Mb de novo deletion completely deleting the B9D1 allele. Immunofluorescence analysis highlighted a significantly lower level of ciliated patient cells compared to controls, confirming a role for B9D1 in ciliogenesis. The fetus inherited an additional likely pathogenic novel missense change to a second MKS gene, CEP290; p.R2210C, suggesting oligogenic inheritance in this disorder.

Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Juvenile polyposis syndrome (JPS) is a hereditary condition characterized by development of gastrointestinal polyps, and caused by mutations in SMAD4 or BMPR1A genes. Juvenile polyps can also be found in a related group of syndromes with multisystemic involvement including Cowden disease, Lhermitte-Duclos disease, Bannayan-Riley-Ruvalcaba syndrome, and Proteus-like syndrome, all grouped as PTEN hamartoma tumor syndromes (PHTS). In all these conditions including JPS, polyps manifest in older childhood or early adulthood. Infantile juvenile polyposis (JPI) is a rare entity, presenting in the first year of life with severe gastrointestinal symptoms. Many of these patients have associated macrocephaly, hypotonia, and congenital anomalies. It was recently recognized that patients with infantile polyposis have a 10q23 microdeletion, involving both BMPR1A and PTEN genes. There is a major risk for gastrointestinal malignancies in these patients, but the risk for development of other tumors is not known. We describe a patient with a history of infantile polyposis, macrocephaly, developmental delay, hypotonia, and a 10q23 microdeletion. At age 14 she presented with bilateral mucinous cystadenoma of the ovary. This type of tumor was not previously reported in association with JPS, 10q23 microdeletion syndrome, or infantile polyposis. We believe that ovarian cystadenomas may be another neoplastic complication of infantile polyposis, and that our report widens the spectrum of the 10q23 microdeletion phenotype., (Copyright © 2010 Wiley-Liss, Inc.)

Clinical testing using various array comparative genomic hybridization platforms is being incorporated rapidly into cytogenetic testing algorithms. Comprehensive validation of these complex assays presents unique challenges and very few studies reporting the validation of commercially available array platforms have been published. Sixty-seven patients with previously defined subtelomere abnormalities, representing deletions and/or duplications of all 41 clinically relevant sites, were tested in a blinded study using the Spectral Genomics Constitutional Chip 3.0. Overall, 72 of 74 (97%) subtelomeric abnormalities were concordant with previous cytogenetic studies. However, two false-negative results were documented, and issues with mismapped and suboptimal clone performance were identified that may result in failure to detect 6q and 20q subtelomeric abnormalities. The results of this study indicate that comprehensive validation is necessary before implementation of array comparative genomic hybridization platforms into a clinical setting. Specific suggestions for validation are discussed in the context of the recently proposed American College of Medical Genetics guidelines for microarray analysis for constitutional cytogenetic abnormalities.