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1.
Front Immunol ; 15: 1337400, 2024.
Article in English | MEDLINE | ID: mdl-38873609

ABSTRACT

Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.


Subject(s)
B7-H1 Antigen , Cyclin-Dependent Kinase Inhibitor p16 , Pilomatrixoma , Skin Neoplasms , Humans , Male , Middle Aged , Cyclin-Dependent Kinase Inhibitor p16/genetics , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Pilomatrixoma/genetics , Pilomatrixoma/pathology , Mutation , Hair Diseases/genetics , Hair Diseases/pathology
2.
Am J Dermatopathol ; 45(10): 712-717, 2023 Oct 01.
Article in English | MEDLINE | ID: mdl-37462164

ABSTRACT

ABSTRACT: Melanocytic matricoma is a rare benign pilar tumor characterized by matrical differentiation and interspersed dendritic melanocytes. It may show cellular atypia and brisk mitotic activity. Histological characterization of some lesions may be difficult. In addition, because the reported cases are few and have limited follow-up, there is insufficient experience to define outcome-based criteria for malignancy. Some cases of melanocytic matricoma with more prominent atypia have been reported as malignant, but their clinical behavior is uncertain. We present a melanocytic matricoma with interspersed benign dendritic melanocytes, but moderate basaloid atypia, focally brisk mitotic activity, and atypical mitoses. Despite the apparently good delimitation of this tumor, higher magnification revealed a slightly irregular border. However, overt malignant features such as necrosis, frank asymmetry, deep infiltration, and ulceration were not present. This tumor showed a complex aberrant genomic profile with multiple whole chromosomes or chromosomal arms, losses, and duplications. The tumor mutational burden was high. A loss-of-function alteration in CDKN2A and a loss-of-function mutation in TP53 were also present. This unexpected molecular profile contrasts with the relatively bland histology of the tumor and is in line with the difficulties in microscopic differential diagnosis between melanocytic matricoma and an indolent malignant pilomatrical tumor. We suggest that molecular studies and longer follow-up periods may help to further understand and more precisely categorize borderline pilomatrical tumors with melanocytic hyperplasia.


Subject(s)
Hair Diseases , Neoplasms, Adnexal and Skin Appendage , Pilomatrixoma , Precancerous Conditions , Skin Neoplasms , Humans , Pilomatrixoma/genetics , Pilomatrixoma/pathology , Immunohistochemistry , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Melanocytes/pathology , Neoplasms, Adnexal and Skin Appendage/pathology , Hair Diseases/genetics , Hair Diseases/pathology , Precancerous Conditions/pathology
4.
Int J Gynecol Pathol ; 40(5): 482-486, 2021 Sep 01.
Article in English | MEDLINE | ID: mdl-33252403

ABSTRACT

Pilomatrix carcinoma (PC) is a rare malignant variant of pilomatrixoma, a skin adnexal tumor originating from hair matrix cells. It is most often located in the head, neck region, upper back and upper extremities. PC has a locally aggressive behavior but metastasis only occur in 10% of cases. Mutations in CTNNB1, the encoding gene of beta-catenin, have been found in both pilomatrixoma and PC, but other molecular alterations are unknown. The authors present a case of PC in the clitoris, the third known reported case located on the external genitalia. The tumor followed an unusual clinical course with the development of multiple metastases. Next-generation sequencing analysis of the tumor identified, in addition to a characteristic CTNNB1 mutation, pathogenic mutations in PTEN, PIK3CA, and ARID1A, which could explain the aggressive course of the disease. The diagnostic criteria of PC and the differential diagnoses of this unusual tumor in the genital area are discussed.


Subject(s)
Hair Diseases/diagnosis , Pilomatrixoma/diagnosis , Skin Neoplasms/diagnosis , Vulvar Neoplasms/diagnosis , beta Catenin/genetics , Diagnosis, Differential , Female , Hair Diseases/genetics , Hair Diseases/pathology , High-Throughput Nucleotide Sequencing , Humans , Middle Aged , Mutation , Pilomatrixoma/genetics , Pilomatrixoma/pathology , Sequence Analysis, DNA , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Vulva/pathology , Vulvar Neoplasms/genetics , Vulvar Neoplasms/pathology
5.
J Invest Dermatol ; 141(3): 533-544, 2021 03.
Article in English | MEDLINE | ID: mdl-32795530

ABSTRACT

Pilomatricoma, a benign skin appendage tumor, also known as calcifying epithelioma, consists of islands of epithelial cells histologically that contain anucleated cells in the center surrounded by basophilic cells and partial calcification. Sporadic pilomatricomas commonly have somatic mutations in the gene CTNNB1, but causative genes from germline and the underlying pathophysiology are unclear. In this study, we identified a germline missense variant of PLCD1 encoding PLCδ1, c.1186G>A (p.Glu396Lys), in a large Chinese family with autosomal dominant multiple pilomatricomas. Phospholipase C, a key enzyme playing critical roles in intracellular signal transduction, is essential for epidermal barrier integrity. The p.Glu396Lys variant increased the enzymatic activity of PLCδ1, leading to protein kinase C/protein kinase D/extracellular signal-regulated kinase1/2 pathway activation and TPRV6 channel closure, which not only resulted in excessive proliferation of keratinocytes in vitro and in vivo but also induced local accumulation of calcium in the pilomatricoma-like tumor that developed spontaneously in the skin of Plcd1E396K/E396K mice. Our results implicate this p.Glu396Lys variant of PLCD1 from germline leading to gain-of-function of PLCδ1 as a causative genetic defect in familial multiple pilomatricomas.


Subject(s)
Calcium Channels/metabolism , Hair Diseases/genetics , Phospholipase C delta/genetics , Pilomatrixoma/genetics , Skin Neoplasms/genetics , TRPV Cation Channels/metabolism , Animals , DNA Mutational Analysis , Disease Models, Animal , Female , Germ-Line Mutation , Hair Diseases/pathology , Humans , MAP Kinase Signaling System/genetics , Male , Mice, Transgenic , Middle Aged , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Mutation, Missense , Pedigree , Pilomatrixoma/pathology , Protein Kinase C/metabolism , Skin/pathology , Skin Neoplasms/pathology
6.
Cancer Genomics Proteomics ; 17(6): 795-802, 2020.
Article in English | MEDLINE | ID: mdl-33099480

ABSTRACT

BACKGROUND: Malignant pilomatricoma (MP) is a rare cancer of the hair matrix with only a few cases reported in literature. Given the rarity of this cancer and the lack of relevant genetic data, very little is known about the nature of the molecular pathophysiology except the involvement of the Catenin Beta 1 (CTNNB1)/Wnt/ß-catenin signaling pathway in some cases. MATERIALS AND METHODS: We describe the whole-exome genomic profiling of four samples from two patients: 1) an MP from patient I, 2) a coexisting benign pilomatricoma (BP) from patient I, 3) a BP from an age and location-matched control patient II, and 4) normal skin tissue from patient II. RESULTS: We detected a pathogenic somatic missense mutation in fibroblast growth factor receptor 4 (FGFR4) (c.1162G>A, p. Gly388Arg) in MP and coexisting BP in patient I, whereas the control BP harbored the classical CTNNB1 mutant. CONCLUSION: This study, the first comparative analysis of benign and MP through whole-exome analysis, identified a novel oncogenic mutation in FGFR4.


Subject(s)
Gene Expression Regulation, Neoplastic , Hair Diseases/pathology , Mutation , Pilomatrixoma/pathology , Receptor, Fibroblast Growth Factor, Type 4/genetics , Skin Neoplasms/pathology , beta Catenin/genetics , Biomarkers, Tumor/genetics , Case-Control Studies , Exome , Hair Diseases/genetics , Humans , Pilomatrixoma/genetics , Prognosis , Skin Neoplasms/genetics , Exome Sequencing , Wnt Signaling Pathway
7.
Pediatr Dermatol ; 37(6): 1139-1141, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32876971

ABSTRACT

Constitutional mismatch repair deficiency (CMMRD) syndrome results from bi-allelic mutations in DNA mismatch repair genes-MLH1, MSH2, MSH6, or PMS2. We present two siblings with CMMRD having p.Arg802Ter (c.2404C >T) homozygous mutations in PMS2 exon 14 with typical cutaneous features. This case report highlights the role of the dermatologist in early diagnosis of this condition.


Subject(s)
Brain Neoplasms , Hair Diseases , Neoplastic Syndromes, Hereditary , Pilomatrixoma , Skin Neoplasms , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Colorectal Neoplasms , Hair Diseases/diagnosis , Hair Diseases/genetics , Humans , Mutation , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Pilomatrixoma/diagnosis , Pilomatrixoma/genetics , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics
8.
J Clin Endocrinol Metab ; 105(6)2020 06 01.
Article in English | MEDLINE | ID: mdl-32242235

ABSTRACT

CONTEXT: Primary Ovarian insufficiency (POI) affects 1% of women aged <40 years and leads most often to definitive infertility with adverse health outcomes. Very recently, genes involved in deoxyribonucleic acid (DNA) repair have been shown to cause POI. OBJECTIVE: To identify the cause of a familial POI in a consanguineous Turkish family. DESIGN: Exome sequencing was performed in the proposita and her mother. Chromosomal breaks were studied in lymphoblastoid cell lines treated with mitomycin (MMC). SETTING AND PATIENTS: The proposita presented intrauterine and postnatal growth retardation, multiple pilomatricomas in childhood, and primary amenorrhea. She was treated with growth hormone (GH) from age 14 to 18 years. RESULTS: We identified a novel nonsense variant in exon 9 of the minichromosome maintenance complex component 8 gene (MCM8) NM_001281522.1: c0.925C > T/p.R309* yielding either a truncated protein or nonsense-mediated messenger ribonucleic acid decay.The variant was homozygous in the daughter and heterozygous in the mother. MMC induced DNA breaks and aberrant metaphases in the patient's lymphoblastoid cells. The mother's cells had intermediate but significantly higher chromosomal breaks compared with a control. CONCLUSION: We describe a novel phenotype of syndromic POI related to a novel truncating MCM8 variant. We show for the first time that spontaneous tumors (pilomatricomas) are associated with an MCM8 genetic defect, making the screening of this gene necessary before starting GH therapy in patients with POI with short stature, especially in a familial or consanguineous context. Appropriate familial monitoring in the long term is necessary, and fertility preservation should be considered in heterozygous siblings to avoid rapid follicular atresia.


Subject(s)
Growth Disorders/pathology , Hair Diseases/pathology , Minichromosome Maintenance Proteins/genetics , Mutation , Pilomatrixoma/pathology , Primary Ovarian Insufficiency/pathology , Skin Neoplasms/pathology , Adolescent , Adult , Biomarkers/analysis , Child , Female , Follow-Up Studies , Growth Disorders/complications , Growth Disorders/genetics , Hair Diseases/complications , Hair Diseases/genetics , Homozygote , Humans , Male , Middle Aged , Pedigree , Phenotype , Pilomatrixoma/complications , Pilomatrixoma/genetics , Primary Ovarian Insufficiency/complications , Primary Ovarian Insufficiency/genetics , Prognosis , Skin Neoplasms/complications , Skin Neoplasms/genetics , Young Adult
9.
PLoS One ; 15(3): e0230003, 2020.
Article in English | MEDLINE | ID: mdl-32155193

ABSTRACT

Myotonic dystrophy type 1 (DM1) is an inherited neuromuscular disease which results from an expansion of repetitive DNA elements within the 3' untranslated region of the DMPK gene. Some patients develop multiple pilomatricomas as well as malignant tumors in other tissues. Mutations of the catenin-ß gene (CTNNB1) could be demonstrated in most non-syndromic pilomatricomas. In order to gain insight into the molecular mechanisms which might be responsible for the occurrence of multiple pilomatricomas and cancers in patients with DM1, we have sequenced the CTNNB1 gene of four pilomatricomas and of one pilomatrical carcinoma which developed in one patient with molecularly proven DM1 within 4 years. We further analyzed the pilomatrical tumors for microsatellite instability as well as by NGS for mutations in 161 cancer-associated genes. Somatic and independent point-mutations were detected at typical hotspot regions of CTNNB1 (S33C, S33F, G34V, T41I) while one mutation within CTNNB1 represented a duplication mutation (G34dup.). Pilomatricoma samples were analyzed for microsatellite instability and expression of mismatch repair proteins but no mutated microsatellites could be detected and expression of mismatch repair proteins MLH1, MSH2, MSH6, PMS2 was not perturbed. NGS analysis only revealed one heterozygous germline mutation c.8494C>T; p.(Arg2832Cys) within the ataxia telangiectasia mutated gene (ATM) which remained heterozygous in the pilomatrical tumors. The detection of different somatic mutations in different pilomatricomas and in the pilomatrical carcinoma as well as the observation that the patient developed multiple pilomatricomas and one pilomatrical carcinoma over a short time period strongly suggest that the patient displays a hypermutation phenotype. This hypermutability seems to be tissue and gene restricted. Simultaneous transcription of the mutated DMPK gene and the CTNNB1 gene in cycling hair follicles might constitute an explanation for the observed tissue and gene specificity of hypermutability observed in DM1 patients. Elucidation of putative mechanisms responsible for hypermutability in DM1 patients requires further research.


Subject(s)
DNA Mutational Analysis , Hair Diseases/genetics , Mutation , Myotonic Dystrophy/complications , Phenotype , Pilomatrixoma/genetics , Skin Neoplasms/genetics , Hair Diseases/complications , High-Throughput Nucleotide Sequencing , Humans , Microsatellite Instability , Pilomatrixoma/complications , Skin Neoplasms/complications , beta Catenin/genetics
11.
Am J Dermatopathol ; 40(9): 631-641, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30119102

ABSTRACT

INTRODUCTION: Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a superficial benign skin tumor that arises from hair follicle matrix cells. Although pilomatrixomas are well-recognized lesions, clinically they are frequently misdiagnosed as other skin conditions. By reviewing all the literature over the past 10 years, the aims of this article are to analyze the cause, clinical presentation, management, and outcome of pilomatrixoma among children and adults to gain a more complete understanding of this lesion in today's clinical context. METHODS: A MEDLINE and EMBASE search was conducted from January 2005 to February 2015 using a combination of the terms: "child," "childhood," "adult," and keywords: "pilomatrixoma," "pilomatricoma," and "calcifying epithelioma of Malherbe." A total of 150 articles were reviewed. RESULTS: The lesions occurred most commonly in the first and second decades (mean age 16 years and 7 months). The commonest presentation was of an asymptomatic, firm, slowly growing, mobile nodule. Only 16% were accurately diagnosed on clinical examination. Imaging in the form of ultrasound, computed tomography, and magnetic resonance imaging has been reported. Pathological diagnosis was achieved through incision, punch, and shave biopsies. Pathological findings are discussed and summarized in this review. CONCLUSION: Pilomatrixomas are thought to arise from mutation in the Wnt pathway and has been linked to several genetic conditions. It is commonly misdiagnosed preoperatively; however, with better awareness of the lesion, it can be appropriately treated while avoiding unnecessary diagnostic tests. Complete surgical excision with clear margins is almost always curative.


Subject(s)
Hair Diseases/pathology , Hair Follicle/pathology , Pilomatrixoma/pathology , Skin Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy , Child , Child, Preschool , Diagnosis, Differential , Female , Genetic Predisposition to Disease , Hair Diseases/diagnostic imaging , Hair Diseases/genetics , Hair Diseases/surgery , Hair Follicle/diagnostic imaging , Hair Follicle/surgery , Humans , Infant , Male , Margins of Excision , Middle Aged , Mutation , Phenotype , Pilomatrixoma/diagnostic imaging , Pilomatrixoma/genetics , Pilomatrixoma/surgery , Predictive Value of Tests , Recurrence , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/genetics , Skin Neoplasms/surgery , Treatment Outcome , Wnt Signaling Pathway/genetics , Young Adult
12.
Dermatol Online J ; 24(1)2018 Jan 15.
Article in English | MEDLINE | ID: mdl-29469775

ABSTRACT

Rubinstein-Taybi syndrome (RTS) is an autosomaldominant hereditary disease, which contains many skeletal and organ anomalies as well as mental retardation. Although high incidence of keloids in RTS is known, it is difficult to find a detailed report on the clinical features of keloids. In the following letter, we report an RTS patient fulfilling diagnostic criteria whosuffered from both keloids and pilomatricoma. We also performed a literature search, which identified the possible involvement of the Wnt/ß-catenin signaling pathway in the pathogenesis of these two skin lesions.


Subject(s)
Keloid/genetics , Pilomatrixoma/genetics , Rubinstein-Taybi Syndrome , Adult , Cyclic AMP Response Element-Binding Protein/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Humans , Keloid/pathology , Male , Rubinstein-Taybi Syndrome/genetics , Signal Transduction , Wnt Proteins/metabolism , beta Catenin/metabolism
14.
Pediatr Blood Cancer ; 65(1)2018 Jan.
Article in English | MEDLINE | ID: mdl-28792655

ABSTRACT

Because children diagnosed with WNT-activated medulloblastoma have a 10-year overall survival rate of 95%, active long-term follow-up is critically important in reducing mortality from other causes. Here, we describe an 11-year-old adopted female who developed multiple pilomatrixomas 3 years after diagnosis of WNT-activated medulloblastoma, an unusual finding that prompted deeper clinical investigation. A heterozygous germline APC gene mutation was discovered, consistent with familial adenomatous polyposis. Screening endoscopy revealed numerous precancerous polyps that were excised. This case highlights the importance of long-term follow-up of pediatric cancer survivors, including attention to unexpected symptoms, which might unveil an underlying cancer predisposition syndrome.


Subject(s)
Adenomatous Polyposis Coli Protein , Adenomatous Polyposis Coli , Cancer Survivors , Cerebellar Neoplasms , Germ-Line Mutation , Hair Diseases , Medulloblastoma , Neoplasms, Second Primary , Pilomatrixoma , Skin Neoplasms , Wnt Proteins , Adenomatous Polyposis Coli/diagnosis , Adenomatous Polyposis Coli/genetics , Adenomatous Polyposis Coli/metabolism , Adenomatous Polyposis Coli/pathology , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Cerebellar Neoplasms/diagnosis , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/pathology , Child , Female , Hair Diseases/diagnosis , Hair Diseases/genetics , Hair Diseases/metabolism , Hair Diseases/pathology , Humans , Medulloblastoma/diagnosis , Medulloblastoma/genetics , Medulloblastoma/metabolism , Medulloblastoma/pathology , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/metabolism , Neoplasms, Second Primary/pathology , Pilomatrixoma/diagnosis , Pilomatrixoma/genetics , Pilomatrixoma/metabolism , Pilomatrixoma/pathology , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Wnt Proteins/genetics , Wnt Proteins/metabolism
16.
Am J Surg Pathol ; 41(6): 738-749, 2017 Jun.
Article in English | MEDLINE | ID: mdl-28368926

ABSTRACT

Basal cell carcinoma (BCC) with matrical differentiation is a fairly rare neoplasm, with about 30 cases documented mainly as isolated case reports. We studied a series of this neoplasm, including cases with an atypical matrical component, a hitherto unreported feature. Lesions coded as BCC with matrical differentiation were reviewed; 22 cases were included. Immunohistochemical studies were performed using antibodies against BerEp4, ß-catenin, and epithelial membrane antigen (EMA). Molecular genetic studies using Ion AmpliSeq Cancer Hotspot Panel v2 by massively parallel sequencing on Ion Torrent PGM were performed in 2 cases with an atypical matrical component (1 was previously subjected to microdissection to sample the matrical and BCC areas separately). There were 13 male and 9 female patients, ranging in age from 41 to 89 years. Microscopically, all lesions manifested at least 2 components, a BCC area (follicular germinative differentiation) and areas with matrical differentiation. A BCC component dominated in 14 cases, whereas a matrical component dominated in 4 cases. Matrical differentiation was recognized as matrical/supramatrical cells (n=21), shadow cells (n=21), bright red trichohyaline granules (n=18), and blue-gray corneocytes (n=18). In 2 cases, matrical areas manifested cytologic atypia, and a third case exhibited an infiltrative growth pattern, with the tumor metastasizing to a lymph node. BerEP4 labeled the follicular germinative cells, whereas it was markedly reduced or negative in matrical areas. The reverse pattern was seen with ß-catenin. EMA was negative in BCC areas but stained a proportion of matrical/supramatrical cells. Genetic studies revealed mutations of the following genes: CTNNB1, KIT, CDKN2A, TP53, SMAD4, ERBB4, and PTCH1, with some differences between the matrical and BCC components. It is concluded that matrical differentiation in BCC in most cases occurs as multiple foci. Rare neoplasms manifest atypia in the matrical areas. Immunohistochemical analysis for BerEP4, EMA, and ß-catenin can be helpful in limited biopsy specimens. From a molecular biological prospective, BCC and matrical components appear to share some of the gene mutations but have differences in others, but this observation must be validated in a large series.


Subject(s)
Carcinoma, Basal Cell/pathology , Hair Diseases/pathology , Pilomatrixoma/pathology , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/metabolism , Carcinoma, Basal Cell/mortality , Cell Differentiation , Female , Follow-Up Studies , Hair Diseases/genetics , Hair Diseases/metabolism , Hair Diseases/mortality , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Pilomatrixoma/genetics , Pilomatrixoma/metabolism , Pilomatrixoma/mortality , Prognosis , Skin Neoplasms/genetics , Skin Neoplasms/metabolism , Skin Neoplasms/mortality
17.
Fam Cancer ; 16(1): 67-71, 2017 01.
Article in English | MEDLINE | ID: mdl-27573199

ABSTRACT

In a 14-year-old boy with polyposis and rectosigmoid carcinoma, we identified a novel POLE germline mutation, p.(Val411Leu), previously found as recurrent somatic mutation in 'ultramutated' sporadic cancers. This is the youngest reported cancer patient with polymerase proofreading-associated polyposis indicating that POLE mutation p.(Val411Leu) may confer a more severe phenotype than previously reported POLE and POLD1 germline mutations. The patient had multiple café-au-lait macules and a pilomatricoma mimicking the clinical phenotype of constitutional mismatch repair deficiency. We hypothesize that these skin features may be common to different types of constitutional DNA repair defects associated with polyposis and early-onset cancer.


Subject(s)
Brain Neoplasms/genetics , Colorectal Neoplasms/genetics , DNA Polymerase II/genetics , Germ-Line Mutation , Neoplastic Syndromes, Hereditary/genetics , Adolescent , Age of Onset , Cafe-au-Lait Spots/genetics , Hair Diseases/genetics , Humans , Male , Microsatellite Instability , Pilomatrixoma/genetics , Poly-ADP-Ribose Binding Proteins , Skin Neoplasms/genetics
20.
Brain Pathol ; 25(4): 429-40, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25521223

ABSTRACT

Pilomyxoid astrocytomas (PMAs) manifest a more aggressive clinical course than pilocytic astrocytomas (PAs). Development of effective therapies demands a better biological understanding of PMA. We first conducted gene expression microarray analysis of 9 PMA and 13 PA from infra- and supratentorial sites. Unsupervised hierarchical clustering analysis demonstrated that tumors are grouped according to anatomic site, not diagnosis. Gene expression profiles were then contrasted between eight PMAs and six PAs, all supratentorial/hypothalamic/chiasmal. Clinical outcome of PMAs varied, with four out of four patients with diencephalic syndrome succumbing to disease, one of whom showed bulky metastatic leptomeningeal spread at autopsy, with bimodal maturation to PA in some areas and de-differentiation to glioblastoma in others. A surviving child has undergone multiple surgical debulking, with progressive maturation to PA over time. Ontology-enrichment analysis identified overexpression in PMAs of extracellular matrix and mitosis-related genes. Genes overexpressed in PMA vs. PA, ranked according to fold-change, included developmental genes H19, DACT2, extracellular matrix collagens (COL2A1; COL1A1) and IGF2BP3 (IMP3), the latter previously identified as an adverse prognostic factor in PMA and PA.


Subject(s)
Astrocytoma/genetics , Brain Neoplasms/genetics , Gene Expression , Mutation/genetics , Pilomatrixoma/genetics , Adolescent , Astrocytoma/pathology , Brain Neoplasms/pathology , Child , Child, Preschool , Cohort Studies , Female , Gene Expression Profiling , Gene Ontology , Humans , Infant , Male , Oligonucleotide Array Sequence Analysis , Pilomatrixoma/pathology , Proto-Oncogene Proteins B-raf/genetics , RNA-Binding Proteins/genetics
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