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1.
Int J Cancer ; 2020 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-32383186

RESUMO

Hyalinizing trabecular tumors of the thyroid are rare and mostly benign epithelial neoplasms of follicular cell origin, which have recently been shown to be underpinned by the PAX8-GLIS3 fusion gene. In our study, we sought to investigate the potential oncogenic mechanisms of the PAX8-GLIS3 fusion gene. Forced expression of PAX8-GLIS3 was found to increase proliferation, clonogenic potential and migration of human nonmalignant thyroid (Nthy-ori 3-1) and embryonic kidney (HEK-293) cells. Moreover, in xenografts, Nthy-ori 3-1 PAX8-GLIS3 expressing cells generated significantly larger and more proliferative tumors compared to controls. These oncogenic effects were found to be mediated through activation of the Sonic Hedgehog (SHH) pathway. Targeting of smoothened (SMO), a key protein in the SHH pathway, using the small molecule inhibitor Cyclopamine partially reversed the increased proliferation, colony formation and migration in PAX8-GLIS3 expressing cells. Our data demonstrate that the oncogenic effects of the PAX8-GLIS3 fusion gene are, at least in part, due to an increased activation of the SHH pathway.

2.
Mod Pathol ; 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32317704

RESUMO

High-grade histologic transformation of low-grade endometrial stromal sarcoma (LGESS) is rare. Here, we describe the clinicopathologic features and gene fusion status of 12 cases (11 primary uterine corpus and 1 primary vaginal), 11 diagnosed prospectively from 2016, and 1 retrospectively collected. Targeted RNA sequencing and/or fluorescence in situ hybridization was employed in all cases. High-grade transformation was seen at the time of initial diagnosis in eight patients and at the time of recurrence in four patients, 4-11 years after initial diagnosis of LGESS. High-grade morphology consisted of generally uniform population of round to epithelioid cells with enlarged nuclei one to two times larger than a lymphocyte, visible nucleoli, and increased mitotic index (range, 6-30; median, 16 per 10 high-power fields); there was often an associated sclerotic and/or myxoid stroma. Estrogen receptor, progesterone receptor, and CD10 expression was absent or significantly decreased (compared with the low-grade component) in the high-grade foci of five tumors. One tumor demonstrated positive (diffuse and strong) cyclin D1 and BCOR staining. p53 staining was wild type in both components of all eight tumors tested. JAZF1-SUZ12 (n = 6), JAZF1-PHF1 (n = 3), EPC1-PHF1, (n = 1), or BRD8-PHF1 (n = 1) fusions were detected in 11 tumors; no fusions were found in one by targeted RNA sequencing. Patients presented with FIGO stages I (n = 4), II (n = 4), III (n = 1), and IV disease (n = 2). Median overall survival calculated from the time of histologic transformation was 22 months (range, 8 months to 8 years) with five patients who died of disease 8-18 months after transformation. High-grade transformation may occur in LGESS with JAZF1 and PHF1 rearrangements at the time of or years after initial diagnosis. Such high-grade transformation is characterized by nuclear enlargement, prominent nucleoli, and increased mitotic index compared with typical LGESS. Histologic high-grade transformation may herald aggressive behavior.

3.
Am J Surg Pathol ; 44(5): 641-648, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32205482

RESUMO

Endometrial carcinoma (EC), as described by Bokhman, has historically been classified as Type I (low-grade, hormone-dependant, young patients, good prognosis) or Type II (high-grade, hormone-independent, older patients, poor prognosis). This classification is no longer pragmatic, however, as EC is a much more heterogeneous disease. Four molecular subtypes of EC were identified by The Cancer Genome Atlas (TCGA), and subsequent studies have demonstrated its utility in predicting prognosis. While endometrial serous carcinoma (ESC), the prototypical Type II EC, largely occurs in older women, younger women with ESC were not accounted for in the Bokhman model and were underrepresented in the TCGA study. We hypothesized that a subset of ESCs in young patients do not represent bona fide serous carcinomas but rather high-grade endometrioid carcinomas mimicking a serous phenotype. We identified ESCs and mixed endometrioid/serous carcinomas in women <60 years (n=37), and analyzed their clinical, morphologic, immunohistochemical, and molecular characteristics. Sixteen percent showed mismatch repair deficiency (MMR-D) and 11% were diagnosed with Lynch syndrome. Additionally, 16% of cases tested harbored a hotspot POLE exonuclease domain mutation (POLE-EDM). Morphologically, 47% of tumors showed confirmatory endometrioid features, including atypical hyperplasia, a low-grade endometrioid carcinoma component, or squamous differentiation. Clinically, the overall survival in patients with MMR-D and POLE-EDM was significantly better than that of patients without these features (P=0.0329). In conclusion, ESCs in young patients comprise a heterogeneous group of tumors, demonstrating diverse clinical, immunohistochemical, morphologic, and molecular features which have implications for prognosis and adjuvant therapy.

4.
Clin Cancer Res ; 2020 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-32220886

RESUMO

PURPOSE: Ductal carcinoma in situ (DCIS) is a nonobligate precursor of invasive breast cancer. Here, we sought to investigate the level of intralesion genetic heterogeneity in DCIS and the patterns of clonal architecture changes in the progression from DCIS to invasive disease. DESIGN: Synchronous DCIS (n = 27) and invasive ductal carcinomas of no special type (IDC-NSTs; n = 26) from 25 patients, and pure DCIS (n = 7) from 7 patients were microdissected separately and subjected to high-depth whole-exome (n = 56) or massively parallel sequencing targeting ≥410 key cancer-related genes (n = 4). Somatic genetic alterations, mutational signatures, clonal composition, and phylogenetic analyses were defined using validated computational methods. RESULTS: DCIS revealed genetic alterations similar to those of synchronously diagnosed IDC-NSTs and of non-related IDC-NSTs from The Cancer Genome Atlas (TCGA), whereas pure DCIS lacked PIK3CA mutations. Clonal decomposition and phylogenetic analyses based on somatic mutations and copy number alterations revealed that the mechanisms of progression of DCIS to invasive carcinoma are diverse, and that clonal selection might have constituted the mechanism of progression from DCIS to invasive disease in 28% (7/25) of patients. DCIS displaying a pattern of clonal selection in the progression to invasive cancer harbored higher levels of intralesion genetic heterogeneity than DCIS where no clonal selection was observed. CONCLUSIONS: Intralesion genetic heterogeneity is a common feature in DCIS synchronously diagnosed with IDC-NST. DCIS is a nonobligate precursor of IDC-NST, whose mechanisms of progression to invasive breast cancer are diverse and vary from case to case.

5.
Mod Pathol ; 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32203090

RESUMO

Adult-type granulosa cell tumor (aGCT) is a rare malignant ovarian sex cord-stromal tumor, harboring recurrent FOXL2 c.C402G/p.C134W hotspot mutations in 97% of cases. These tumors are considered to have a favorable prognosis, however aGCTs have a tendency for local spread and late recurrences, which are associated with poor survival rates. We sought to determine the genetic alterations associated with aGCT disease progression. We subjected primary non-recurrent aGCTs (n = 7), primary aGCTs that subsequently recurred (n = 9) and their matched recurrences (n = 9), and aGCT recurrences without matched primary tumors (n = 10) to targeted massively parallel sequencing of ≥410 cancer-related genes. In addition, three primary non-recurrent aGCTs and nine aGCT recurrences were subjected to FOXL2 and TERT promoter Sanger sequencing analysis. All aGCTs harbored the FOXL2 C134W hotspot mutation. TERT promoter mutations were found to be significantly more frequent in recurrent (18/28, 64%) than primary aGCTs (5/19, 26%, p = 0.017). In addition, mutations affecting TP53, MED12, and TET2 were restricted to aGCT recurrences. Pathway annotation of altered genes demonstrated that aGCT recurrences displayed an enrichment for genetic alterations affecting cell cycle pathway-related genes. Analysis of paired primary and recurrent aGCTs revealed that TERT promoter mutations were either present in both primary tumors and matched recurrences or were restricted to the recurrence and absent in the respective primary aGCT. Clonal composition analysis of these paired samples further revealed that aGCTs display intra-tumor genetic heterogeneity and harbor multiple clones at diagnosis and relapse. We observed that in a subset of cases, recurrences acquired additional genetic alterations not present in primary aGCTs, including TERT, MED12, and TP53 mutations and CDKN2A/B homozygous deletions. Albeit harboring relatively simple genomes, our data provide evidence to suggest that aGCTs are genetically heterogeneous tumors and that TERT promoter mutations and/or genetic alterations affecting other cell cycle-related genes may be associated with disease progression and recurrences.

6.
Nat Genet ; 52(2): 198-207, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31932695

RESUMO

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores Estrogênicos/metabolismo , Fatores de Transcrição/genética , Animais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Fator 3-alfa Nuclear de Hepatócito/genética , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Camundongos , Mutação , Receptores Estrogênicos/genética , Fatores de Transcrição/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Mod Pathol ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896809

RESUMO

Tall cell carcinoma with reverse polarity is a rare subtype of breast carcinoma with solid and papillary growth and nuclear features reminiscent of those of the tall cell variant of papillary thyroid carcinoma. These tumors harbor recurrent IDH2 R172 hotspot mutations or TET2 mutations, co-occurring with mutations in PI3K pathway genes. Diagnosis of tall cell carcinomas with reverse polarity is challenging in view of their rarity and the range of differential diagnosis. We sought to determine the sensitivity and specificity of IDH2 R172 immunohistochemistry for the detection of IDH2 R172 hotspot mutations in this entity. We evaluated 14 tall cell carcinomas with reverse polarity (ten excision and five core needle biopsy specimens), 13 intraductal papillomas, 16 solid papillary carcinomas, and 5 encapsulated papillary carcinomas by Sanger sequencing of the IDH2 R172 hotspot locus and of exons 9 and 20 of PIK3CA, and by immunohistochemistry using monoclonal antibodies (11C8B1) to the IDH2 R172S mutation. The 14 tall cell carcinomas with reverse polarity studied harbored IDH2 R172 hotspot mutations, which co-occurred with PIK3CA hotspot mutations in 50% of cases. None of the other papillary neoplasms analyzed displayed IDH2 R172 mutations, however PIK3CA hotspot mutations were detected in 54% of intraductal papillomas, 6% of solid papillary carcinomas, and 20% of encapsulated papillary carcinomas tested. Immunohistochemical analysis with anti-IDH2 R172S antibodies (11C8B1) detected IDH2 R172 mutated protein in 93% (14/15) of tall cell carcinomas with reverse polarity samples including excision (n = 9/10) and core needle biopsy specimens (n = 5), whereas the remaining papillary neoplasms (n = 34) were negative. Our findings demonstrate that immunohistochemical analysis of IDH2 R172 is highly sensitive and specific for the detection of IDH2 R172 hotspot mutations, and likely suitable as a diagnostic tool in the evaluation of excision and core needle biopsy material of tall cell carcinomas with reverse polarity.

8.
Nat Commun ; 11(1): 44, 2020 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896750

RESUMO

Sclerosing stromal tumor (SST) of the ovary is a rare type of sex cord-stromal tumor (SCST), whose genetic underpinning is currently unknown. Here, using whole-exome, targeted capture and RNA-sequencing, we report recurrent FHL2-GLI2 fusion genes in 65% (17/26) of SSTs and other GLI2 rearrangements in additional 15% (4/26) SSTs, none of which are detected in other types of SCSTs (n = 48) or common cancer types (n = 9,950). The FHL2-GLI2 fusions result in transcriptomic activation of the Sonic Hedgehog (SHH) pathway in SSTs. Expression of the FHL2-GLI2 fusion in vitro leads to the acquisition of phenotypic characteristics of SSTs, increased proliferation, migration and colony formation, and SHH pathway activation. Targeted inhibition of the SHH pathway results in reversal of these oncogenic properties, indicating its role in the pathogenesis of SSTs. Our results demonstrate that the FHL2-GLI2 fusion is likely the oncogenic driver of SSTs, defining a genotypic-phenotypic correlation in ovarian neoplasms.


Assuntos
Proteínas com Homeodomínio LIM/genética , Proteínas Musculares/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Neoplasias Ovarianas/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Fatores de Transcrição/genética , Proteína Gli2 com Dedos de Zinco/genética , Adolescente , Adulto , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Pessoa de Meia-Idade , Mutação , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Ovarianas/patologia , Esclerose , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Células Estromais/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
9.
Mod Pathol ; 33(1): 65-73, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31492931

RESUMO

Polymorphous adenocarcinoma (PAC) and cribriform adenocarcinoma of (minor) salivary gland (CASG) are salivary gland tumors with overlapping spectrum of morphology. Whether these represent distinct entities or a histologic spectrum of the same tumor remains contentious. PACs harbor recurrent PRKD1 E710D hotspot mutations in >70% of cases, whereas 80% of CASGs display rearrangements involving PRKD1, PRKD2, or PRKD3 (PRKD1/2/3). We studied the molecular and morphologic features of 37 PACs/CASGs, seeking to identify the associations among genotype, histologic phenotype, and classification. DNA was subjected to Sanger sequencing analysis of the PRKD1 hotspot locus. Fluorescence in situ hybridization (FISH) analysis for PRKD1/2/3 was performed using dual-color break-apart probes. Tumors were classified into four categories as described previously: PAC, CASG, tumor with indeterminate features (TIF), and tumor with a predominant papillary pattern (TPPP). PRKD1 E710D hotspot mutations were identified in 56%, 20%, 43% and 0% of PACs, CASGs, TIFs, and TPPPs, respectively. FISH demonstrated PRKD1/2/3 rearrangements in 13%, 78%, 36%, and 75% of PACs, CASGs, TIFs, and TPPPs, respectively. Histologically, fusion-positive tumors were associated with a high percentage of papillary growth, low percentage of single filing arrangement, a propensity of base of tongue location, and frequent (50%) lymph node metastasis, compared with the mutation-related tumors which had negligible nodal metastasis risk. Our results demonstrated that (1) PACs/CASGs are underpinned by genetic alterations affecting PRKD genes; (2) despite the associations between PAC and PRKD1 hotspot mutations and CASG and PRKD1/2/3 fusion, such distinction is not absolute; and (3) there is of a novel genotypic-phenotypic association whereby fusion-positive tumors are usually located in the base of the tongue, show papillary architecture and have a high risk of nodal metastasis. Genetic analysis of PRKD genes appears to be useful characterizing this spectrum of tumors, not only histologically but also clinically identifying those tumors with high risk of nodal metastasis.

10.
Gynecol Oncol ; 156(1): 194-202, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31757464

RESUMO

OBJECTIVES: Assess outcomes of a clinical cohort of patients with endometrioid endometrial cancer (EEC) harboring somatic POLE exonuclease domain mutations (EDMs). METHODS: Patients were consented to a protocol of tumor-normal massively parallel sequencing of 410-468 cancer related genes. EECs subjected to sequencing from 2014 to 2018 were reviewed. Tumors with somatic POLE EDMs were identified. EECs were assessed for microsatellite instability (MSI) using MSIsensor and immunohistochemical analysis for mismatch repair (MMR) proteins. RESULTS: Of the 451 EECs sequenced, 23 had a POLE EDM (5%): 20 primary and 3 recurrent tumors sequenced. Nineteen cases (83%) were stage I/II and 4 (17%) were stages III/IV. Thirteen EECs (57%) were of FIGO grades 1/2, 10 (43%) grade 3. All patients were treated with surgery and 17 (89%) received adjuvant therapy. Five (22%) demonstrated loss of DNA MMR protein expression, none were due to Lynch syndrome. MSIsensor scores were conclusive for 21 samples: 19 were microsatellite stable and 2 MSI-high. After median follow-up of 30 months, 4/23 (17%) developed recurrences: 3 with initial grade 3 stage I and 1 with grade 1 stage III disease. One patient with grade 2 stage IV EEC had progressive disease after treatment. CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy.


Assuntos
Carcinoma Endometrioide/genética , DNA Polimerase II/genética , Neoplasias do Endométrio/genética , Proteínas de Ligação a Poli-ADP-Ribose/genética , Adulto , Idoso , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/terapia , Estudos de Coortes , Reparo de Erro de Pareamento de DNA , DNA Polimerase II/metabolismo , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/terapia , Feminino , Humanos , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Prognóstico , Estudos Prospectivos
11.
Int J Surg Pathol ; : 1066896919890401, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801397

RESUMO

Aims. The aim of this study was to identify potential driver genetic alterations in a dedifferentiated liposarcoma (DDLPS) with rhabdomyosarcomatous differentiation. Methods and Results. A 24-year-old female underwent resection of an abdominal mass, which on a previous biopsy demonstrated rhabdomyosarcomatous differentiation concerning for embryonal rhabdomyosarcoma. Histologically the resected tumor displayed a high-grade sarcoma with rhabdomyosarcomatous differentiation in the background of well-differentiated liposarcoma consistent with DDLPS. Fluorescence in situ hybridization confirmed MDM2 amplification, as did array-based copy number profiling. Whole-exome sequencing revealed a somatic FGFR1 hotspot mutation and RNA sequencing an LMNB2-MAP2K6 fusion only within the dedifferentiated component. Conclusions. This study represents an in-depth examination of a rare DDLPS with rhabdomyosarcomatous differentiation in a young individual. Additionally, it is also instructive of a potential pitfall when assessing for MDM2 amplification in small biopsies. Despite exhaustive analysis, mutation and gene copy number analysis did not identify any molecular events that would underlie the rhabdomyoblastic differentiation. Our understanding of what causes some tumors to dedifferentiate as well as undergo divergent differentiation is limited, and larger studies are needed.

12.
Mod Pathol ; 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383964

RESUMO

We have encountered pancreatic tumors with unique histologic features, which do not conform to any of the known tumors of the pancreas or other anatomical sites. We aimed to define their clinicopathologic features and whether they are characterized by recurrent molecular signatures. Eight cases were identified; studied histologically and by immunohistochemistry. Selected cases were also subjected to whole-exome sequencing (WES; n = 4), RNA-sequencing (n = 6), Archer FusionPlex assay (n = 5), methylation profiling using the Illumina MethylationEPIC (850k) array platform (n = 6), and TERT promoter sequencing (n = 5). Six neoplasms occurred in females. The mean age was 43 years (range: 26-75). Five occurred in the head/neck of the pancreas. All patients were treated surgically; none received neoadjuvant/adjuvant therapy. All patients are free of disease after 53 months of median follow-up (range: 8-94). The tumors were well-circumscribed, and the median size was 1.8 cm (range: 1.3-5.8). Microscopically, the unencapsulated tumors had a geographic pattern of epithelioid cell nests alternating with spindle cell fascicles. Some areas showed dense fibrosis, in which enmeshed tumor cells imparted a slit-like pattern. The predominant epithelioid cells had scant cytoplasm and round-oval nuclei with open chromatin. The spindle cells displayed irregular, hyperchromatic nuclei. Mitoses were rare. No lymph node metastases were identified. All tumors were positive for vimentin, CD99 and cytokeratin (patchy), while negative for markers of solid pseudopapillary neoplasm, neuroendocrine, acinar, myogenic/rhabdoid, vascular, melanocytic, or lymphoid differentiation, gastrointestinal stromal tumor as well as MUC4. Whole-exome sequencing revealed no recurrent somatic mutations or amplifications/homozygous deletions in any known oncogenes or tumor suppressor genes. RNA-sequencing and the Archer FusionPlex assay did not detect any recurrent likely pathogenic gene fusions. Single sample gene set enrichment analysis revealed that these tumors display a likely mesenchymal transcriptomic program. Unsupervised analysis (t-SNE) of their methylation profiles against a set of different mesenchymal neoplasms demonstrated a distinct methylation pattern. Here, we describe pancreatic neoplasms with unique morphologic/immunophenotypic features and a distinct methylation pattern, along with a lack of abnormalities in any of key genetic drivers, supporting that these neoplasms represent a novel entity with an indolent clinical course. Given their mesenchymal transcriptomic features, we propose the designation of "sclerosing epithelioid mesenchymal neoplasm" of the pancreas.

13.
Histopathology ; 75(6): 931-937, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31361912

RESUMO

AIMS: Acinic cell carcinoma (ACC) of the breast is a rare histological form of triple-negative breast cancer (TNBC). Despite its unique histology, targeted sequencing analysis has failed to identify recurrent genetic alterations other than those found in common forms of TNBC. Here we subjected three breast ACCs to whole-exome and RNA sequencing to determine whether they would harbour a pathognomonic genetic alteration. METHODS AND RESULTS: DNA and RNA samples from three breast ACCs were subjected to whole-exome sequencing and RNA-sequencing, respectively. Somatic mutations, copy number alterations, mutational signatures and fusion genes were determined with state-of-the-art bioinformatics methods. Our analyses revealed TP53 hotspot mutations associated with loss of heterozygosity of the wild-type allele in two cases. Mutations affecting homologous recombination DNA repair-related genes were found in two cases, and an MLH1 pathogenic germline variant was found in one case. In addition, copy number analysis revealed the presence of a somatic BRCA1 homozygous deletion and focal amplification of 12q14.3-12q21.1, encompassing MDM2, HMGA2, FRS2, and PTPRB. No oncogenic in-frame fusion transcript was identified in the three breast ACCs analysed. CONCLUSIONS: No pathognomonic genetic alterations were detected in the breast ACCs analysed. These tumours have somatic genetic alterations similar to those of common forms of TNBC, and may show homologous recombination deficiency or microsatellite instability. These findings provide further insights into why breast ACCs, which are usually clinically indolent, may evolve into or in parallel with high-grade TNBC.

14.
Mod Pathol ; 32(12): 1734-1743, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31273314

RESUMO

The hyalinizing trabecular adenoma/tumor is a rare and poorly characterized follicular-derived thyroid neoplasm recently shown to harbor recurrent PAX8-GLIS1 or PAX8-GLIS3 gene fusions. Here we sought to define the repertoire of genetic alterations of hyalinizing trabecular tumors, and whether PAX8-GLIS3 fusions are pathognomonic for hyalinizing trabecular tumors. A discovery series of eight hyalinizing trabecular tumors was subjected to RNA-sequencing (n = 8), whole-exome sequencing (n = 3) or targeted massively parallel sequencing (n = 5). No recurrent somatic mutations or copy number alterations were identified in hyalinizing trabecular tumor, whereas RNA-sequencing revealed the presence of a recurrent genetic rearrangement involving PAX8 (2q14.1) and GLIS3 (9p24.2) genes in all cases. In this in-frame fusion gene, which comprised exons 1-2 of PAX8 and exons 3-11 of GLIS3, GLIS3 is likely placed under the regulation of PAX8. Reverse transcription RT-PCR and/or fluorescence in situ hybridization analyses of a validation series of 26 hyalinizing trabecular tumors revealed that the PAX8-GLIS3 gene fusion was present in all hyalinizing trabecular tumors (100%). No GLIS1 rearrangements were identified. Conversely, no PAX8-GLIS3 gene fusions were detected in a cohort of 237 control thyroid neoplasms, including 15 trabecular thyroid lesions highly resembling hyalinizing trabecular tumor from a morphological standpoint, as well as trabecular/solid follicular adenomas, solid/trabecular variants of papillary carcinoma, and Hurthle cell adenomas or carcinomas. Our data provide evidence to suggest that the PAX8-GLIS3 fusion is pathognomonic for hyalinizing trabecular tumors, and that the presence of the PAX8-GLIS3 fusion in thyroid neoplasms may be used as an ancillary marker for the diagnosis of hyalinizing trabecular tumor, thereby avoiding overtreatment in case of misdiagnoses with apparently similar malignant tumors.

15.
Cancer Discov ; 9(9): 1182-1191, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31227518

RESUMO

We report the emergence of the novel MEK1 V211D gatekeeper mutation in a patient with BRAF K601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1 V211D mutation concurrently occurs in the same cell with BRAF K601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance. SIGNIFICANCE: We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A MEK1 V211D mutation developed in a patient with BRAF K601E colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors.This article is highlighted in the In This Issue feature, p. 1143.

16.
Histopathology ; 75(1): 139-145, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30843622

RESUMO

AIMS: Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)-positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas. METHODS AND RESULTS: DNA from five MPMCs was subjected to whole-exome sequencing. Somatic mutations, copy number alterations and mutational signatures were determined with state-of-the-art bioinformatics methods. No mutations in genes significantly mutated in breast cancer, including TP53, PIK3CA, GATA3, and MAP3K1, were detected. We identified copy number alterations that have been reported in invasive micropapillary carcinomas, such as recurrent gains in 1q, 6p, 8q, and 10q, and recurrent losses in 16q, 11q, and 13q, as well as a recurrent 8p12-8p11.2 amplification encompassing FGFR1. Like mucinous carcinomas, three of the five MPMCs analysed lacked PIK3CA mutations, 1q gains, and 16q losses, which are the hallmark genetic alterations of ER-positive breast cancers, whereas two MPMCs harboured 16q losses and/or a complex pattern of copy number alterations similar to those found in breast-invasive micropapillary carcinomas. CONCLUSIONS: MPMCs are heterogeneous at the genetic level; some tumours show a pattern of somatic genetic alterations similar to those of mucinous carcinomas, whereas others resemble invasive micropapillary carcinomas at the genetic level. These findings suggest that MPMCs may not constitute one histological subtype, but rather a convergent phenotype that can stem from mucinous carcinomas or invasive micropapillary carcinomas.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Adenocarcinoma Mucinoso/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Carcinoma Papilar/metabolismo , Variações do Número de Cópias de DNA , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Fenótipo , Receptores Estrogênicos/metabolismo
17.
NPJ Breast Cancer ; 5: 6, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30675516

RESUMO

Breast adenomyoepitheliomas (AMEs) are rare epithelial-myoepithelial neoplasms that may occasionally produce myxochondroid matrix, akin to pleomorphic adenomas (PAs). Regardless of their anatomic location, PAs often harbor rearrangements involving HMGA2 or PLAG1. We have recently shown that the repertoire of somatic genetic alterations of AMEs varies according to their estrogen receptor (ER) status; whilst the majority of ER-positive AMEs display mutually exclusive PIK3CA or AKT1 hotspot mutations, up to 60% of ER-negative AMEs harbor concurrent HRAS Q61 hotspot mutations and mutations affecting either PIK3CA or PIK3R1. Here, we hypothesized that a subset of AMEs lacking these somatic genetic alterations could be underpinned by oncogenic fusion genes, in particular those involving HMGA2 or PLAG1. Therefore, we subjected 13 AMEs to RNA-sequencing for fusion discovery (n = 5) and/or fluorescence in situ hybridization (FISH) analysis for HMGA2 and PLAG1 rearrangements (n = 13). RNA-sequencing revealed an HMGA2-WIF1 fusion gene in an ER-positive AME lacking HRAS, PIK3CA and AKT1 somatic mutations. This fusion gene, which has been previously described in salivary gland PAs, results in a chimeric transcript composed of exons 1-5 of HMGA2 and exons 3-10 of WIF1. No additional in-frame fusion genes or HMGA2 or PLAG1 rearrangements were identified in the remaining AMEs analyzed. Our results demonstrate that a subset of AMEs lacking mutations affecting HRAS and PI3K pathway-related genes may harbor HMGA2-WIF1 fusion genes, suggesting that a subset of breast AMEs may be genetically related to PAs or that a subset of AMEs may originate in the context of a PA.

18.
J Natl Cancer Inst ; 2019 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-30649385

RESUMO

Mucinous carcinoma of the breast (MCB) is a rare histologic form of estrogen receptor (ER)-positive/HER2-negative breast cancer (BC) characterized by tumor cells floating in lakes of mucin. We assessed the genomic landscape of 32 MCBs by whole-exome sequencing and/or RNA-sequencing. GATA3 (23.8%), KMT2C (19.0%), and MAP3K1 (14.3%) were the most frequently mutated genes in pure MCBs. In addition, two recurrent but not pathognomonic fusion genes, OAZ1-CSNK1G2 and RFC4-LPP, were detected in 3/31 (9.7%) and 2/31 (6.5%) samples, respectively. Compared with ER-positive/HER2-negative common forms of BC, MCBs displayed lower PIK3CA and TP53 mutation rates and fewer concurrent 1q gains and 16q losses. Clonal decomposition analysis of the mucinous and ductal components independently microdissected from five mixed MCBs revealed that they are clonally related and evolve following clonal selection or parallel evolution. Our findings indicate that MCB represents a genetically distinct ER-positive/HER2-negative form of BC.

19.
Gynecol Oncol ; 152(1): 11-19, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30415991

RESUMO

OBJECTIVE: Mutational signatures provide insights into the biological processes shaping tumor genomes and may inform patient therapy. We sought to define the mutational signatures of i) endometrioid and serous endometrial carcinomas (ECs), stratified into the four molecular subtypes, ii) uterine carcinosarcomas, and iii) matched primary and metastatic ECs. METHODS: Whole-exome sequencing MC3 data from primary endometrioid and serous carcinomas (n = 232) and uterine carcinosarcomas (n = 57) from The Cancer Genome Atlas (TCGA), and matched primary and metastatic ECs (n = 61, 26 patients) were reanalyzed, subjected to mutational signature analysis using deconstructSigs, and correlated with clinicopathologic and genomic data. RESULTS: POLE (ultramutated) and MSI (hypermutated) molecular subtypes displayed dominant mutational signatures associated with POLE mutations (15/17 cases) and microsatellite instability (55/65 cases), respectively. Most endometrioid and serous carcinomas of copy-number low (endometrioid) and copy-number high (serous-like) molecular subtypes, and carcinosarcomas displayed a dominant aging-associated signature 1. Only 15% (9/60) of copy-number high (serous-like) ECs had a dominant signature 3 (homologous recombination DNA repair deficiency (HRD)-related), a prevalence significantly lower than that found in high-grade serous ovarian carcinomas (54%, p < 0.001) or basal-like breast cancers (46%, p < 0.001). Shifts from aging- or POLE- to MSI-related mutational processes were observed in the progression from primary to metastatic ECs in a subset of cases. CONCLUSIONS: The mutational processes underpinning ECs vary even among tumors of the same TCGA molecular subtype and in the progression from primary to metastatic ECs. Only a minority of copy-number high (serous-like) ECs display genomics features of HRD and would likely benefit from HRD-directed therapies.


Assuntos
Reparo do DNA , Neoplasias do Endométrio/genética , Mutação , Carcinossarcoma/genética , Progressão da Doença , Neoplasias do Endométrio/patologia , Feminino , Dosagem de Genes , Humanos , Instabilidade de Microssatélites , Metástase Neoplásica , Neoplasias Uterinas/genética
20.
J Clin Pathol ; 72(3): 258-262, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30467240

RESUMO

AIMS: Most benign breast fibroepithelial lesions (FEL) in adults harbour recurrent somatic MED12 exon 2 mutations and rare TERT promoter hotspot mutations. We sought to determine the frequency of MED12 exon 2 and TERT promoter hotspot mutations in fibroadenomas (FA) and benign phyllodes tumours (BePT) in adolescents and young adults. METHODS: DNA from 21 consecutive FAs and eight consecutive BePTs in adolescents and young adults was subjected to Sanger sequencing of the exon 2 of MED12 and the TERT promoter hotspot locus. RESULTS: We identified MED12 exon 2 mutations in 62% and 88% of FAs and BePTs, respectively, and no TERT promoter hotspot mutations. The majority of the MED12 exon 2 mutations identified were in-frame deletions (60%). CONCLUSIONS: As in adults, benign FELs in juvenile patients harbour recurrent MED12 exon 2 mutations.


Assuntos
Neoplasias da Mama/genética , Fibroadenoma/genética , Complexo Mediador/genética , Tumor Filoide/genética , Adolescente , Adulto , Éxons/genética , Feminino , Humanos , Mutação , Adulto Jovem
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