RESUMO
DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving kidney, lung, and female reproductive system. Over 70% of sarcomas in DICER1 tumor predisposition syndrome occur in females. Notably, pediatric cystic nephroma (pCN), a classic DICER1 tumor predisposition syndrome lesion, shows estrogen receptor (ER) expression in stromal cells. There are also renal, hepatic, and pancreatic lesions unassociated with DICER1 tumor predisposition syndrome that have an adult female predominance and are characterized/defined by ER-positive stromal cells. Except for pCN, the expression of ER in DICER1-associated lesions remains uninvestigated. In the present study, ER expression was assessed by immunohistochemistry in 89 cases of DICER1-related lesions and 44 lesions lacking DICER1 pathogenic variants. Expression was seen in stromal cells in pCN and pleuropulmonary blastoma (PPB) types I and Ir, whereas anaplastic sarcoma of kidney and PPB types II and III were typically negative, as were other solid tumors of non-Müllerian origin. ER expression was unrelated to the sex or age of the patient. Expression of ER showed an inverse relationship to preferentially expressed antigen in melanoma (PRAME) expression; as lesions progressed from cystic to solid (pCN/anaplastic sarcoma of kidney, and PPB types I to III), ER expression was lost and (PRAME) expression increased. Thus, in DICER1 tumor predisposition syndrome, there is no evidence that non-Müllerian tumors are hormonally driven and antiestrogen therapy is not predicted to be beneficial. Lesions not associated with DICER1 pathogenic variants also showed ER-positive stromal cells, including cystic pulmonary airway malformations, cystic renal dysplasia, and simple renal cysts in adult kidneys. ER expression in stromal cells is not a feature of DICER1 perturbation but rather is related to the presence of cystic components.
Assuntos
Biomarcadores Tumorais , RNA Helicases DEAD-box , Imuno-Histoquímica , Receptores de Estrogênio , Ribonuclease III , Humanos , Ribonuclease III/genética , RNA Helicases DEAD-box/genética , Feminino , Masculino , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Criança , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Adolescente , Pessoa de Meia-Idade , Pré-Escolar , Adulto Jovem , Neoplasias Renais/patologia , Neoplasias Renais/genética , Neoplasias Renais/enzimologia , Blastoma Pulmonar/patologia , Blastoma Pulmonar/genética , Blastoma Pulmonar/enzimologia , Predisposição Genética para Doença , Lactente , IdosoRESUMO
AIMS: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma-associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. METHODS AND RESULTS: The five cases comprised three teratoma-associated (two mature and one immature) and two pure WTs. Two of the teratoma-associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel-based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma-associated WTs. Furthermore, copy number variation and clustering-based whole-genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma-associated WTs. CONCLUSION: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs.
Assuntos
Neoplasias Renais , Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Teratoma , Tumor de Wilms , Masculino , Feminino , Humanos , Variações do Número de Cópias de DNA , Tumor de Wilms/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Teratoma/genética , Teratoma/patologia , Neoplasias Renais/genética , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
DICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1. However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.
Assuntos
Síndromes Neoplásicas Hereditárias , Neoplasias Ovarianas , Tumor de Células de Sertoli-Leydig , Masculino , Feminino , Adolescente , Humanos , Tumor de Células de Sertoli-Leydig/diagnóstico , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Mutação em Linhagem Germinativa , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Glândula Tireoide/patologia , Ribonuclease III/genética , Células Germinativas/patologia , Mutação , RNA Helicases DEAD-box/genéticaRESUMO
Sertoli-Leydig cell tumors (SLCTs) are uncommon ovarian sex cord-stromal neoplasms which are currently classified into well, moderately, and poorly differentiated and retiform types. Well-differentiated SLCT is the least common and typically occurs in pure form, whereas moderately and poorly differentiated and retiform types often comprise a morphologic spectrum with an admixture of all 3. DICER1 pathogenic variants are very common in SLCTs but, as far as we are aware, have not been reported in well-differentiated neoplasms, although the number of cases studied is small due to the rarity of this neoplasm. We undertook DICER1 molecular testing in a cohort of 18 well-differentiated SLCTs and show all these to be DICER1 wild-type. None of the cases harbored the p. FOXL2 C134W hotspot mutation. Based upon the DICER1 molecular results, together with morphologic observations, we propose that well-differentiated SLCT is an unrelated neoplasm to the more common moderately/poorly differentiated and retiform SLCTs and is a fundamentally distinct and unrelated tumor type within the ovarian sex cord-stromal tumor family. The implications for tumor nomenclature and recommendations for future tumor classification are discussed within the context of tumors collectively known as SLCTs.
Assuntos
Neoplasias Ovarianas , Tumor de Células de Sertoli-Leydig , Tumores do Estroma Gonadal e dos Cordões Sexuais , Masculino , Feminino , Humanos , Tumor de Células de Sertoli-Leydig/genética , Tumor de Células de Sertoli-Leydig/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Mutação , Técnicas de Diagnóstico Molecular , Ribonuclease III/genética , RNA Helicases DEAD-box/genéticaRESUMO
Gynecologic sarcomas are uncommon neoplasms, the majority occurring in the uterus. Due to the diverse nature of these, the description of "new" morphological types and the rarity of some of them, pathological diagnosis and treatment is often challenging. Finding genetic alterations specific to, and frequently occurring, in a certain type can aid in the diagnosis. DICER1 is a highly conserved ribonuclease crucial in the biogenesis of microRNAs and mutations in DICER1 (either somatic or germline) have been detected in a wide range of sarcomas including genitourinary embryonal rhabdomyosarcomas (ERMS) and adenosarcomas. Importantly, DICER1-associated sarcomas share morphological features irrespective of the site of origin such that the pathologist can strongly suspect a DICER1 association. A review of the literature shows that almost all gynecologic ERMS reported (outside of the vagina) harbor DICER1 alterations, while approximately 20% of adenosarcomas also do so. These two tumor types exhibit significant morphological overlap and DICER1 tumor testing may be helpful in distinguishing between them, because a negative result makes ERMS unlikely. Given that germline pathogenic DICER1 variants are frequent in uterine (corpus and cervix) ERMS and pathogenic germline variants in this gene cause a hereditary cancer predisposition syndrome (DICER1 syndrome), patients diagnosed with these neoplasms should be referred to medical genetic services. Cooperation between pathologists and geneticists is crucial and will help in improving the diagnosis and management of these uncommon sarcomas.
Assuntos
RNA Helicases DEAD-box/genética , Neoplasias dos Genitais Femininos/genética , Rabdomiossarcoma Embrionário/genética , Ribonuclease III/genética , Adenossarcoma/genética , Adenossarcoma/patologia , RNA Helicases DEAD-box/metabolismo , Feminino , Neoplasias dos Genitais Femininos/metabolismo , Mutação em Linhagem Germinativa , Humanos , MicroRNAs/genética , Técnicas de Diagnóstico Molecular/métodos , Mutação , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/patologia , Ribonuclease III/metabolismoRESUMO
Embryonal rhabdomyosarcoma of the uterine cervix is a rare neoplasm which is almost invariably associated with pathogenic somatic or germline DICER1 mutations; patients with germline mutations have DICER1 syndrome. We report 2 subtle cervical embryonal rhabdomyosarcoma, one occurring in a 21-yr-old woman with a known history of DICER1 syndrome and the other in a 19-yr-old woman with no history of DICER1 syndrome or DICER1-associated neoplasms. Both neoplasms focally involved otherwise benign endocervical polyps and were characterized histologically by subtle areas of increased stromal cellularity, nuclear atypia and mitotic activity; there was focal nuclear staining of these areas with the skeletal muscle markers myogenin and myoD1. In both cases, demonstration of a somatic DICER1 RNase IIIb mutation in the tumor was instrumental in establishing the diagnosis. We believe these neoplasms represent the earliest discernible phase of cervical embryonal rhabdomyosarcoma. Pathologists should have a high index of suspicion when atypical stromal elements are present in endocervical polyps and immunohistochemistry together with DICER1 sequencing will assist in diagnosis.
Assuntos
RNA Helicases DEAD-box/genética , Rabdomiossarcoma Embrionário/diagnóstico , Ribonuclease III/genética , Neoplasias do Colo do Útero/diagnóstico , Feminino , Mutação em Linhagem Germinativa , Humanos , Imuno-Histoquímica , Músculo Esquelético/patologia , Mutação , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/patologia , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Adulto JovemRESUMO
Molecular profiling was performed in 50 problematic ovarian sex cord-stromal tumours (SCSTs) most of which were seen in consultation. Following analysis, 17 were classified as adult granulosa cell tumour (AGCT), 16 of which showed a FOXL2 sequence variant (mutation); the initial favoured diagnosis in five of the cases was benign thecoma/fibrothecoma. Thirteen tumours ultimately classified as cellular fibroma or thecoma were FOXL2 sequence variant negative which was helpful in excluding AGCT. All six Sertoli-Leydig cell tumours (SLCTs) demonstrated DICER1 'hot spot' sequence variants, and one case each of AGCT and SLCT showed high grade histological transformation associated with a concurrent TP53 sequence variant. All eight unclassified SCSTs were negative for FOXL2 mutations and the six tested cases were DICER1 wild type; however, three tumours demonstrated MET, CTNNB1 or TP53 sequence variants. Four cases were classified as juvenile granulosa cell tumour, and one of these harboured a GNAS sequence variant. The single gynandroblastoma and microcystic stromal tumours in the series demonstrated FOXL2 and CTNNB1 alterations, respectively. In summary, molecular analysis aids in accurate classification of challenging ovarian SCSTs and sometimes leads to revision of the favoured provisional diagnosis. TP53 sequence variants may be associated with dedifferentiation in both SLCTs and AGCTs.
Assuntos
Neoplasias Ovarianas/classificação , Tumores do Estroma Gonadal e dos Cordões Sexuais/classificação , Tumor da Célula Tecal/classificação , Proteína Supressora de Tumor p53/genética , beta Catenina/genética , Desdiferenciação Celular , RNA Helicases DEAD-box/genética , Feminino , Proteína Forkhead Box L2/genética , Humanos , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Ovário/patologia , Ribonuclease III/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/genética , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumor da Célula Tecal/genética , Tumor da Célula Tecal/patologiaRESUMO
OBJECTIVES: Gemcitabine/carboplatin treatment is known to cause severe adverse drug reactions which can lead to the need for reduction or cessation of chemotherapy. It would be beneficial to identify patients at risk of severe hematological toxicity in advance before treatment start. This study aims to identify genetic markers for gemcitabine/carboplatin-induced leukopenia and neutropenia in non-small cell lung cancer patients. MATERIAL AND METHODS: Whole-exome sequencing was performed on 215 patients. Association analysis was performed on single-nucleotide variants (SNVs) and genes, and the validation was based on an independent genome-wide association study (GWAS). Based on the association and validation analyses the genetic variants were then selected for and used in weighted genetic risk score (wGRS) prediction models for leukopenia and neutropenia. RESULTS: Association analysis identified 50 and 111 SNVs, and 12 and 20 genes, for leukopenia and neutropenia, respectively. Of these SNVS 20 and 19 were partially validated for leukopenia and neutropenia, respectively. The genes SVIL (p = 2.48E-06) and EFCAB2 (p = 4.63E-06) were significantly associated with leukopenia contain the partially validated SNVs rs3740003, rs10160013, rs1547169, rs10927386 and rs10927387. The wGRS prediction models showed significantly different risk scores for high and low toxicity patients. CONCLUSION: We have identified and partially validated genetic biomarkers in SNVs and genes correlated to gemcitabine/carboplatin-induced leukopenia and neutropenia and created wGRS models for predicting the risk of chemotherapy-induced hematological toxicity. These results provide a strong foundation for further studies of chemotherapy-induced toxicity.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Leucopenia , Neoplasias Pulmonares , Neutropenia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Desoxicitidina/análogos & derivados , Estudo de Associação Genômica Ampla , Humanos , Leucopenia/induzido quimicamente , Leucopenia/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neutropenia/induzido quimicamente , Neutropenia/genética , Sequenciamento do Exoma , GencitabinaAssuntos
Anaplasia/patologia , RNA Helicases DEAD-box/genética , Neoplasias Renais/patologia , Mutação , Síndromes Neoplásicas Hereditárias/patologia , Neuroblastoma/patologia , Ribonuclease III/genética , Sarcoma/patologia , Anaplasia/complicações , Anaplasia/genética , Criança , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/genética , Masculino , Síndromes Neoplásicas Hereditárias/complicações , Síndromes Neoplásicas Hereditárias/genética , Neuroblastoma/complicações , Neuroblastoma/genética , Prognóstico , Sarcoma/complicações , Sarcoma/genéticaRESUMO
Individuals with DICER1 syndrome, a genetic disorder caused by pathogenic germline variants in DICER1, are at increased risk of developing a wide array of predominantly childhood onset conditions, including genitourinary sarcomas. However, data on DICER1 involvement in paratesticular sarcomas have not been published. Herein, we analyse a series of 15 paediatric paratesticular sarcomas and describe in detail the case of a male infant with a paratesticular myxoid tumour, considered to be a low-grade sarcoma, who also manifested a cystic nephroma, a classic DICER1 syndrome phenotype. He harboured a pathogenic germline DICER1 variant and different somatic hot-spot mutations in each tumour. The paratesticular tumour showed strong and diffuse expression for WT1 and CD10, an unusual immunophenotype in paediatric sarcomas, but typical of tumours of Müllerian origin. The tumour was postulated to arise from the appendix testis, a Müllerian remnant located in the paratestis. Such an origin would be analogous to other DICER1-associated non-epithelial gynaecological tumours, thought to arise from Müllerian derivatives. These findings point towards a key role of DICER1 in Müllerian-derived structures. Supporting this hypothesis is the fact that the other paratesticular sarcomas from the series were either negative or focally positive for WT1 and for CD10, and none had any DICER1 mutations. In summary, we present the first case of a paratesticular sarcoma associated with DICER1 syndrome, emphasising that paratesticular tumours with an unusual histological appearance may suggest an underlying DICER1 mutation, especially in the presence of a personal or family history of DICER1-associated disease. In this context, DICER1 mutation testing could lead to changes in clinical care including implementation of cancer care surveillance strategies.
Assuntos
RNA Helicases DEAD-box/genética , Ribonuclease III/genética , Sarcoma/genética , Neoplasias Urológicas , Adolescente , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Lactente , Masculino , Ductos Paramesonéfricos/patologia , Síndromes Neoplásicas Hereditárias , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Testículo/patologia , Anormalidades Urogenitais/patologia , Neoplasias Urológicas/genética , Neoplasias Urológicas/patologiaRESUMO
Embryonal rhabdomyosarcomas (ERMS) account for 2-3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5-69) for ERMS, 57.5 years (range 27-82) for adenosarcoma, and 65.5 years (range 32-86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas (p < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.
Assuntos
Adenossarcoma/genética , RNA Helicases DEAD-box/genética , Mutação , Rabdomiossarcoma/genética , Ribonuclease III/genética , Neoplasias Uterinas/genética , Adenossarcoma/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Rabdomiossarcoma/patologia , Neoplasias Uterinas/patologia , Adulto JovemRESUMO
DICER1 mutations (somatic or germline) are associated with a variety of uncommon neoplasms including cervical and genitourinary embryonal rhabdomyosarcoma (ERMS). We report a primary ovarian and 2 primary fallopian tube ERMS occurring in 60-, 13-, and 14-year-olds, respectively. The 3 neoplasms exhibited a similar morphologic appearance being polypoid and containing edematous hypocellular areas and hypercellular foci composed of small cells with scant cytoplasm exhibiting rhabdomyoblastic differentiation (desmin, myogenin, myoD1 positive). There was cellular cartilage in all cases and extensive foci of anaplasia, eosinophilic globules, and bone/osteoid in 1 case each. All 3 neoplasms exhibited DICER1 mutations; in 1 of the tubal cases, the patient had a germline mutation and in the other 2 cases, the DICER1 mutations were somatic. Accompanying DICER1 "second hits" were identified in all cases. In 2 of the neoplasms, SALL4-positive glandular structures were present which we speculate may represent an unusual primitive "metaplastic" phenomenon. Our study adds to the literature on ERMS at unusual sites associated with DICER1 mutations. ERMS arising at such sites, especially when they contain cartilage or bone/osteoid, are especially likely to be associated with DICER1 mutations. Pathologists should be aware of this as these may be the sentinel neoplasms in patients with DICER1 syndrome and confirming a germline mutation can facilitate the screening of the individual and affected family members for other neoplasms which occur in this syndrome.
Assuntos
RNA Helicases DEAD-box/genética , Neoplasias das Tubas Uterinas/genética , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/genética , Rabdomiossarcoma Embrionário/genética , Ribonuclease III/genética , Adolescente , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Rabdomiossarcoma Embrionário/patologiaRESUMO
BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen.
Assuntos
Predisposição Genética para Doença , Bócio Nodular/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Neurilemoma/genética , Neurofibromatoses/genética , Proteínas de Ligação a RNA/genética , Neoplasias Cutâneas/genética , Substituição de Aminoácidos , Criança , Cromossomos Humanos Par 22/genética , Feminino , Dosagem de Genes , Estudo de Associação Genômica Ampla , Bócio Nodular/patologia , Células HEK293 , Humanos , Masculino , Neurilemoma/patologia , Neurofibromatoses/patologia , Neoplasias Cutâneas/patologia , Sequenciamento do ExomaRESUMO
Chemotherapy-induced myelosuppression, including thrombocytopenia, is a recurrent problem during cancer treatments that may require dose alterations or cessations that could affect the antitumor effect of the treatment. To identify genetic markers associated with treatment-induced thrombocytopenia, we whole-exome sequenced 215 non-small cell lung cancer patients homogeneously treated with gemcitabine/carboplatin. The decrease in platelets (defined as nadir/baseline) was used to assess treatment-induced thrombocytopenia. Association between germline genetic variants and thrombocytopenia was analyzed at single-nucleotide variant (SNV) (based on the optimal false discovery rate, the severity of predicted consequence, and effect), gene, and pathway levels. These analyses identified 130 SNVs/INDELs and 25 genes associated with thrombocytopenia (P-value < 0.002). Twenty-three SNVs were validated in an independent genome-wide association study (GWAS). The top associations include rs34491125 in JMJD1C (P-value = 9.07 × 10-5), the validated variants rs10491684 in DOCK8 (P-value = 1.95 × 10-4), rs6118 in SERPINA5 (P-value = 5.83 × 10-4), and rs5877 in SERPINC1 (P-value = 1.07 × 10-3), and the genes CAPZA2 (P-value = 4.03 × 10-4) and SERPINC1 (P-value = 1.55 × 10-3). The SNVs in the top-scoring pathway "Factors involved in megakaryocyte development and platelet production" (P-value = 3.34 × 10-4) were used to construct weighted genetic risk score (wGRS) and logistic regression models that predict thrombocytopenia. The wGRS predict which patients are at high or low toxicity risk levels, for CTCAE (odds ratio (OR) = 22.35, P-value = 1.55 × 10-8), and decrease (OR = 66.82, P-value = 5.92 × 10-9). The logistic regression models predict CTCAE grades 3-4 (receiver operator characteristics (ROC) area under the curve (AUC) = 0.79), and large decrease (ROC AUC = 0.86). We identified and validated genetic variations within hematopoiesis-related pathways that provide a solid foundation for future studies using genetic markers for predicting chemotherapy-induced thrombocytopenia and personalizing treatments.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Desoxicitidina/análogos & derivados , Hematopoese/genética , Neoplasias Pulmonares/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Trombocitopenia/induzido quimicamente , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , DNA/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Trombocitopenia/genética , GencitabinaRESUMO
Mesenchymal hamartoma of the liver (MHL) is a benign tumor affecting children that is characterized by a primitive myxoid stroma with cystically dilated bile ducts. Alterations involving chromosome 19q13 are a recurrent underlying cause of MHL; these alterations activate the chromosome 19 microRNA cluster (C19MC). Other cases remain unexplained. We describe two children with MHLs that harbored germline DICER1 pathogenic variants. Analysis of tumor tissue from one of the children revealed two DICER1 "hits." Mutations in DICER1 dysregulate microRNAs, mimicking the effect of the activation of C19MC. Our data suggest that MHL is a new phenotype of DICER1 syndrome. (Funded by the Canadian Institutes of Health Research and others.).
Assuntos
Cromossomos Humanos Par 19 , RNA Helicases DEAD-box/genética , Mutação em Linhagem Germinativa , Hamartoma/genética , Hepatopatias/genética , MicroRNAs/metabolismo , Síndromes Neoplásicas Hereditárias/genética , Ribonuclease III/genética , Pré-Escolar , Feminino , Predisposição Genética para Doença , Hamartoma/diagnóstico por imagem , Hamartoma/patologia , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Masculino , Mesoderma , Linhagem , FenótipoRESUMO
BACKGROUND: This study aimed to characterize the neurotoxicity of three different regimens of nab-paclitaxel compared with a standard regimen of solvent-based (sb) paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer based on the Total Neurotoxicity Score (TNS), a tool specifically developed to assess chemotherapy-induced neurotoxicity. MATERIALS AND METHODS: This was a randomized, open-label study testing 4-week cycles of 80 mg/m2 sb-paclitaxel (PACL80/w) on days 1, 8, and 15; 100 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB100/w); 150 mg/m2 nab-paclitaxel on days 1, 8, and 15 (NAB150/w); and 150 mg/m2 nab-paclitaxel on days 1 and 15 (NAB150/2w). In addition to the TNS, neuropathy was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE). Tumor response and quality of life were also evaluated. RESULTS: Neurotoxicity, as evaluated by the TNS, did not significantly differ between the sb-paclitaxel group and any of the nab-paclitaxel groups. The frequency of (any grade) polyneuropathy, as measured by the NCI-CTCAE, was lower in the PACL80/w (n = 7, 50%) and NAB150/2w (n = 10, 62.5%) groups than in the NAB100/w (n = 13, 81.3%) or NAB150/w (n = 11, 78.6%) group. Although the differences were not statistically significant, compared with the other groups, in the NAB150/w group, the time to occurrence of grade ≥2 polyneuropathy was shorter, and the median time to recovery from grade ≥2 polyneuropathy was longer. Dose delays and reductions due to neurotoxicity and impact of neurotoxicity on the patients' experience of symptoms and functional limitations was greater with NAB150/w. Among the seven polymorphisms selected for genotyping, the variant alleles of EPHA5-rs7349683, EPHA6-rs301927, and EPHA8-rs209709 were associated with an increased risk of paclitaxel-induced neuropathy. CONCLUSION: The results of this exploratory study showed that, regardless of the dose, nab-paclitaxel did not differ from sb-paclitaxel in terms of neurotoxicity as evaluated with the TNS. However, results from NCI-CTCAE, dose delays and reductions, and functional tools consistently indicate that NAB150/w regimen is associated with a greater risk of chemotherapy-induced neuropathy. Thus, our results question the superiority of the TNS over NCI-CTCAE for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and potentially supported by pharmacogenetic analysis. Registry: EudraCT, 2012-002361-36; NCT01763710 IMPLICATIONS FOR PRACTICE: The results of this study call into question the superiority of the Total Neurotoxicity Score over the National Cancer Institute Common Terminology Criteria for Adverse Events for evaluating chemotherapy-induced neuropathy and guiding treatment decisions in this context and suggest that a regimen of 150 mg/m2 nab-paclitaxel administered on days 1, 8, and 15 is associated with a greater risk of chemotherapy-induced neuropathy and hematological toxicity compared with other lower-dose nab-paclitaxel regimens or a standard regimen of solvent-based paclitaxel. The selection of the nab-paclitaxel regimen should be individualized based on the clinical context and could benefit from pharmacogenetics analysis.
Assuntos
Albuminas/efeitos adversos , Antineoplásicos Fitogênicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/efeitos adversos , Polineuropatias/induzido quimicamente , Polineuropatias/patologia , Idoso , Albuminas/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/secundário , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Predisposição Genética para Doença , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Polimorfismo Genético , Polineuropatias/genética , Qualidade de Vida , Receptor ErbB-2/metabolismo , Receptores da Família Eph/genéticaRESUMO
BACKGROUND: Peripheral neuropathy is the dose-limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology-related paclitaxel-induced neuropathy risk factors in a large cohort of well-characterized patients. PATIENTS AND METHODS: Analyses included 503 patients with breast or ovarian cancer who received paclitaxel treatment. Paclitaxel dose modifications caused by the neuropathy were extracted from medical records and patients self-reported neuropathy symptoms were collected. Multivariate logistic regression analyses were performed to identify concomitant medications and comorbidities associated with paclitaxel-induced neuropathy. RESULTS: Older patients had higher neuropathy: for each increase of 1 year of age, the risk of dose modifications and grade 3 neuropathy increased 4% and 5%, respectively. Cardiovascular drugs increased the risk of paclitaxel dose reductions (odds ratio [OR], 2.51; p = .006), with a stronger association for beta-adrenergic antagonists. The total number of concomitant medications also showed an association with dose modifications (OR, 1.25; p = .012 for each concomitant drug increase). A dose modification predictive model that included the new identified factors gave an area under the curve of 0.74 (p = 1.07 × 10-10). Preexisting nerve compression syndromes seemed to increase neuropathy risk. CONCLUSION: Baseline characteristics of the patients, including age and concomitant medications, could be used to identify individuals at high risk of neuropathy, personalizing chemotherapy treatment and reducing the risk of severe neuropathy. IMPLICATIONS FOR PRACTICE: Peripheral neuropathy is a common adverse effect of many cancer drugs, including chemotherapeutics, targeted therapies, and immune checkpoint inhibitors. About 40% of survivors of cancer have functional deficits caused by this toxicity, some of them irreversible. Currently, there are no effective treatments to prevent or treat this neuropathy. This study, performed in a large cohort of well-characterized patients homogenously treated with paclitaxel, identified concomitant medications, comorbidities, and demographic factors associated with peripheral neuropathy. These factors could serve to identify patients at high risk of severe neuropathy for whom alternative non-neurotoxic alternatives may be considered.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/epidemiologia , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologia , Doenças do Sistema Nervoso Periférico/epidemiologia , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
BACKGROUND: Renal epithelioid angiomyolipomas (EAML) are rare tumors with aggressive behavior. EAML can be sporadic or develop within the tuberous sclerosis complex syndrome, where mutations of TSC1 or TSC2 genes (critical negative regulators of mTOR Complex 1) result in an increased activation of mTOR pathway. Optimal EAML treatment, including mTOR inhibitors, remains undetermined. CASE PRESENTATION: Here we present the case of a young adult with a renal EAML that after radical nephrectomy developed metastases, first in liver and then in lumbar vertebrae. After complete surgical resection of these lesions, liver recurrence was detected, this time with incomplete surgical resection. After finding a new liver lesion, systemic treatment with sirolimus started. The patient exhibited a complete and durable response to this drug, being disease free at the time of publication, after 36 months of treatment. Targeted next generation sequencing (NGS) of MTOR, TSC1 and TSC2 genes in the primary tumor, metastasis and blood of the patient, revealed one inactivating TSC2 mutation (c.2739dup; p.K914*) in the tumor cells. Immunohistochemistry revealed decreased TSC2 protein content and increased phospho-S6 in the tumor cells, demonstrating mTOR pathway activation. CONCLUSION: NGS on an EAML patient with an extraordinary response to sirolimus uncovered TSC2 inactivation as the mechanism for the response. This study supports NGS as a useful tool to identify patients sensitive to mTOR inhibitors and supports the treatment of malignant EAML with these drugs.
Assuntos
Angiomiolipoma/terapia , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Renais/cirurgia , Neoplasias Hepáticas/terapia , Sirolimo/uso terapêutico , Neoplasias da Coluna Vertebral/terapia , Adulto , Angiomiolipoma/genética , Angiomiolipoma/patologia , Quimioterapia Adjuvante/métodos , Hepatectomia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Masculino , Mutação , Nefrectomia , Transdução de Sinais/genética , Neoplasias da Coluna Vertebral/genética , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/secundário , Serina-Treonina Quinases TOR/metabolismo , Resultado do Tratamento , Proteína 2 do Complexo Esclerose Tuberosa/genéticaRESUMO
mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Mutação , Sirolimo/análogos & derivados , Proteína 2 do Complexo Esclerose Tuberosa/genética , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Biópsia , Análise Mutacional de DNA , Feminino , Humanos , Imuno-Histoquímica , Terapia de Alvo Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
DICER1 syndrome is an inherited disorder associated with at least a dozen rare, mainly pediatric-onset tumors. Its characterization remains incomplete. Some studies suggested that neuroblastoma (NB) may be involved in this syndrome. Here, we describe the case of a 14-year-old female presenting with a multinodular goiter (MNG) and a collision tumor composed of NB and cystic nephroma (CN). She is a carrier of a deleterious germline mutation in exon 23 of DICER1 and harbored different somatic mutations in the CN and MNG. However, no second hit was found in the NB, questioning its status as a DICER1-related tumor.