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1.
Anticancer Res ; 41(2): 1035-1040, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517312

RESUMO

BACKGROUND/AIM: The definition of multiple oral cancers is based on the distances between the tumors. However, it is not possible to accurately predict tumor origins based only on clinical criteria. PATIENTS AND METHODS: We performed whole-exome sequencing (WES) to analyze the genetic alterations in five tumors of two patients who underwent surgery in our hospital. RESULTS: In case 1, the distances between tumors on the right mandibular gingiva and buccal mucosa were more than 15 mm, leading to a clinical diagnosis of multiple primary tumors. WES revealed common mutations between tumors, suggesting that the tumors were derived from the same clone. In contrast, in case 2, the distance between tumors on the right side of the tongue was only 10 mm, but the tumors were diagnosed as double primary tumors because their mutations were completely different. CONCLUSION: WES, rather than the available clinical criteria, can clarify the clonal origins of multiple oral cancers.


Assuntos
Células Clonais/patologia , Neoplasias Bucais/diagnóstico , Mutação , Neoplasias Primárias Múltiplas/diagnóstico , Sequenciamento Completo do Exoma/métodos , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/cirurgia , Metástase Neoplásica , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/cirurgia , Especificidade da Espécie
2.
Medicine (Baltimore) ; 99(41): e22497, 2020 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-33031286

RESUMO

RATIONALE: Paragangliomas (PGLs) are rare neuroendocrine tumors that are strongly influenced by genetics, and succinate dehydrogenase-deficient PGLs appear to constitute one of the most important categories. Interestingly, somatic PGLs only possess genomic alterations involving the SDHB and SDHD subunits, and no SDHA alterations have been described. Here, we are presenting the clinical and genetic analyses of 2 cases with the first somatic SDHA variant identified in PGLs. PATIENT CONCERNS: Here, we reported 2 family members with the diagnosis of PGL. Patient 1 is a 55-year-old woman with a functionally perigastric PGL that co-occurred with a gastric gastrointestinal stromal tumor (GIST), and patient 2 is a 43-year-old woman with a nonfunctionally pericardial PGL, who was the younger sister of the first patient. DIAGNOSES: Imaging surveys of the 2 cases depicted the presence of a perigastric and a pericardial mass, respectively. A diagnosis of paragangliomas was established by immunohistochemistry (IHC). INTERVENTIONS: Both patients underwent single-stage resection of the lesion after preoperative oral α-adrenoceptor therapy for 2 weeks. We later performed comprehensive genomic profiling on the tumor samples, including PGL and GIST from patient 1 and PGL from patient 2, and searched for novel actionable mutations, including in all succinate dehydrogenase subunits, as the IHC results were negative for SDHB. OUTCOMES: Both patients had an uneventful recovery after surgery and the sequencing showed a novel somatic variant in the SDHA gene on chromosome 5q11 (c.1945_1946delTT). Regular follow-up with biochemical testing and image studies showed no evidence of recurrence after a year for patient 1 and 6 years for patient 2. LESSONS: PGLs often lead to considerable diagnostic difficulty due to their multiple anatomical locations and variable symptoms, as presented by our cases. The comprehensive use of images and plasma/urine catecholamine measurement can aid the diagnosis of PGLs. In addition, our findings also demonstrate the usefulness and importance of genetic analysis of SDHA mutations in patients exhibiting SDHB IHC-negative PGL. Additional studies utilizing comprehensive genomic profiling are needed to identify the group of PGLs harboring this SDHA genomic alteration.


Assuntos
Complexo II de Transporte de Elétrons/genética , Tumores do Estroma Gastrointestinal/genética , Neoplasias Primárias Múltiplas/genética , Paraganglioma Extrassuprarrenal/genética , Neoplasias Gástricas/genética , Adulto , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/patologia , Testes Genéticos , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Paraganglioma Extrassuprarrenal/diagnóstico , Paraganglioma Extrassuprarrenal/patologia , Irmãos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologia
3.
Anticancer Res ; 40(11): 6159-6170, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109553

RESUMO

BACKGROUND/AIM: Malignant rhabdoid tumor (MRT) is a rare, aggressive neoplasm found in young children, caused by inactivation of a single gene, SNF5 (INI1, SMARCB1). MRT cases with multifocal tumors at diagnosis are categorized as synchronous MRT, often with a germline mutation of SNF5. The aim of this study was to establish new models useful in clarifying the biological basis of synchronous MRT. MATERIALS AND METHODS: We established two novel MRT cell lines, designated as KP-MRT-KS and KP-MRT-KSa, derived from different lesions and at a different time from a synchronous multifocal 7-month-old female MRT patient. RESULTS: Both cells showed typical morphology of MRT, with a compound genomic mutation in exons 2 and 5 of the SNF5 gene. The exon 2 mutation was found in the germline. CONCLUSION: These cell lines could serve as powerful tools for unveiling the molecular mechanism of refractory synchronous MRT.


Assuntos
Neoplasias Primárias Múltiplas/patologia , Tumor Rabdoide/patologia , Sequência de Bases , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Análise por Conglomerados , Metilação de DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Neoplasias Primárias Múltiplas/genética , Tumor Rabdoide/diagnóstico por imagem , Tumor Rabdoide/genética , Proteína SMARCB1/genética , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Beijing Da Xue Xue Bao Yi Xue Ban ; 52(5): 971-974, 2020 Oct 18.
Artigo em Chinês | MEDLINE | ID: mdl-33047739

RESUMO

The rearrangement of the gene encoding the transcription factor ETS-related gene (ERG) is thought to play a key role in the development of prostate cancer. However, the studies on the ERG mutations have been rarely reported in non-small cell lung carcinoma (NSCLC). Here, we reported genetic features regarding a case of a 68-year-old male patient who presented the primary synchronous multiple tumor lesions in the separated lungs. The patient was hospitalized due to the presence of tumor lesions at the right and left lungs revealed by a chest computerized tomography (CT) scan. After conducting lobectomies at the both lungs, the tumor nodules were all removed, and the histological analysis suggested adenocarcinoma at the both tumor lesions. The patient was diagnosed with synchronous multiple primary lung cancer (SMPLC) based on Martini-Melamed criteria and American College of Chest Physicians practice guidelines. An exome analysis of 315 genes in the two tumor lesions and a non-tumor lesion was conducted by using Illumina Nextseq500 platform from each tumor region to decipher a potential evolutional progress of SMPLC. Single or pair-end reads were first mapped to a human genome reference and filtered based on the mapping quality score. The read depth was ≥ 1 000× and the depth of coverage was 95%. The data revealed a discordant epidermal growth factor receptor (EGFR) from the separate lungs; additionally, a high frequency of point mutation on exon 9 H310P of the ERG gene was detected at the both sites of the tumor lesions. This case showed that a potential role of the molecular features analysis from each tumor lesion might contribute to the understanding of the evolutional development of SMPLC. This study suggests that the same environment may contribute certain gene(s) mutations in the same sites in the early stages of polyclonal tumor origins; meanwhile the extensive studies on these genes may help us understand the evolution and progress of tumor clones.


Assuntos
Adenocarcinoma , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias Primárias Múltiplas , Idoso , Humanos , Neoplasias Pulmonares/genética , Masculino , Neoplasias Primárias Múltiplas/genética , Mutação Puntual , Regulador Transcricional ERG
7.
Cancer Imaging ; 20(1): 51, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32690092

RESUMO

BACKGROUND: In multiple primary lung adenocarcinomas (MPLAs), the relationship between imaging and gene mutations remains unclear. This retrospective study aimed to identify the correlation of epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) status with CT characteristics in MPLA patients. METHODS: Sixty-seven patients (135 lesions) with MPLAs confirmed by pathology were selected from our institution. All subjects were tested for EGFR mutations and ALK status and underwent chest CT prior to any treatment. The criteria for MPLA definitions closely adhered to the comprehensive histologic assessment (CHA). RESULTS: Among MPLA patients, EGFR mutations were more common in females (p = 0.002), in those who had never smoked (p = 0.010), and in those with less lymph node metastasis (p < 0.001), and the tumours typically presented with ground-glass opacity (GGO) (p = 0.003), especially mixed GGO (p < 0.001), and with air bronchograms (p = 0.012). Logistics regression analysis showed that GGO (OR = 6.550, p = 0.010) was correlated with EGFR mutation, while air bronchograms were not correlated with EGFR mutation (OR = 3.527, p = 0.060). A receiver operating characteristic (ROC) curve yielded area under the curve (AUC) values of 0.647 and 0.712 for clinical-only or combined CT features, respectively, for prediction of EGFR mutations, and a significant difference was found between them (p = 0.0344). ALK-positive status was found most frequently in MPLA patients who were younger (p = 0.002) and had never smoked (p = 0.010). ALK positivity was associated with solid nodules or masses in MPLAs (p < 0.004) on CT scans. Logistics regression analysis showed that solid nodules (OR = 6.550, p = 0.010) were an independent factor predicting ALK positivity in MPLAs. For prediction of ALK positivity, the ROC curve yielded AUC values of 0.767 and 0.804 for clinical-only or combined CT features, respectively, but no significant difference was found between them (p = 0.2267). CONCLUSION: Among MPLA patients, nonsmoking women with less lymph node metastasis and patients with lesions presenting GGO or mixed GGO and air bronchograms on CT were more likely to exhibit EGFR mutations. In nonsmoking patients, young patients with solid lesions on CT are recommended to undergo an ALK status test.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Quinase do Linfoma Anaplásico/análise , Neoplasias Pulmonares/diagnóstico por imagem , Mutação , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Estudos Retrospectivos
9.
J Cancer Res Clin Oncol ; 146(9): 2359-2367, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32333141

RESUMO

PURPOSE: Multiple lung lesions found in a single patient at the time of diagnosis often pose a diagnostic dilemma: are these lesions independent primary tumors (IPT) or the result of intrapulmonary metastases (IPM)? While traditional pathological methods sometimes have difficulty distinguishing IPM from IPT, modern molecular profiling based on next-generation sequencing techniques may provide a new strategy. METHODS: Sixteen patients with multiple tumors were enrolled in this study. We performed targeted deep sequencing (~ 2000 × coverage) on a total of 40 tumors and matched blood samples. We compared mutational profiles between tumors within each patient and across patients to evaluate if they were genetically related. Computed tomographic images and histological staining were also used to validate tumor relationships. RESULTS: A total of 125 mutations were identified in 16 patients. Twelve out of fourteen patients whose histological diagnoses favored IPT did not have any shared mutations in their multiple tumors. The other two showed discrepancies: Pt01 had a shared EGFR exon19 deletion in the two lung tumors found, and Pt16 had one common mutation (BRAFD594G) in two out of five lung tumors. Pt14 with lung metastasis from salivary gland adenoid cystic carcinoma had shared mutations; and Pt15 with suspected intrapulmonary metastasis (IPM) had identical mutations between the two tumors. Visualized data can be readily accessed through the website: mlc.opengene.org. CONCLUSION: Analysis of overlapping mutations among different tumors assists physicians in distinguishing IPM from IPT. Our findings demonstrate that DNA sequencing can provide additional evidence in clinical practice when pathology is inadequate to make a conclusive diagnosis.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Adulto , Idoso , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Análise de Sequência de DNA/métodos
10.
Am J Clin Pathol ; 154(1): 57-69, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32146481

RESUMO

OBJECTIVES: To determine concordance/discordance between morphology and molecular testing (MT) among synchronous pulmonary carcinomas using targeted next generation sequencing (NGS), with and without comprehensive molecular review (CMR), vs analyses of multiple singe genes (non-NGS). METHODS: Results of morphologic and MT assessment were classified as concordant, discordant, or indeterminate. For discordant cases, comprehensive histologic assessment (CHA) was performed. RESULTS: Forty-seven cases with 108 synchronous tumors were identified and underwent MT (NGS, n = 23 and non-NGS, n = 24). Histology and MT were concordant, discordant, and indeterminate in 53% (25/47), 21% (10/47), and 26% (12/47) of cases, respectively. CHA of the 10 discordant cases revised results of three cases. CONCLUSIONS: There is discordance between histology and MT in a subset of cases and MT provides an objective surrogate for staging synchronous tumors. A limited gene panel is sufficient for objectively assessing a relationship if the driver mutations are distinct. Relatedness of mutations require CMR with a larger NGS panel (eg, 50 genes).


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Metástase Neoplásica/genética , Neoplasias Primárias Múltiplas/genética , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , Metástase Neoplásica/patologia , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/patologia
11.
BMC Med Genet ; 21(1): 52, 2020 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171268

RESUMO

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal dominant genodermatosis characterized by benign growth of the hair follicles, the presence of pulmonary cysts, spontaneous pneumothorax, and bilateral renal tumors that are usually hybrid oncocytic or multifocal chromophobe renal cell carcinoma. The diagnosis is confirmed by the presence of a pathogenic variant in the tumor suppressor folliculin (FLCN) gene mapped at 17p11.2. Although the dermatological lesions typical of BHDS are benign and only cause aesthetic concerns, and the pulmonary manifestations are controllable, the greater tendency of patients with this syndrome to present benign or malignant renal tumors, often bilateral and multifocal, makes the diagnosis of this syndrome important for the prognosis of the patients. The objective was to report the case of a patient with BHDS, without pulmonary manifestations and with hyperplastic polyposis of the gastrointestinal tract, and to perform a literature review. CASE PRESENTATION: A 60-year-old man complained of abdominal pain and diarrhoea for 2 months. Physical examination was normal except for the presence of normochromic papules in the frontal region of the face associated with hyperkeratotic and hyperchromic papules in the dorsal region. The excisional biopsies of the skin lesions indicated trichodiscomas. Esophagogastroduodenoscopy, enteroscopy, and colonoscopy showed the presence of hyperplastic polyps in the stomach, duodenum, jejunum, colon, and rectum. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen revealed multiple expansive solid lesions in both kidneys, with necrotic and calcified areas. Renal magnetic resonance angiography also showed a solid lesion in the right kidney measuring 5 cm in diameter and another solid lesion in the left kidney measuring 8 cm in diameter, both suggestive of renal angiomyolipoma. CT scans of the skull, chest, and temporal bones were normal. The genetic study revealed the presence of a variant of FLCN in the intron 13. CONCLUSIONS: To the best of our knowledge, this is the first reported case of BHDS with the simultaneous finding of gastrointestinal hyperplastic polyposis, which may represent a possible phenotypic expression of this syndrome that has not yet been described.


Assuntos
Síndrome de Birt-Hogg-Dubé/complicações , Neoplasias Gastrointestinais/complicações , Trato Gastrointestinal/patologia , Pólipos/complicações , Síndrome de Birt-Hogg-Dubé/diagnóstico , Síndrome de Birt-Hogg-Dubé/genética , Diagnóstico Diferencial , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/genética , Humanos , Hiperplasia/complicações , Hiperplasia/diagnóstico , Hiperplasia/genética , Pólipos Intestinais/complicações , Pólipos Intestinais/diagnóstico , Pólipos Intestinais/genética , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Pólipos/diagnóstico , Pólipos/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Supressoras de Tumor/genética
12.
Int J Gynecol Pathol ; 39(2): 136-140, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32039937

RESUMO

Muir-Torre syndrome is a rare subtype of Lynch syndrome characterized by coincidence of skin neoplasm and visceral malignancies. Here, we report a case of this rare disease, whose diagnosis of the syndrome was first suspected by the pathologist. This was a 60-yr-old woman who presented with an axillary skin nodule, which was diagnosed as basal cell carcinoma. Further inquiry revealed that she was hospitalized for evaluation of a recurrent vaginal stump endometrial carcinoma. Histologic workup and immunohistochemistry for mismatch repair proteins of both the skin and vaginal tumor suggested the possibility of Muir-Torre syndrome. NexGen sequencing identified a frame-shift mutation in the MSH2 gene. The patient was found to have a metachronous colorectal carcinoma, uterine endometrial carcinoma, and skin cancer from 1998 to 2016. Five family members had also suffered from colorectal cancer or glioma. This case report illustrates the importance of the multidisciplinary care approach, mismatch repair protein and gene testing, and detailed medical history taking into consideration the diagnosis of Muir-Torre syndrome.


Assuntos
Síndrome de Muir-Torre/genética , Proteína 2 Homóloga a MutS/genética , Feminino , Mutação da Fase de Leitura , Humanos , Pessoa de Meia-Idade , Síndrome de Muir-Torre/patologia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia
13.
J Thorac Cardiovasc Surg ; 160(2): e71-e79, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32007245

RESUMO

OBJECTIVE: Multifocal non-small cell lung cancer has historically been separated into synchronous primary lung cancers or intrapulmonary metastases with the use of histopathology. We hypothesize that using targeted next-generation sequencing of key driver mutations in multifocal non-small cell lung cancer will improve our ability to differentiate intrapulmonary metastases from synchronous primary lung cancers. METHODS: We identified patients who underwent surgery for non-small cell lung cancer between 2013 and 2018 with multifocal tumors. Archived specimens were reviewed with a 4-gene next-generation sequencing panel identifying mutations of EGFR, KRAS, BRAF, and NRAS. Synchronous primary lung cancers were classified as lesions with different histopathologic subtypes or driver mutations. Tests of hypotheses were performed with the Fisher exact test. Calculations were performed in Stata (v13.0; StataCorp LLC, College Station, Tex). RESULTS: A total of 18 patients had non-small cell lung cancer tumor specimens (n = 41) available from 2 or more sites. The pathologic diagnosis was predominantly adenocarcinoma (39/41 specimens). We detected a driver mutation in 68.3% (28/41) of all tumors. The most common mutations observed were in KRAS (n = 17/41) and EGFR (n = 7/41). Eleven patients had synchronous primary lung cancers, and 4 patients had intrapulmonary metastases based on combined histopathologic and molecular profiling results. Three lacked driver mutations in either lesion. Eight synchronous primary lung cancers (8/18, 44%) were downstaged when compared with their original diagnosis (P = .08). Of these, 4 patients received adjuvant chemotherapy unnecessarily in hindsight. CONCLUSIONS: Molecular non-small cell lung cancer profiling using a 4-gene next-generation sequencing panel allows for better distinction between synchronous primary lung cancers and intrapulmonary metastases than histopathology alone. Routine use of next-generation sequencing for multifocal lesions prevents unnecessary adjuvant treatment for patients with histologically similar synchronous primary lung cancers.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Neoplasias Pulmonares/genética , Mutação , Neoplasias Primárias Múltiplas/genética , Transcriptoma , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/terapia , Quimioterapia Adjuvante , Tomada de Decisão Clínica , Receptores ErbB/genética , Feminino , GTP Fosfo-Hidrolases/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Pneumonectomia , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reprodutibilidade dos Testes , Estudos Retrospectivos
14.
Nat Commun ; 11(1): 837, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054861

RESUMO

Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53. The PTEN/TP53-deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53, while the Gleason 7 PTEN-intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer.


Assuntos
Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Antagonistas de Androgênios/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Deleção de Genes , Humanos , Masculino , Mutação , Terapia Neoadjuvante , Gradação de Tumores , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , PTEN Fosfo-Hidrolase/deficiência , PTEN Fosfo-Hidrolase/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Análise de Sequência de DNA , Proteína Supressora de Tumor p53/deficiência , Proteína Supressora de Tumor p53/genética
15.
BMC Med Genet ; 21(1): 42, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32106822

RESUMO

BACKGROUND: von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL. Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations. Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood. CASE PRESENTATION: We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro). At 47-years, MRI revealed pheochromocytoma in the left adrenal gland and hemangioblastomas in the spine and brain. Pheochromocytoma was treated by adrenalectomy. Radiotherapy, followed by craniotomy and resection were needed to reduce hemangioblastomas to residual lesions. Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments. Primary skin fibroblasts carrying the heterozygous mutation or wild type VHL were established from the family. Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level. CONCLUSIONS: Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma. This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease. This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts. The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.


Assuntos
Neoplasias Cerebelares/genética , Hemangioblastoma/genética , Processamento de RNA/genética , Mutação Silenciosa , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/complicações , Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias Cerebelares/complicações , Neoplasias Cerebelares/diagnóstico , Criança , Pré-Escolar , Família , Feminino , Mutação da Fase de Leitura/genética , Mutação em Linhagem Germinativa , Hemangioblastoma/complicações , Hemangioblastoma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico , Neoplasias Primárias Múltiplas/genética , Linhagem , Feocromocitoma/complicações , Feocromocitoma/diagnóstico , Feocromocitoma/genética , Prolina/genética , Neoplasias da Retina/complicações , Neoplasias da Retina/diagnóstico , Neoplasias da Retina/genética , Neoplasias da Coluna Vertebral/complicações , Neoplasias da Coluna Vertebral/diagnóstico , Neoplasias da Coluna Vertebral/genética , Doença de von Hippel-Lindau/complicações , Doença de von Hippel-Lindau/genética
17.
Endocr Pathol ; 31(1): 84-93, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31981075

RESUMO

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.


Assuntos
Adenocarcinoma Papilar/patologia , Adenocarcinoma/patologia , Carcinoma Neuroendócrino/patologia , Neoplasias da Vesícula Biliar/patologia , Neoplasias Primárias Múltiplas/patologia , Adenocarcinoma/genética , Adenocarcinoma Papilar/genética , Idoso , Biomarcadores Tumorais/análise , Carcinoma Neuroendócrino/genética , Feminino , Neoplasias da Vesícula Biliar/genética , Humanos , Mutação , Neoplasias Primárias Múltiplas/genética , Proteína Supressora de Tumor p53/genética
18.
Br J Cancer ; 122(5): 697-704, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31929516

RESUMO

BACKGROUND: Multiplicity in breast cancer is common. Studies on multiple breast cancers have revealed high concordance in biomarker status among individual lesions. However, genomic differences among multiple lesions are not well-established. We aimed to investigate the potential genomic heterogeneity of multiple breast cancer. METHODS: Twenty-one patients with radiologically and histologically evident multiple breast cancer with similar histology were included. Two lesions from each of the 21 patients were selected, and biomarker status was evaluated for each lesion. Capture-based targeted next-generation sequencing was performed using a cancer gene panel consisting of 170 genes. RESULTS: We identified discordance in intrinsic subtype in 2 (10%) of the 21 patients. Pathogenic mutations were detected in 13 of the 21 patients, of whom 11 shared oncogenic variants in the two lesions. The remaining two patients yielded different mutation results for TP53, ATM, and PIK3CA. Difference in copy number alteration was observed in 7 (33%) of the 21 patients including ERBB2 (n = 2), FGFR1 (n = 2), and FGFR2 (n = 1) genes. CONCLUSION: Despite similar histologic features of the individual lesions, inter-lesional genomic difference was identified in more than one-third of the patients. Inter-lesional genomic heterogeneity needs to be considered when performing a genomic test in multiple breast cancers.


Assuntos
Neoplasias da Mama/genética , Neoplasias Primárias Múltiplas/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Dosagem de Genes , Heterogeneidade Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imuno-Histoquímica , Terapia Neoadjuvante , Neoplasias Primárias Múltiplas/tratamento farmacológico , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/cirurgia , Mutação Puntual , Polimorfismo de Nucleotídeo Único
19.
Virchows Arch ; 476(6): 835-842, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31900636

RESUMO

The presence of multiple synchronous lung cancer with the same histopathological type for a patient is a common situation and an issue for staging. Pathological criteria exist to distinguish multiple primaries from intra-pulmonary metastases of the same tumor, but they lack standardization. We wondered how molecular analysis with a limited Next Generation Sequencing panel could bring further information for tumor staging in this setting. We analyzed 24 patients with a total of 50 tumor nodules (22 pairs, two triplets). We compared histopathological examination with molecular analysis. A total of 50 tumors were molecularly tested. Nucleoli size was associated with molecular analysis concordance (p = 0.047). The presence of lepidic component in any of the two larger tumors was associated with molecular analysis concordance (p = 0.012). For molecular analysis, the proportion of progression-free patients was at the limits of significance (p = 0.054) whereas the presence of lepidic component, architectural concordance, and the concordance of comprehensive histologic assessments was not related to progression-free survival. For two patients with a discordant TTF-1 immunohistochemistry, molecular analysis showed a different mutation. Our results show that a limited NGS panel brings supplementary data to classify synchronous lung adenocarcinoma in most patients. We show that molecular staging seems in accordance with progression-free survival. Histopathological examination alone might not be accurate enough to assess a correct staging for synchronous tumors. We also suggest that TTF-1 immunohistochemistry, for the rare discrepant cases, might be a surrogate to molecular analysis.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Fator Nuclear 1 de Tireoide/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores Tumorais/metabolismo , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Mutação , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/patologia , Análise de Sequência de DNA , Fator Nuclear 1 de Tireoide/metabolismo
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