RESUMEN
Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Mutación , Análisis de la Célula Individual , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Secuenciación del Exoma , Femenino , Genómica , Masculino , Linfocitos T CD8-positivos/inmunología , Persona de Mediana Edad , Heterogeneidad Genética , Anciano , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/inmunología , Neoplasias Primarias Múltiples/patologíaRESUMEN
In advanced non-squamous non-small-cell lung cancer (NSCLC), routine testing with next-generation sequencing (NGS) is recommended to identify actionable genomic alterations (AGAs). The therapeutic implications of repeated NGS testing on synchronous and metachronous tumors are unclear. Between February 2017 and October 2020, NSCLC samples from a single institution were reflex-tested using a targeted 15-gene NGS panel (TruSight Tumor 15, Illumina). Thirty-eight patients were identified with multiple NGS results from 82 samples: 11% were from single unifocal, 51% were from synchronous, and 38% were from metachronous tumors. Changes in EGFR, KRAS, PI3KCA, and TP53 variants were found in 22 patients' samples (58%). No changes were seen with longitudinal testing of multiple samples from single unifocal tumors, while changes were observed in 60% of synchronous and 71% of metachronous tumors. Of these, 26% of patients had AGA differences between samples. Acknowledging the limited sample size, a significant difference in overall survival was observed between synchronous separate primaries and metastasis. Repeat NGS testing of synchronous and metachronous NSCLC tumors may identify differing variants in >50% of patients. These changes may reflect separate primary lung carcinomas, tumor heterogeneity among intrapulmonary metastases, and clonal evolution. NGS testing of multiple tumors may enhance the identification of therapeutic targets for treatment decisions.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Adulto , Neoplasias Primarias Múltiples/genética , MutaciónRESUMEN
BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1-mutated synchronous and metachronous PACC. CASE: A 58-year-old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab-paclitaxel therapy was administered as first-line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second- line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC-related cancers was initiated. CONCLUSION: We diagnosed a 58-year-old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Carcinoma de Células Acinares , Mutación de Línea Germinal , Neoplasias Pancreáticas , Humanos , Persona de Mediana Edad , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína BRCA1/genética , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Oxaliplatino/administración & dosificación , Leucovorina/administración & dosificación , Irinotecán/administración & dosificación , Paclitaxel/administración & dosificación , Fluorouracilo/administración & dosificaciónRESUMEN
RATIONALE: 3P association (3PA) is a rare condition with co-occurrence of pituitary adenoma and pheochromocytoma/paraganglioma. There have been less than a hundred documented cases of 3PA, which can be sporadic or related to genetic mutations. The present case report describes the first Iranian patient with 3PA and a 90th case of 3PA in the available literature. PATIENT CONCERNS AND INTERVENTIONS: A 36-year-old Caucasian male was admitted with headache and sudden increase in blood pressure. An abdominal CT scan revealed a retroperitoneal mass posterior to the inferior vena cava, later removed and diagnosed as a pheochromocytoma. Four years later, he noticed occasional mild headaches and a painless mass on the right side of his neck. The ultrasonography evaluations suggested a carotid body tumor, which was surgically removed. About a month after his second surgery, the severity of the patient's headaches worsened, and he developed right homonymous hemianopia. A brain MRI showed a mass in favor of macroadenoma, craniopharyngioma, or meningioma, and elevated prolactin level led to the diagnosis of macroprolactinoma. DIAGNOSES: Based on the provided history, this patient was diagnosed with 3PA, and a genetic study identified a positive succinate-dehydrogenase-complex subunit b mutation, possibly linked to his family history of carotid body tumor. OUTCOMES: He has remained symptom-free during his visits every 3 months. LESSONS: The number of cases diagnosed with 3PA worldwide is increasing. Using clinical and genetic assessments, we can timely diagnose and adequately monitor individuals with or at risk of 3PA.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Paraganglioma , Feocromocitoma , Neoplasias Hipofisarias , Humanos , Masculino , Adulto , Neoplasias Hipofisarias/diagnóstico , Neoplasias Hipofisarias/complicaciones , Neoplasias Hipofisarias/genética , Feocromocitoma/diagnóstico , Feocromocitoma/complicaciones , Feocromocitoma/cirugía , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/complicaciones , Neoplasias de las Glándulas Suprarrenales/cirugía , Paraganglioma/diagnóstico , Paraganglioma/complicaciones , Paraganglioma/genética , Paraganglioma/cirugía , Adenoma/complicaciones , Adenoma/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patologíaAsunto(s)
Linfoma de Células B Grandes Difuso , Neoplasias Primarias Múltiples , Humanos , Masculino , Anciano , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/genética , Linfoma de Células T/patología , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/metabolismo , Neoplasias Gastrointestinales/genética , Intestino Delgado/patología , Ciclofosfamida/uso terapéutico , Vincristina/uso terapéutico , Doxorrubicina/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Diagnóstico Diferencial , Prednisona/uso terapéuticoRESUMEN
INTRODUCTION: Concurrent non-serous endometrial and ovarian tumours are often managed clinically as two separate primary tumours, but almost all exhibit evidence of a genomic relationship. METHODOLOGY: This study investigates the extent of relatedness using whole exome sequencing, which was performed on paired non-serous endometrial and ovarian carcinomas from 27 patients with concurrent tumours in a cohort with detailed clinicopathological annotation. Four whole exome sequencing-derived parameters (mutation, mutational burden, mutational signatures and mutant allele tumour heterogeneity scores) were used to develop a novel unsupervised model for the assessment of genomic similarity to infer genomic relatedness of paired tumours. RESULTS: This novel model demonstrated genomic relatedness across all four parameters in all tumour pairs. Mutations in PTEN, ARID1A, CTNNB1, KMT2D and PIK3CA occurred most frequently and 24 of 27 (89 %) tumour pairs shared identical mutations in at least one of these genes, with all pairs sharing mutations in a number of other genes. Ovarian endometriosis, CTNNB1 exon 3 mutation, and progression and death from disease were present across the similarity ranking. Mismatch repair deficiency was associated with less genomically similar pairs. DISCUSSION: Although there was diversity across the cohort, the presence of genomic similarity in all paired tumours supports the hypothesis that concurrent non-serous endometrial and ovarian carcinomas are genomically related and may have arisen from a common origin.
Asunto(s)
Neoplasias Endometriales , Secuenciación del Exoma , Mutación , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Persona de Mediana Edad , Anciano , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Adulto , Fosfohidrolasa PTEN/genética , Genómica/métodos , Exoma/genética , Proteínas de Unión al ADN , Factores de Transcripción , beta CateninaRESUMEN
Genetic sequencing has revolutionized immunotherapy in colorectal cancer (CRC). Recent clinical trials have revealed a positive response to immunotherapy-based systemic therapies in CRC patient subgroups with microsatellite instability (MSI)-High or DNA polymerase epsilon (POLE) mutation. However, the unsatisfactory response rates was the major limitation in real-world practice of the precision immunotherapy in CRC. Adding photodynamic therapy (PDT) to systemic immunotherapy has showed synergetic anti-tumor effect by modulating tumor microenvironment, while the eligible patient's subgroups which would benefit from this combination remained equivocal. Here we reported a synchronous colorectal cancer patient with MSI-High and POLE mutation who had accelerated response in less than 2 cycles (42 days) of immunotherapy-based systemic therapies after tumor-directed PDT and has remained progression-free by far. This case enlightened the synergetic effect of PDT in immunotherapy-treated CRC patients, with the MSI and POLE-mutation status as predictors of survival benefits.
Asunto(s)
Neoplasias Colorrectales , ADN Polimerasa II , Inmunoterapia , Inestabilidad de Microsatélites , Mutación , Fotoquimioterapia , Proteínas de Unión a Poli-ADP-Ribosa , Humanos , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/genética , Fotoquimioterapia/métodos , ADN Polimerasa II/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Inmunoterapia/métodos , Terapia Combinada , Masculino , Resultado del Tratamiento , Neoplasias Primarias Múltiples/terapia , Neoplasias Primarias Múltiples/genética , Persona de Mediana Edad , FemeninoRESUMEN
Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.
Asunto(s)
Hepatoblastoma , Neoplasias Renales , Neoplasias Hepáticas , Neoplasias Primarias Múltiples , Tumor Rabdoide , Neoplasias Gástricas , Humanos , Masculino , Niño , Femenino , Preescolar , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Renales/patología , Neoplasias Renales/genética , Lactante , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Hepatoblastoma/genética , Hepatoblastoma/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Neoplasias del Plexo Coroideo/genética , Neoplasias del Plexo Coroideo/patología , Neoplasias del Plexo Coroideo/diagnóstico , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/genética , Teratoma/patología , Teratoma/genética , Teratoma/cirugía , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteína SMARCB1/genética , Homólogo 1 de la Proteína MutL/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patologíaRESUMEN
Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.
Asunto(s)
Mutación de Línea Germinal , Neoplasias Renales , Neuroblastoma , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Neuroblastoma/genética , Neoplasias Gastrointestinales/genética , Neoplasias Gastrointestinales/patología , Masculino , Complejo II de Transporte de Electrones/genética , Mosaicismo , Femenino , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patologíaRESUMEN
INTRODUCTION: Oncological outcomes in patients with nonclear cell renal cell carcinoma (non-ccRCC) treated with surgery for locoregional nodal disease (ND) remain incompletely characterized. The objective was to investigate the characteristics and outcomes of non-ccRCC patients treated with lymph node dissection (LND) and salvage-LND (S-LND). METHODS: A total of 1627 patients underwent nephrectomy for nonmetastatic non-ccRCC at Memorial Sloan Kettering Cancer Center between 2007 and 2023. Histology was grouped as papillary, chromophobe, unclassified, and rare subtypes. Retrospective evaluation identified 2.5% (n = 40) of patients with nodal disease at time of nephrectomy (synchronous-ND) and 1.1% (n = 18) with metachronous nodal disease limited to the retroperitoneum (metachronous-ND). Patients' demographics and tumor characteristics were recorded and evaluated by univariate and multivariate cox regression models. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Patients who underwent tumor DNA sequencing during their clinical course were considered for genomic analysis. RESULTS: OS trended toward longer in metachronous-ND (51 vs 105 months; P = .2), though 23% of patients with synchronous-ND were recurrence-free at 45 months median follow-up. In multivariate analysis, rare histologies were associated with decreased OS (P = .030) and metachronous-ND with improved OS (P = .036). RFS and OS after S-LND was 15 and 96 months, respectively. Late onset of metachronous-ND/recurrence was associated with improved OS (P = .008). Genetic alterations in SETD2, TP53, B2M, and FGFR3 were exclusively seen in synchronous-ND, and tumor mutation burden (TMB) was also higher in patients with synchronous-ND (P = .016). CONCLUSIONS: Patients with metachronous-ND tend to have prolonged OS compared to synchronous-ND, but a substantial portion of patients with synchronous-ND still enter a durable disease-free state following LND. S-LND can likewise provide long-term survival, particularly in patients with longer time to metachronous nodal recurrence. Synchronous-ND was associated with SETD2, TP53, and NF2 alteration as well as higher TMB.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Escisión del Ganglio Linfático , Nefrectomía , Humanos , Masculino , Femenino , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Nefrectomía/métodos , Anciano , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Metástasis Linfática/genética , Metástasis Linfática/patología , Resultado del Tratamiento , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/mortalidad , Genómica , Adulto , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/cirugía , Neoplasias Primarias Secundarias/mortalidadRESUMEN
BACKGROUND: The incidence of breast and colorectal cancer (CRC) in younger-than-average-age patients is rising and poorly understood. This is the largest study on patients with both cancers who are less than 60 years old and aims to characterize demographic, clinicopathologic, and genetic features and describe therapeutic dilemmas and management strategies. MATERIALS AND METHODS: This is a retrospective medical records review of patients at the University of California San Francisco with both primary breast and CRC before age 60. RESULTS: Fifty-one patients were identified; 41 had detailed medical records. Median age of diagnosis with breast cancer was 43 (range 27-59) and CRC was 50 (28-59). Most were Caucasian (38, 74.5%) and never smokers (23, 56.1%); about half were current alcohol consumers (20, 48.8%) and about one-third had sedentary jobs (14, 34.1%). Average BMI was 25.8 (range: 14-49), and 30% were overweight or obese. Breast was the first cancer diagnosed in 36 patients (70.6%) and 44 (86.3%) had a metachronous CRC diagnosis. Breast cancer was early stage (0-2) in 32 (78.0%) patients whereas CRC was split between early stage (1-2) in 14 (34.1%) and later stage (3-4) in 19 (46.2%). Ten patients (24.3%) had a known germline mutation, although 23 (56.1%) had a family history of cancer in a first-degree relative. CONCLUSION: Younger patients with both breast and CRC are a unique cohort, often without known risk factors. Alcohol consumption and sedentary jobs were the most common risk factors, and about one-quarter had a known genetic predisposition. Comanagement of both cancers requires individualized, multidisciplinary care.
Asunto(s)
Neoplasias de la Mama , Neoplasias Colorrectales , Neoplasias Primarias Secundarias , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Primarias Múltiples/genética , Masculino , Factores de Edad , Factores de RiesgoRESUMEN
POT1 is the second most frequently reported gene (after CDKN2A) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72×10-12) in carriers compared with a control population. Majority of naevi were on the probands' back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant POT1 variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.
Asunto(s)
Melanoma , Fenotipo , Complejo Shelterina , Neoplasias Cutáneas , Proteínas de Unión a Telómeros , Humanos , Melanoma/genética , Melanoma/patología , Femenino , Masculino , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Proteínas de Unión a Telómeros/genética , Persona de Mediana Edad , Adulto , Predisposición Genética a la Enfermedad , Anciano , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patologíaRESUMEN
In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.
Asunto(s)
Neoplasias Renales , Humanos , Neoplasias Renales/genética , Neoplasias Renales/patología , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/diagnóstico , Enfermedad de von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/patología , Enfermedad de von Hippel-Lindau/complicacionesRESUMEN
The CDKN2A gene remains understudied in melanoma compared to BRAF alterations. Inactivation of this tumor suppressor gene through homozygous deletions in the 9p21 chromosomal region leads to cellular proliferation and disrupts pro-apoptotic pathways. Genetic changes in CDKN2A are linked to multiple primary melanomas (MPM), with patients diagnosed with melanoma facing an elevated risk of developing additional primaries. We present the rare case of a 72-year-old Caucasian woman with nine metastasizing melanomas across diverse anatomical sites, posing a diagnostic challenge. Initial diagnosis in 2022 revealed ulcerated superficial spreading melanomas, progressing to intradermal and papillary dermal populations with neurotropism and angiotropism by early 2023. Lymph node metastases were identified, classifying the condition as pT3b N3b. Subsequent assessments in April 2023 revealed clinically suspicious melanocytic lesions diagnosed as intradermal and traumatized junctional nevi. In late 2023, cutaneous pigmented lesions and subcutaneous metastases were confirmed as nodular nevoid low-CSD multiple melanomas. Fluorescence in situ hybridization testing revealed homozygous CDKN2A deletion, necessitating close multidisciplinary collaboration for an optimized care plan for effective monitoring and intervention in this intricate clinical scenario. In summary, this case report highlights the diagnostic challenges of MPM in a single patient. Stressing the importance of immuno-histochemistry and CDKN2A genetic testing, our findings underscore the crucial role of these tools in accurately distinguishing malignant melanocytic proliferations from nevi and characterizing MPM cases.
Asunto(s)
Inhibidor p16 de la Quinasa Dependiente de Ciclina , Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/diagnóstico , Femenino , Anciano , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Cutáneas/genética , Mutación , Neoplasias Primarias Múltiples/genéticaRESUMEN
Improved cancer screening and treatment programs have led to an increased survivorship of patients with cancer, but consequently also to the rise in number of individuals with multiple primary tumors (MPT). Germline testing is the first approach investigating the cause of MPT, as a positive result provides a diagnosis and proper clinical management to the affected individual and their family. Negative or inconclusive genetic results could suggest non-genetic causes, but are negative genetic results truly negative? Herein, we discuss the potential sources of missed genetic causes and highlight the trove of knowledge MPT can provide. See related article by Borja et al., p. 209.
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Predisposición Genética a la Enfermedad , Pruebas Genéticas , Neoplasias Primarias Múltiples , Humanos , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/diagnóstico , Pruebas Genéticas/métodos , Mutación de Línea Germinal , Detección Precoz del Cáncer/métodos , Diagnóstico Erróneo/estadística & datos numéricosRESUMEN
Effective diagnosis and understanding of the mechanism of intrapulmonary metastasis (IM) from multiple primary lung cancers (MPLC) aid clinical management. However, the actual detection panels used in the clinic are variable. Current research on tumor microenvironment (TME) of MPLC and IM is insufficient. Therefore, additional investigation into the differential diagnosis and discrepancies in TME between two conditions is crucial. Two hundred and fourteen non-small cell lung cancer patients with multiple tumors were enrolled and 507 samples were subjected to DNA sequencing (NGS 10). Then, DNA and RNA sequencing (master panel) were performed on the specimens from 32 patients, the TME profiles between tumors within each patient and across patients and the differentially expressed genes were compared. Four patients were regrouped with NGS 10 results. Master panel resolved the classifications of six undetermined patients. The TME in MPLC exhibited a high degree of infiltration by natural killer (NK) cells, CD56dim NK cells, endothelial cells, etc., Pâ <â 0.05. Conversely, B cells, activated B cells, regulatory cells, immature dendritic cells, etc., Pâ <â 0.001, were heavily infiltrated in the IM. NECTIN4 and LILRB4 mRNA were downregulated in the MPLC (Pâ <â 0.0001). Additionally, NECTIN4 (Pâ <â 0.05) and LILRB4 were linked to improved disease-free survival in the MPLC. In conclusion, IM is screened from MPLC by pathology joint NGS 10 detections, followed by a large NGS panel for indistinguishable patients. A superior prognosis of MPLC may be associated with an immune-activating TME and the downregulation of NECTIN4 and LILRB4 considered as potential drug therapeutic targets.
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Carcinoma de Pulmón de Células no Pequeñas , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Pulmonares , Transcriptoma , Microambiente Tumoral , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Masculino , Femenino , Microambiente Tumoral/genética , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Anciano , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Pronóstico , Genómica/métodos , Perfilación de la Expresión Génica , Nectinas/genética , Células Asesinas Naturales/inmunologíaRESUMEN
BACKGROUND AND AIM: We previously identified that ever-smoking and severe gastric atrophy in pepsinogen are risk factors for synchronous gastric cancers (SGCs). This study aimed to determine the association of alcohol drinking status or alcohol-related genetic polymorphism with SGCs and also stratify their risk. METHODS: This multi-center prospective cohort study included patients who underwent endoscopic submucosal dissection for the initial early gastric cancers at 22 institutions in Japan. We evaluated the association of alcohol drinking status or alcohol dehydrogenase 1B (ADH1B) and acetaldehyde dehydrogenase 2 (ALDH2) genotypes with SGCs. We then stratified the risk of SGCs by combining prespecified two factors and risk factors identified in this study. RESULTS: Among 802 patients, 130 had SGCs. Both the ADH1B Arg and ALDH2 Lys alleles demonstrated a significant association with SGCs on multivariate analysis (odds ratio, 1.77), although alcohol drinking status showed no association. The rates of SGCs in 0-3 risk factors in the combined evaluation of three risk factors (ever-smoking, severe gastric atrophy in pepsinogen, and both the ADH1B Arg and ALDH2 Lys alleles) were 7.6%, 15.0%, 22.0%, and 32.1%, respectively. The risk significantly increased from 0 to 3 risk factors on multivariate analysis (P for trend <0.001). CONCLUSIONS: Both the ADH1B Arg and ALDH2 Lys alleles were at high risk for SGCs. The risk stratification by these three factors may be a less invasive and promising tool for predicting their risk.
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Alcohol Deshidrogenasa , Consumo de Bebidas Alcohólicas , Aldehído Deshidrogenasa Mitocondrial , Polimorfismo Genético , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Alcohol Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial/genética , Masculino , Femenino , Consumo de Bebidas Alcohólicas/efectos adversos , Anciano , Persona de Mediana Edad , Factores de Riesgo , Estudios Prospectivos , Medición de Riesgo , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Estudios de Cohortes , Fumar/efectos adversos , Japón/epidemiología , Riesgo , GenotipoRESUMEN
A 47-year-old woman presented with multiple gastric tumors, each up to 10 mm in diameter, in the gastric body and fundus without mucosal atrophy. White spots and numerous transparent, light-brownish, small, and rounded spots were observed in the background gastric mucosa. Biopsy specimens obtained from the tumors revealed gastric neuroendocrine tumors. The patient exhibited hypergastrinemia and achlorhydria and tested negative for serum parietal cell antibody, intrinsic factor antibody, and Helicobacter pylori infection. Moreover, no additional lesions were detected on imaging. These findings were inconsistent with Rindi's classification. The tumor was resected via endoscopic submucosal resection. Histopathological examination revealed gastric neuroendocrine tumors G2 infiltrating the submucosa with no atrophy of the gastric mucosa, dilated fundic glands, parietal cell protrusions, and hyperplasia of enterochromaffin-like cells. Immunohistochemically, the parietal cells were negative for both α- and ß-subunits of H+/K+ ATPase, suggesting parietal cell dysfunction. A genomic variant was identified in adenosine triphosphatase H+/K+ transporting subunit alpha. After 7 years of treatment, there was no evidence of residual or metastatic lesions. Modification of adenosine triphosphatase H+/K+ transporting subunit alpha may be a significant factor in the pathogenesis of multiple gastric neuroendocrine tumors in the context of gastric parietal cell dysfunction.
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Tumores Neuroendocrinos , Células Parietales Gástricas , Neoplasias Gástricas , Humanos , Femenino , Persona de Mediana Edad , Células Parietales Gástricas/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , ATPasa Intercambiadora de Hidrógeno-Potásio/genética , ATPasa Intercambiadora de Hidrógeno-Potásio/metabolismo , Aclorhidria/genética , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Mucosa Gástrica/patología , Resección Endoscópica de la MucosaRESUMEN
PURPOSE: There exists a barrier between developing and disseminating risk prediction models in clinical settings. We hypothesize that this barrier may be lifted by demonstrating the utility of these models using incomplete data that are collected in real clinical sessions, as compared with the commonly used research cohorts that are meticulously collected. MATERIALS AND METHODS: Genetic counselors (GCs) collect family history when patients (ie, probands) come to MD Anderson Cancer Center for risk assessment of Li-Fraumeni syndrome, a genetic disorder characterized by deleterious germline mutations in the TP53 gene. Our clinical counseling-based (CCB) cohort consists of 3,297 individuals across 124 families (522 cases of single primary cancer and 125 cases of multiple primary cancers). We applied our software suite LFSPRO to make risk predictions and assessed performance in discrimination using AUC and in calibration using observed/expected (O/E) ratio. RESULTS: For prediction of deleterious TP53 mutations, we achieved an AUC of 0.78 (95% CI, 0.71 to 0.85) and an O/E ratio of 1.66 (95% CI, 1.53 to 1.80). Using the LFSPRO.MPC model to predict the onset of the second cancer, we obtained an AUC of 0.70 (95% CI, 0.58 to 0.82). Using the LFSPRO.CS model to predict the onset of different cancer types as the first primary, we achieved AUCs between 0.70 and 0.83 for sarcoma, breast cancer, or other cancers combined. CONCLUSION: We describe a study that fills in the critical gap in knowledge for the utility of risk prediction models. Using a CCB cohort, our previously validated models have demonstrated good performance and outperformed the standard clinical criteria. Our study suggests that better risk counseling may be achieved by GCs using these already-developed mathematical models.
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Síndrome de Li-Fraumeni , Humanos , Síndrome de Li-Fraumeni/genética , Medición de Riesgo , Femenino , Masculino , Neoplasias Primarias Múltiples/genética , Proteína p53 Supresora de Tumor/genética , Mutación de Línea Germinal , Asesoramiento Genético , Adulto , Predisposición Genética a la Enfermedad , Genes p53 , Persona de Mediana EdadRESUMEN
Classic Hodgkin lymphoma (CHL) can arise in patients with low-grade B-cell lymphoma. The features of CHL arising in follicular lymphoma (FL) and its outcome are still unclear, mainly due to the very few cases reported. This study compares 17 patients with CHL and FL to 2 control groups: 1 of 26 patients with FL and a second of 60 patients older than 40 when diagnosed with CHL. Of the FL and CHL patients, 8 had simultaneous FL and CHL, while 9 had FL first, followed by CHL 4.7 years later on average. The age at the diagnosis of FL was 61 years for patients with synchronous FL and CHL and of 60 years for FL, followed by CHL at 65 years. Patients with FL only were, on average, 59 years old at presentation, while CHL patients were 61. FL was grade 1-2 in 75% of FL and CHL patients and 67% of FL first and CHL second patients, lower proportions than in the FL control group-92%. Epstein-Barr virus (EBV) was detected in a lower fraction (29%) of the FL and CHL group than in CHL-only controls (46%). BCL2 translocations were detected in 4 of the 7 cases with FL, but in positive cases, the rearrangement was also present in the CHL component, indicating a clonal relationship between FL and CHL. Patients with FL and CHL treated for CHL had an initial outcome more similar to FL than to CHL controls.