RESUMEN
BACKGROUND: Although the prognostic biomarkers associated with colorectal cancer (CRC) survival are well known, there are limited data on the association between the molecular characteristics and survival after recurrence (SAR). The purpose of this study was to assess the association between pathway mutations and SAR. METHODS: Of the 516 patients with stage III or high risk stage II CRC patients treated with surgery and adjuvant chemotherapy, 87 who had distant recurrence were included in the present study. We analyzed the association between SAR and mutations of 40 genes included in the five critical pathways of CRC (WNT, P53, RTK-RAS, TGF-ß, and PI3K). RESULTS: Mutation of genes within the WNT, P53, RTK-RAS, TGF-ß, and PI3K pathways were shown in 69(79.3%), 60(69.0%), 57(65.5%), 21(24.1%), and 19(21.8%) patients, respectively. Patients with TGF-ß pathway mutation were younger and had higher incidence of mucinous adenocarcinoma (MAC) histology and microsatellite instability-high. TGF-ß pathway mutation (median SAR of 21.6 vs. 44.4 months, p = 0.021) and MAC (20.0 vs. 44.4 months, p = 0.003) were associated with poor SAR, and receiving curative resection after recurrence was associated with favorable SAR (Not reached vs. 23.6 months, p < 0.001). Mutations in genes within other critical pathways were not associated with SAR. When MAC was excluded as a covariate, multivariate analysis revealed TGF-ß pathway mutation and curative resection after distant recurrence as an independent prognostic factor for SAR. The impact of TGF-ß pathway mutations were predicted using the PROVEAN, SIFT, and PolyPhen-2. Among 25 mutations, 23(92.0%)-24(96.0%) mutations were predicted to be damaging mutation. CONCLUSIONS: Mutation in genes within TGF-ß pathway may have negative prognostic role for SAR in CRC. Other pathway mutations were not associated with SAR.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Recurrencia Local de Neoplasia/genética , Transducción de Señal/genética , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Capecitabina , Quimioterapia Adyuvante/métodos , Colon/patología , Colon/cirugía , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/análogos & derivados , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Compuestos Organoplatinos/uso terapéutico , Oxaloacetatos , Cuidados Paliativos/métodos , Pronóstico , Recto/patología , Recto/cirugía , Análisis de Supervivencia , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). There were significantly more damaging variants in high-grade versus low-grade tumor cohorts. Both cohorts contained damaging, heterozygous germline variants (catenin ß1; notch receptor 1 and 4) in pathways associated with cell-lineage specification (WNT, NOTCH). Damaging, somatic KRAS proto-oncogene, GTPase mutations were present in both cohorts, while somatic GNAS complex locus mutations were confined to low-grade neoplasms. Variants predominantly affected transcription factors, kinases, and stem cell signaling molecules in canonical pathways including epithelial to mesenchymal transition, stem cell pluripotency, p53, PTEN, and NF-ÒB signaling pathways. High-grade tumors demonstrated MYC proto-oncogene, bHLH transcription factor (MYC) and death domain associated protein (DAXX) amplification and damaging somatic variants in tumor protein p53 (TP53), likely to amplify an aggressive phenotype. Damaging APC, WNT signaling pathway regulator (APC) deletions were identified in metastatic tissue of both cohorts suggesting a role in invasive disease. Our data suggest that germline dysregulation of WNT and/or NOTCH pathways predisposes patients toward a secretory cell phenotype (i.e., goblet-like cells) upon acquisition of somatic KRAS mutations. Additional somatically acquired variants activating oncogenes MYC and DAXX and inhibiting the critical tumor suppressor, tumor protein TP53, were consistent with manifestation of a high-grade phenotype. These additional changes within the epithelial to mesenchymal transition signaling network (WNT, NOTCH, RAS/ERK/PI3K, PTEN, NF-ÒB), produce aggressive high-grade tumor characteristics by actively driving cells towards dedifferentiation, proliferation, and migration.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Neoplasias del Apéndice/genética , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Dosificación de Gen , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Polimorfismo de Nucleótido Simple , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Neoplasias del Apéndice/mortalidad , Neoplasias del Apéndice/patología , Neoplasias del Apéndice/cirugía , Variaciones en el Número de Copia de ADN , Diagnóstico Diferencial , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Humanos , Clasificación del Tumor , Fenotipo , Valor Predictivo de las Pruebas , Proto-Oncogenes MasRESUMEN
Multiple primary malignancy is defined as two or more malignancies detected in an individual person. In particular, synchronous quintuple primary malignancy is extremely rare. A 52-year-old male with anal pain and intermittent blood-tinged stool was diagnosed with malignancies in the stomach, jejunum, ascending colon, transverse colon and rectum. He underwent a subtotal gastrectomy, segmental resection of the jejunum and total protocolectomy with end ileostomy. The postoperative pathologic findings were moderate differentiated gastric adenocarcinoma (pT1bN0M0, pStageIA), combined adenocarcinoma and neuroendocrine carcinoma of the jejunum (pT3N0M0, pStageIIA), three mucinous adenocarcinoma of the ascending colon (pT3N0M0, pStageIIA), transverse colon (pT1N0M0, pStageI) and rectum (pT3N1aM0, pStageIIIB). The tumors did not lack MLH-1 and MSH-2 expression, as the markers (bat26, D5S346, bat25, D2S123) suggest MSI-H presence. Adjuvant chemoradiotherapy was started according to regimen, FOLFOX 4 for advanced rectal cancer. Six years post-operation, the patient is currently attending regular follow-ups without recurrence or metastasis.
Asunto(s)
Adenocarcinoma Mucinoso/diagnóstico , Neoplasias del Colon/diagnóstico , Neoplasias del Yeyuno/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias del Recto/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/análisis , Dolor en Cáncer/etiología , Quimioradioterapia Adyuvante , Colectomía , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Endoscopía Gastrointestinal , Fluorouracilo/uso terapéutico , Gastrectomía/métodos , Hemorragia Gastrointestinal/etiología , Humanos , Ileostomía , Neoplasias del Yeyuno/genética , Neoplasias del Yeyuno/patología , Neoplasias del Yeyuno/terapia , Leucovorina/uso terapéutico , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Compuestos Organoplatinos/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias del Recto/genética , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Although KRAS mutation has a predictive role in stage IV colorectal cancer (CRC) patients treated with anti-EGFR therapy, there have been controversies in the prognostic impact of KRAS mutation in stage II or III disease. The purpose of this study was to assess the prognostic impact of KRAS and BRAF mutation in patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX). METHODS: KRAS exon 2 and BRAF codon 600 were analyzed in patients with stage II and III CRC who underwent curative resection followed by adjuvant FOLFOX. Clinicopathologic features and disease-free survival (DFS) were compared. RESULTS: Among a total of 437 patients, mutational data of KRAS and BRAF were available in 388 and 433 patients, respectively. KRAS mutation (codon 12 and 13) and BRAF V600E mutation was found in 26.5 and 3.7 % of patients. DFS was significantly worse in the KRAS mutant patients compared to KRAS wild type patients (3-year DFS 79 and 92 %, p = 0.006). Multivariate analysis revealed KRAS mutation as an independent negative prognostic factor for DFS (adjusted hazard ratio 2.30, 95 % confidence interval 1.23-4.32). Among the various subtypes of KRAS mutation, G13D (3-year DFS 76 %, p = 0.008) was significantly associated with poor DFS, while G12D was not associated with prognosis (3-year DFS 86 %, p = 0.61). There was no association between BRAF mutation and DFS. CONCLUSIONS: KRAS mutation has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias del Colon/genética , Mutación/genética , Recurrencia Local de Neoplasia/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/mortalidad , Adenocarcinoma Mucinoso/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Tasa de SupervivenciaRESUMEN
BACKGROUND: The close association between mucinous histology and microsatellite instability (MSI) may have hindered the evaluation of prognostic significance of mucinous histology. The aim of this retrospective study was to investigate whether mucinous histology was associated with a worse prognosis, independent of MSI status, compared to nonmucinous histology in patients with stage III colon cancer. METHODS: This study enrolled 394 consecutive patients with stage III colorectal cancer treated with adjuvant FOLFOX after curative resection (R0). Clinicopathological information was retrospectively reviewed. Tumors were analyzed for MSI by polymerase chain reaction to determine MSI status. Kaplan-Meier method, log-rank test, and Cox proportional hazard regression models were used. RESULTS: The estimated rate of 3-year disease-free survival (DFS) in patients with nonmucinous adenocarcinoma (NMA 79.2 %) was significantly greater than that in patients with mucinous adenocarcinoma (MA) and adenocarcinoma with mucinous component (MC) (56.9 %; log-rank, P = 0.002). In univariate analysis, histology (NMA vs. MA/MC), American Joint Committee on Cancer stage (IIIA, IIIB, and IIIC), and lymphovascular invasion (present vs. absent) were significantly associated with DFS. In multivariate analysis, mucinous histology (MA/MC) was associated with decreased DFS in all patients (hazard ratio 1.82, 95 % confidence interval 1.03-3.23, P = 0.0403). In patients with MA/MC, no difference in DFS was observed between MSI and microsatellite stability (log-rank, P = 0.732). CONCLUSIONS: Mucinous histology is an independent poor prognostic factor for DFS in patients with stage III colon cancer after adjuvant FOLFOX chemotherapy.
Asunto(s)
Adenocarcinoma Mucinoso/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/mortalidad , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia/mortalidad , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: The determination of sensitive chemotherapy drugs for gastric cancer (GC) is one of the greatest challenges of adjuvant therapy. Here we evaluated the chemosensitivity of GC to anticancer drugs and the telomerase reverse transcriptase (hTERT) mRNA expression, and investigated the relationship of them. METHODS: The GC cells which were collected from 68 patients with primary GC were primary cultured. The chemosensitivity of GC cells to anticancer drugs was evaluated successfully using the MTT assay for 60 cases of GC cells, and the hTERT mRNA expression was examined in 60 cases of GC tissues and corresponding normal gastric mucosa and 6 cases of chronic superficial gastritis mucosa by in situ hybridization. RESULTS: Taxol, cisplatin and 5-fluorouracil were in general more effective than adriamycin and mitomycin for GC cells, and the chemosensitivity to anticancer drugs was associated with tumor histological types and a worse tumor grade. Compared to normal gastric mucosa tissues, hTERT mRNA expression was significantly increased in GC (P<0.05), which was related with a worse differentiation and drug-resistance to 5-fluorouracil or adriamycin in GC. CONCLUSIONS: These data demonstrate for the first time that examinations of hTERT mRNA expression as an important factor could be used to select the chemotherapeutic drugs for GC patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793217009875483.
Asunto(s)
Adenocarcinoma/genética , Antineoplásicos/farmacología , Biomarcadores de Tumor/genética , Resistencia a Antineoplásicos/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/genética , Telomerasa/genética , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/enzimología , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Papilar/enzimología , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/patología , Carcinoma de Células en Anillo de Sello/enzimología , Carcinoma de Células en Anillo de Sello/genética , Carcinoma de Células en Anillo de Sello/patología , Estudios de Casos y Controles , Diferenciación Celular , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Doxorrubicina/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Fluorouracilo/farmacología , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Hibridación in Situ , Mitomicina/farmacología , Clasificación del Tumor , Paclitaxel/farmacología , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patología , Células Tumorales CultivadasRESUMEN
The prognostic impact of CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the treatment outcome of colon cancer patients receiving adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI status in colorectal cancer patients treated with adjuvant FOLFOX. Stages II and III sporadic colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Eight CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, CDKN2A (p16), RUNX3 and SOCS1) and five microsatellite markers were examined. Disease-free survival (DFS) was analyzed according to CIMP and MSI status. A total of 322 patients were included: male/female 192/130, median age 61 years (range 30-78), proximal/distal location 118/204 and Stages II/III 43/279. CIMP status was high in 25 patients (7.8%) and 21 patients (6.5%) had MSI-high tumor. CIMP/MSI status was not significantly associated with DFS: 3-year DFS 100% in CIMP(-)/MSI(+), 84% in CIMP(-)/MSI(-), 82% in CIMP(+)/MSI(-) and 75% in CIMP(+)/MSI(+) (p = 0.33). Results of exploratory analysis showed that concurrent methylation at NEUROG1 and CDKN2A (p16) was associated with shorter DFS: 3-year DFS 69% in NEUROG1(+)/CDKN2A (p16)(+) versus 87% in NEUROG1(-)/CDKN2A (p16)(-) (p = 0.006). In conclusion, concurrent methylation of NEUROG1 and CDKN2A (p16) is associated with recurrence following adjuvant FOLFOX in Stages II/III colorectal cancer.
Asunto(s)
Adenocarcinoma Mucinoso/genética , Adenocarcinoma/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Metilación de ADN , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/mortalidad , Adulto , Anciano , Quimioterapia Adyuvante , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Islas de CpG/genética , ADN de Neoplasias/genética , Femenino , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Compuestos Organoplatinos/uso terapéutico , Reacción en Cadena de la Polimerasa , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
AIM: To determine the effect of allitridi on cell cycle of human gastric cancer (HGC) cell lines MGC803 and SGC7901 and its possible mechanism. METHODS: Trypan blue dye exclusion was used to evaluate the proliferation, inhibition of cells and damages of these cells were detected with electron microscope. Flow cytometry and cell mitotic index were used to analyze the change of cell cycle, immunohistochemistry, and RT-PCR was used to examine expression of the p21(WAF1) gene. RESULTS: MGC803 cell growth was inhibited by allitridi with 24 h IC50 being 6.4 microg/mL. SGC7901 cell growth was also inhibited by allitridi with 24 h IC50 being 7.3 microg/mL. After being treated with allitridi at the concentration of 12 microg/mL for 24 h, cells were found to have direct cytotoxic effects, including broken cellular membrane, swollen and vesiculated mitochondria and rough endoplasmic reticula, and mass lipid droplet. When cells were treated with allitridi at the concentration of 3, 6, and 9 microg/mL for 24 h, the percentage of G0/G1 phase cells was decreased and that of G2/M phase cells was significantly increased (P = 0.002) compared with those in the group. When cells were treated with allitridi at the concentration of 6 microg/mL, cell mitotic index was much higher (P = 0.003) than that of control group, indicating that allitridi could cause gastric cancer cell arrest in M phase. Besides, the expression levels of p21(WAF1) gene of MGC803 cells and p21(WAF1) gene of SGC7901 cells were remarkably upregulated after treatment. CONCLUSION: Allitridi can cause gastric cancer cell arrest in M phase, and this may be one of the mechanisms for inhibiting cell proliferation. Effect of allitridi on cells in M phase may be associated with the upregulation of p21(WAF1) genes. This study provides experimental data for clinical use of allitridi in the treatment of gastric carcinoma.
Asunto(s)
Compuestos Alílicos/farmacología , Antineoplásicos/farmacología , Neoplasias Gástricas/tratamiento farmacológico , Sulfuros/farmacología , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/patología , Secuencia de Bases , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , ADN de Neoplasias/genética , Ajo , Humanos , Microscopía Electrónica , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
An altered protein expression of Ca(2+)-dependent protein kinase C (PKC) isoforms and a point mutation in the PKC alpha cDNA (position 908 of the nucleotide sequence, position 294 of the amino acid sequence, substitution of an aspartic acid by a glycine) have been previously described in a subpopulation of human pituitary tumors. In this work, we screened 16 thyroid tissue samples (four follicular adenomas, five colloid adenomas, three papillary carcinomas, one follicular carcinoma and three normal tissues adjacent to the tumors) for the presence of the PKC alpha point mutation and for PKC alpha, beta 1, beta 2, epsilon and delta protein expression. Screening for the presence of the PKC alpha mutant was performed by a subcloning technic. The polymerase chain reaction products were generated using reverse-transcribed cDNAs, subcloned and sequenced (10 clones were routinely sequenced). The PKC alpha point mutation at position 908 of the cDNA sequence was found in four out of the nine adenomas and in the follicular carcinoma. It was neither detected in the papillary carcinomas nor in the adjacent normal tissues (one was the adjacent normal tissue of the follicular carcinoma; in this sample, genomic DNA and cDNA were used to look for the presence of the mutant), demonstrating the somatic nature of this mutant. Western blot analysis of PKC isoforms showed that the expression of all isoforms was higher in the thyroid neoplasms as compared with their adjacent normal tissue (n = 3). It was also higher in the samples containing the PKC mutant (two follicular adenomas, two colloid adenomas and the follicular carcinoma) as compared with the tumors where it was not detected (three papillary carcinomas and five adenomas). Samples could be ordered according to their increasing PKC expression as follows: normal adjacent tissue < follicular adenomas without PKC alpha mutant < or = papillary carcinoma < follicular adenomas with PKC mutant < follicular carcinoma with PKC mutant. In conclusion, the discovery of the PKC alpha mutant in thyroid neoplasms demonstrates that this mutant is not particular to human pituitary tumors where it was originally detected. It is a somatic mutation and its presence is concomitant with high levels of all of the PKC isoforms analysed. The presence of the PKC mutant in thyroid neoplasms raises the question of its importance in thyroid tumorigenesis.