Combined methylation of p16 and hMLH1 (CMETH2) discriminates a subpopulation with better prognosis in colorectal cancer patients with microsatellite instability tumors.

The aim of this study was to determine the frequency of p16 and hMLH1 genes simultaneous methylation in colorectal cancer patients with Microsatellite Instability (MSI) tumors. We also wanted to analyze the relationship with other clinical features, with BRAF gene V600E mutation and with prognosis. Samples from fifty one patients with MSI positive sporadic colorectal cancer were included. DNA was extracted from tumor samples. Promoter methylation was analyzed using bisulfite modification and was detected by quantitative methylation-specific PCR. BRAF gene was amplified using specific primers and mutations were detected by real time PCR. Simultaneous methylation was transformed in a new variable called CMETH2. Frequency of CMETH2 was analyzed and compared with other clinicopathological variables. 33.3 % of patients were positive for CMETH2 and 25 % had BRAF V600E mutation. CMETH2 was related with proximal location, with poorly differentiated tumors and with BRAF V600E mutation. CMETH2 only showed influence in the overall survival (OS) in patients with distal tumors. However, with regard to the disease free survival (DFS) measure, CMETH2 was independent prognostic factor. We were able to discriminate tumors with high methylation features using a transformation analysis of variables into a new computed one (CMETH2). CMETH2 has demonstrated to be a useful prognostic factor in MSI tumors. The prognostic value of CMETH2 in DFS was independent of other clinicopathological variables. The use of CMETH2 could help in the election of the best therapeutic alternative for CCR patients with MSI tumors.

Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer.

BACKGROUND: The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS: Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS: CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), ≥2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), ≥3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and ≥5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION: CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.

Diagnostic and predictive value of urine PCA3 gene expression for the clinical management of patients with altered prostatic specific antigen.

OBJECTIVE: Analyze the impact of the introduction of the study of PCA3 gene in post-prostatic massage urine in the clinical management of patients with PSA altered, evaluating its diagnostic ability and predictive value of tumor aggressiveness. METHODS: Observational, prospective, multicenter study of patients with suspected prostate cancer (PC) candidates for biopsy. We present a series of 670 consecutive samples of urine collected post-prostatic massage for three years in which we determined the "PCA3 score" (s-PCA3). Biopsy was only indicated in cases with s-positive PCA3. RESULTS: The s-PCA3 was positive in 43.7% of samples. In the 124 biopsies performed, the incidence of PC or atypical small acinar proliferation was 54%, reaching 68,6% in s-PCA3≥100. Statistically significant relationship between the s-PCA3 and tumor grade was demonstrated. In cases with s-PCA3 between 35 and 50 only 23% of PC were high grade (Gleason≥7), compared to 76.7% in cases with s-PCA3 over 50. There was a statistically significant correlation between s-PCA3 and cylinders affected. Both relationships were confirmed by applying a log-linear model. CONCLUSIONS: The incorporation of PCA3 can avoid the need for biopsies in 54% of patients. s-PCA3 positivity increases the likelihood of a positive biopsy, especially in higher s-PCA3 100 (68.6%). s-PCA3 is also an indicator of tumor aggressiveness and provides essential information in making treatment decisions.

Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation.

INTRODUCTION: Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients. MATERIALS AND METHODS: We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23. RESULTS: Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024). CONCLUSIONS: Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss.

Hibridación in situ fluorescente (FISH), hibridación in situ cromogénica (CISH) e hibridacion in situ cromogénica con plata (SISH): su uso para la detección de la amplificación del gen HER2 en cáncer de mama / No disponible

La importancia en la detección de la amplificación del gen HER2 es esencial en el cáncer de mama puesto que estas pacientes no responden a los tratamientos de quimioterapia y hormonales convencionales. La determinación del HER2 tiene un papel crucial como diana terapéutica del trastuzumab. A continuación discutiremos la efectividad y utilidad clínica de la técnica hibridación in situ fluorescente (FISH), la hibridación in situ cromogénica (CISH) y la hibridación in situ cromogénica con plata (SISH), como métodos usados para el estudio del gen HER2 en la selección correcta de las pacientes con cáncer de mama, que son candidatas a recibir trastuzumab(AU)

The importance of determining HER2 status lays on the fact that breast cancer patients with HER2 amplification are more reluctant to conventional chemotherapy and hormonal treatments. Thus the HER2 analysis is an essential requisite to determine which patients are eligible to be treated with trastuzumab. The aim of this article is reviewing the effectiveness and clinical utility of HER 2 diagnostic test with fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH) and silver chromogenic in situ hybridization (SISH) to correctly select breast cancer patients who are candidates to be treated with trastuzumab(AU)

The prevalence of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T and its influence on mycophenolic acid pharmacokinetics in stable renal transplant patients.

UNLABELLED: The aim of this study was to evaluate the distribution of UGT1A9 promoter region T-275A and C-2152T single nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on mycophenolic acid (MPA) pharmacokinetics. METHODS: In total, 133 Caucasian renal transplant recipients were studied. Also a complete 12-hour pharmacokinetic profile was recorded for 15 transplant patients who had the polymorphism and for 15 controls who were randomly chosen since they received the same type and dosage of mycophenolate, same posttransplant time and similar renal function. RESULTS: The T-275A promoter mutation was detected in 12.03% of patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) experienced more admissions owing to gastrointestinal side effects (P < .05). The pharmacokinetics studies showed that carriers of T-275A and/or C-2152T displayed a smaller area under-concentration time curve (AUC): 57.8 +/- 4.3 vs 78.9 +/- 10.8 mg/L*h (P < .03). CONCLUSION: It seemed that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region in the late posttransplant recipient group, showed a greater incidence of gastrointestinal side effects and a lower MPA exposure.

Colorectal carcinoma prognosis can be predicted by alterations in gene p53 exons 5 and 8.

BACKGROUND AND AIMS: Gene p53 alteration is a genetic event described in the progression from adenoma to colorectal carcinoma. Most of the p53 mutations occur in exons 5 to 8 in highly preserved regions and in the three main structural domains of the p53 protein. It is possible that mutations affecting different structural regions may present different effects on the p53 protein function and, due to this, they may have different prognostic meaning. MATERIALS AND METHODS: The study population consisted of 353 patients diagnosed with sporadic colorectal cancer. Mutations in 5-8 exons of p53 gene were detected by means of single strand conformation polymorphism (SSCP). All samples that showed different migration bands in SSCP were confirmed by sequencing. RESULTS: A total of 69 patients (19.7%) showed alterations of the gene p53. It was observed that mutation in codon 175 in exon 5 was related to tumors located in the colon (p = 0.01) and the mutation in the codon 288 in exon 8 was related to rectal tumors (p = 0.02). In the study of overall survival, mutation in codon 175 of exon 5 conferred a better prognosis and alterations of exon 8 were related to a worse prognosis in different population subgroups: in men, in patients younger than 71 years old, in the tumors located in the proximal colon, the ones moderately differentiated, and those that are mucinous. CONCLUSION: According to this study, mutations in different exons of p53 are related to different phenotypes in colorectal cancer. These phenotypes could mean differences in the clinical evolution of the patients.

Circulating tumor cells in colorectal cancer: correlation with clinical and pathological variables.

BACKGROUND: The CellSearch System is a technique to detect circulating tumor cells (CTCs) in patients with cancer. Few data have been published concerning the role of CTCs detection by this method in colorectal cancer. The aim of this study was to correlate the presence of CTCs with the commonest clinical and morphological variables. PATIENTS AND METHODS: Blood samples were collected from 97 patients and 30 healthy volunteers. Quantification of CTCs in 7.5 ml of blood was carried out with the CellSearch System. The results were expressed as number of CTCs/7.5 ml and the cut-off of >or=2 CTCs/7.5 ml was chosen to define the test as positive. RESULTS: Positive CTCs were detected in 34 of 94 patients (36.2%). Correlation was not found among positive CTCs and location of primary tumor, increased carcinoembryonic antigen level, increased lactate dehydrogenase level or grade of differentiation. Only stage correlated with positive CTCs (20.7% in stage II, 24.1% in stage III and 60.7% in stage IV, P = 0.005). CONCLUSIONS: CTCs detection by CellSearch is a highly reproducible method that correlates with stage but not with other clinical and morphological variables in patients with colorectal cancer. Colon cancer tumor cells are detectable in all stages. Further studies are warranted.

Telomerase activity in colorectal cancer, prognostic factor and implications in the microsatellite instability pathway.

AIM: To determine whether the telomerase activity is related to the Microsatellite instability (MSI) genetic pathway and whether it means a difference in the survival. METHODS: The population consisted of 97 colorectal cancer patients. MSI determination was performed in accordance with the NCI criteria using PCR and Genescan. Telomerase activity was determined by the TRAP-assay, an ELISA procedure based on the amplification of telomeric repeat sequences. RESULTS: 6.2% showed high MSI (MSI-H), 10.3% showed low MSI (MSI-L) and 83.5% did not show this alteration (MSS). Positive telomerase activity was detected in 92.8% of the patients. 83.3% of MSI-H tumors showed positive telomerase against 93.8% of MSS tumors. In the overall survival analysis the absence of telomerase activity conferred a better prognosis. CONCLUSION: Previous works have shown that tumors which develop via the MSI pathway present a better prognosis. No link between telomerase activity and MSI status is observed, although sample sizes are small. Patients with telomerase negative tumors had better overall survival than patients with telomerase positive tumors.

Role of the BRAF mutations in the microsatellite instability genetic pathway in sporadic colorectal cancer.

BACKGROUND AND AIMS: Between 10 and 15% of all cases of colorectal cancer are the result of microsatellite instability (MSI) in the genetic pathway due to an alteration in the DNA repair genes. Tumors with high MSI are characterized by a better prognosis. The BRAF oncogene has been linked to the MSI pathway in tumorogenesis. The objective of this study was to determine whether alterations in BRAF are related to MSI and whether they can result in differences in survival rates. METHODS: The study cohort comprised 351 patients diagnosed with sporadic colorectal cancer. MSI was determined in accordance with the National Cancer Institute's (NCI) recommendations by means of PCR and sequence analyses. Mutational analysis of the BRAF gene was performed by real-time PCR and subsequent sequencing of the altered samples. The methylation pattern of the hMLH1 gene was determined using methylation-specific PCR analyses of bisulfite-treated DNA and the results confirmed by sequencing. RESULTS: Of the patients tested, 6.9% showed high MSI and 3.7% showed a BRAF gene mutation. hMLH1 methylation was observed in 67.2% of the patients with MSI and/or the BRAF alteration. The BRAF mutation was related to the MSI genetic pathway (P < 0.0001) and with hMLH1 methylation. In the analysis of overall survival only MSI had an independent prognostic value for the risk of death. Patients with the BRAF mutation showed a higher risk of death, although this association was found not to be statistically significant. CONCLUSIONS: There is a subgroup of carcinomas which develop via the MSI pathway that carry an alteration of the BRAF gene. This alteration confers a poorer outcome on these patients within the total group of patients with MSI who have a better prognosis. This hypothesis should be further investigated in a larger study population due to the low incidence of BRAF mutations in colorectal cancer.

Effects of pork vs veal consumption on serum lipids in healthy subjects.

AIMS: To analyse the influence of lean pork (P) and veal (V) consumption on the lipid profile of healthy subjects within the framework of a healthy diet comprising low levels of total fat (TF), saturated fatty acids (SFA) and cholesterol. DESIGN: Double-crossover, randomized and controlled trial SUBJECTS: 44 healthy individuals (22 male and 22 female), recruited voluntarily from the University Complutense of Madrid. The weight and lipid profiles of these volunteers were normal and their dietary patterns were typical for people in our area. INTERVENTIONS: The study comprised 4 phases: stabilisation phase (5 weeks), the participants followed their normal diet; second phase (6 weeks), half of the subjects, were randomised to lean pork or veal consumption, 150 g per day, for their main meal of the day; washout period (5 weeks) and final phase, which was the second phase of intervention (6 weeks). During the intervention stages, only the main meal of the day was taken in the Hospital. The rest of the subjects' diets consisted of different fortnightly menus designed in accordance with the recommendations of the Spanish Society of Arteriosclerosis (SEA). RESULTS: After both stages of intervention had been completed, there was a mean reduction of 5.5% in low-density lipoprotein cholesterol. However, after each intervention there were no significant differences between those who had consumed P, 2.62 (0.55) mmol/L and those who had consumed V, 2.71 (0.47) mmol/L. No differences were observed in any of the other parameters between those who had consumed P and those who had consumed V. CONCLUSIONS: Lean pork and veal produces similar effects on the lipid profiles of healthy subjects. Its consumption, as part of the saturated fat and cholesterol-controlled diet, could therefore be included in food guidelines, both for normal and therapeutic diets.

p16 Gene methylation in colorectal tumors: correlation with clinicopathological features and prognostic value.

BACKGROUND: Methylation of the CpG islands in the p16 gene promoter region is an important transcription repression mechanism that has been identified as an alternative mechanism for inactivating specific genes in cancer. Given that, DNA methylation is a common event in colorectal cancer. MATERIALS AND METHODS: The aim of this study was to establish the methylation status of the p16 gene in 104 patients with colorectal carcinoma and evaluate its prognostic value. DNA was bisulfite-modified and analyzed for p16 promoter methylation by methylation-specific PCR. RESULTS: Methylation of thep16 gene was determined in 18.3% of our patient population (19/104). The methylated state did not correlate with any clinicopathological factors. During a median follow-up period of 72 months, the overall survival rate for patients with gene methylation was 75% and without gene methylation it was 61% (p = 0.09). CONCLUSIONS: Although not statistically significant, this difference indicates a clinically valuable tendency.

Prognostic significance of the p185 protein in colorectal cancer.

The amplification and/or overexpression of the c-erbB-2/neu oncogene may play a role in tumor development and progression. The aim of this prospective study was to evaluate the prognostic value of p185 protein in colorectal cancer using immunohistochemical techniques. We analyzed 106 colorectal tumor tissue specimens from patients who had been operated on by the same surgeon and subjected to a median follow-up of 3 years. Thirty-three per cent of patients showed p185 overexpression related to an advanced stage of the disease. In patients with adenocarcinoma tumors of the colon without distant metastases, p185 detection was found to be of clinical prognostic relevance (p = 0.06).

Prevalencia de la enfermedad de Anderson-Fabry en varones con hipertrofia ventricular izquierda / Prevalence of Anderson-Fabry diseases in men with ventricular hypertrophy. AEBM reference 2003 award

La enfermedad de Anderson-Fabry es causa de hipertrofia ventricular izquierda en adultos. En este estudio se pretende analizar la incidencia de la enfermedad deAnderson-Fabry en varones con hipertrofia ventricular izquierda. Se trata de un estudio monocéntrico y prospectivo de 200 pacientes varones con hipertrofia ventricular izquierda. Se realiza la determinación de la actividad de alfa galactosidasa plasmática, confirmándose con la actividad enzimática en leucocitos. Se realizó el diagnóstico de enfermedad de Anderson-Fabry mediante análisis de actividad enzimática plasmática en tres pacientes, en dos de ellos se confirmó el diagnóstico mediante análisis de la actividad enzimática en leucocitos, descartándose dicho diagnóstico en el tercer paciente mediante esta técnica. La hipertrofia ventricular izquierda puede ser una manifestación de la enfermedad de Anderson-Fabry. Se debe tener en cuenta su diagnóstico en todos los pacientes varones con hipertrofia ventricular izquierda, especialmente si es moderada o severa, independientemente de la existencia de posibles causas de ésta (AU)

Importancia de la inestabilidad microsatélite en tumores borderline y carcinomas de ovario / Relevance of microsatellite instability in borderline tumors and ovarian carcinoma. AEBM reference 2003 award

El objetivo de nuestro estudio es determinar la inestabilidad de seis microsatélites (BAT25, BAT26, NME1, D17S250, D5S346 Y D2S123) y observar si está implicada en el desarrollo de los tumores esporádicos de ovario. El trabajo se ha realizado en 40 pacientes intervenidas quirúrgicamente por tumor de ovario esporádico. La comprobación de la inestabilidad se realizó por comparación del tejido sano y tumoral de cada una de las pacientes. Sólo se encontró inestabilidad en: inestabilidad en BAT26 en tumor borderline, inestabilidad en BAT25 en cistoadenocarcinoma de células claras e inestabilidad en NME1 encistoadenocarcinoma papilar seroso en diferentes pacientes. La inestabilidad microsatélite no parece estar implicada en la aparición o desarrollo de los tumores esporádicos de ovario (AU)

Loss of heterozygosity and methylation of p16 in renal cell carcinoma.

To investigate the possible role of genomic aberrations of chromosome 9p21 in the tumorigenesis of human renal cell carcinoma (RCC), 40 sporadic RCCs were studied using PCR analyses. The tumours were predominantly low stage and low grade. Loss of heterozygosity (LOH) was observed in nine of 39 informative cases, but no homozygous deletion was noticed. Hypermethylation of the promoter region of p16 occurred in eight of the 40 RCCs. No correlation was found between hypermethylation of the p16 gene and LOH on 9p21. A similar level of LOH and methylation was observed in the 40 RCCS regardless of histology, grade and stage. These results suggest that inactivation of p16 and the possibility of other unknown tumour suppressor genes located on other chromosomes could be involved in the pathogenesis of RCC.

Estudio de la inestabilidadmicrosatélite en tumoresborderline y carcinomade ovario / Microsatellite instability in borderline tumors and ovarian carcinoma

El objetivo de nuestro estudio es determinar la inestabilidad de tres microsatélites (BAT25, BAT26 y NME1) y observar si está implicada en el desarrollo de los tumores esporádicos de ovario. El trabajo se ha llevado a cabo en 40 pacientes intervenidas quirúrgicamente por tumor de ovario esporádico. La comprobación de la inestabilidad se realizó por comparación del tejido sano y tumoral de cada una de las pacientes. Sólo se encontró inestabilidad en 3 casos: en BAT26 en tumor borderline; en BAT25 en cistoadenocarcinoma de células claras, y en NME1 en cistoadenocarcinoma papilar seroso en diferentes pacientes. La inestabilidad microsatélite no parece estar implicada en la aparición o el desarrollo de los tumores esporádicos de ovario. (AU)

Role of microsatellite instability in borderline ovarian tumors.

This study was designed to establish the role of microsatellite instability (MSI) in the development of sporadic tumors of the ovary. The instability of 6 microsatellites (BAT25, BAT26, NME1, D17S250, D5S346 and D2S123) was determined by comparing MSI in healthy and tumoral tissue in each of 40 patients undergoing surgery for a sporadic ovarian tumor. BAT26 and D2S123 instability was detected in borderline tumors, and ovarian carcinomas were found to present instability in the microsatellites BAT25, NME1 and D17S250. Our findings indicate that microsatellite instability lacks a significant role in the appearance or progression of sporadic ovarian tumors.

Metilación del gen p16 en el carcinoma broncogénico no microcítico. Implicación pronóstica / Methylation of gene p16 in non-small cell bronchogenic carcinoma. Prognostic implication

La importancia sociosanitaria del cáncer de pulmón radica en su elevada incidencia y mortalidad. En la actualidad se considera el cáncer como el resultado de una acumulación de alteraciones genéticas que afectan a diversos genes con distintas funciones celulares. Los estudios genéticos han demostrado alteraciones en la región 21 del brazo corto del cromosoma 9 (9p21), que son frecuentemente identificadas en el cáncer humano. Esta región contiene un gen supresor llamado p16, que codifica las proteínas p16 y p19. Se ha observado que, aunque la pérdida de heterocigosidad (LOH) es un mecanismo frecuente de inactivación del gen, la metilación del promotor de p16 también es una alteración importante que suprime la función del gen. Se estudió una serie de 98 pacientes diagnosticados de carcinoma de pulmón no microcítico. Se analizó la LOH en 9p21 mediante el análisis de polimorfismos de microsatélites y el estado de metilación del gen p16. El 23,5 per cent de los pacientes presentaban LOH y/o inestabilidad en 9p21 y el 54,5 per cent metilación de p16. Los pacientes que no presentaban alteraciones genéticas en p16 tenían un riesgo relativo de fallecer 1,67 veces mayor (p = 0,1) que los que sí presentaban alguna de estas alteraciones (AU)

Valor pronóstico de la pérdida de heterozigosidad en la región 9p21 en el carcinoma broncogénico no microcítico / Prognostic value of loss of heterozygosity at chromosome 9p21 in nonsmall cell bronchogenic carcinoma

La importancia sociosanitaria del cáncer de pulmón radica en su elevada incidencia y mortalidad. En la actualidad se considera el cáncer como el resultado de una acumulación de alteraciones que afectan a diversos genes con distintas funciones celulares. Diversos estudios genéticos han demostrado una pérdida de material genético en la región 21 del brazo corto del cromosoma 9 (9p21), siendo una de las alteraciones genéticas más frecuentemente identificadas en el cáncer humano. Esta región contiene un gen supresor llamado p16, que codifica las proteínas p16 y p19.Se estudió una serie de 98 pacientes diagnosticados de carcinoma de pulmón no microcítico. Se analizó la pérdida de heterozigosidad (LOH) en 9p21 mediante el análisis de polimorfismos de microsatélites. El 23,5 por ciento de los pacientes presentaba LOH y/o inestabilidad en 9p21. Contrariamente a lo que se esperaba, los pacientes que no presentaban alteraciones genéticas en p16 tenían un riesgo relativo de fallecer 1,7 veces mayor (p = 0,1) que los que sí presentaban LOH y/o inestabilidad (AU)