Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The status of the P16 gene was investigated by Southern blot, polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP), and DNA sequencing analyses in 30 primary resected non-small cell lung carcinomas (NSCLCs) with metastatic involvement of thoracic lymph nodes and 33 NSCLCs without node metastases. Direct sequencing of tumour DNA samples scored positive by PCR-SSCP showed five somatic mutations of the P16 gene: four nonsense and one frameshift. The Southern blot analysis revealed the presence of a homozygous deletion of the P16 locus in one tumour. All of the six NSCLCs with somatic aberrations of the P16 gene belonged to the series of tumours with metastatic diffusion to thoracic lymph nodes. In each of these six cases, the genetic aberration was seen in both the primary tumour and the node metastasis. No P16 alteration was found in tumours without metastatic lymph nodes. This difference was statistically significant (P = 0.02). No correlation was present between P16 alterations and other clinicopathological parameters including age of patients, tumour size, histological type, and grade. In three tumours with genetic aberration of P16, there was a concomitant alteration of the p53 gene. Our results indicate that the P16 gene is infrequently mutated (10 per cent of the cases examined) in primary resected NSCLC. However, since P16 mutations were found only in metastatic tumours, they may be important events in late phases of tumour progression and could represent useful markers of tumour aggressiveness in NSCLC.
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PMID:Alterations of P16 (MTS1) in node-positive non-small cell lung carcinomas. 912 Jul 22

Four cases of brain metastasis from hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) are reported in an area not endemic for HBV infection. Two cases are unusual, since cerebral metastases were the only secondary localization. In these cases, no other sites of metastasization were detected either before or immediately following neurosurgical treatment. In all cases the expression of pRB, p53 and p16 tumor suppressor protein was studied with immunohistochemistry, both, in the primary and metastatic lesions. The pRB expression was as follows: in two cases, lack and moderate expression were observed both, in the primary and in the metastases; in the other two, pRB was not detected. In all cases p53 expression was negative both, in the primary and the metastases. P16 expression was moderately expressed in three cases, both in the primary and the metastases. In one case it was absent. Hepatocarcinogenesis is a multistep process, in which several oncogenes and oncosuppressor genes are involved. In four unusual cases of spread to the brain, we evidenced that tumor suppressor protein expression of p16, p53, and particularly pRB (its aberrated expression is usually associated with metastasis) were altered. We also suggest that HBV and its X protein (HBX) might play an important role in such aggressive behavior of the neoplasia.
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PMID:Brain metastasis from hepatocellular carcinoma associated with hepatitis B virus. 1238 72

Despite clearly defined histologic criteria, the prediction of tumor behavior for patients with gastrointestinal stromal tumors (GIST) still poses a challenge to pathologists. Therefore, searching for alternative markers that allow for better prognostic evaluation is an important task. To determine the practicability of immunohistochemical staining for p16 in clinical cases, we examined p16 protein expression in a group of 284 GISTs, a subset of which had long-term follow-up (median, 45 months; range, 1-204 months). P16 protein expression was ascertained on tissue microarrays as well as on standard sections. Survival analyses were carried out in 157 patients. P16 loss was found in 50% of GISTs, there being no correlation with age, sex, histologic subtype, signs of necrosis, or metastases. Patients having p16-negative tumors had a worse prognosis than those with p16-positive tumors (P = 0.012) with a 2.3-fold relative increased risk of dying of disease. P16 loss identified a subgroup of gastric tumors with a worse prognosis (P = 0.03). The multivariate configural frequency analysis identified two "antitypes," whose observed frequency was found to be significantly lower than the expected frequency [i.e., marker combinations: p16 positive, no metastases, and death of disease and p16 loss, metastases, and still alive]. The "type" whose observed frequency was significantly higher than the expected frequency consisted of the following marker pattern: p16 loss, necrosis, and death of disease (P < 0.001). In the multivariate Cox regression analysis, p16 loss, necrosis, and metastases each had independent prognostic value. P16 loss is a common molecular abnormality in GISTs and might be used in routine diagnosis to identify patients with high-risk tumors.
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PMID:Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. 1570 51

Promoter hypermethylation is responsible for gene inactivation during carcinogenesis. It has been proposed that there is some degree of specificity in the set of genes that become altered by this mechanism in distinct tumor types. To understand whether promoter hypermethylation may differentiate the site of origin, 49 lung adenocarcinomas from 31 lung primaries and 18 metastases from colorectal primaries, respectively, were tested for the presence of this alteration in the APC, CDH1, DAPK, GSTP1, MLH1, MGMT, P14, P16, RARbeta2, RASSF1, sFRP1 and WIF-1 genes. A distinct profile was apparent for the 2 groups of lung tumors and the frequencies of promoter hypermethylation at sFRP1 and WIF-1, 2 genes involved in Wnt signaling, and at CDH1 were significantly higher in colorectal metastases than in lung primaries, whereas methylation of the APC promoter was significantly more common in lung primary adenocarcinomas. Some tumors showed concomitant APC, sFRP1 and WIF-1 gene inactivation, indicating that multiple DNA methylation events must have occurred to definitively down-regulate the signaling through Wnt. However, promoter hypermethylation at the APC and CDH1 genes tended to be mutually exclusive (Fisher's exact test, p = 0.006), suggesting a similar role in carcinogenesis. In conclusion, we propose that inactivation by promoter hypermethylation at the APC, CDH1, sFRP1 and WIF-1 genes may contribute to the discrimination of lung primary adenocarcinomas from colorectal metastasis to the lung, and report the simultaneous presence of methylation at the promoters of multiple genes involved in the Wnt signaling. This may have biological consequences for carcinogenesis.
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PMID:Wnt signaling promoter hypermethylation distinguishes lung primary adenocarcinomas from colorectal metastasis to the lung. 1699 Nov 25

We examined a series of 667 patients with node-negative breast carcinomas in order to identify prognostic immunohistochemical molecular signatures for the prediction of early metastasis, and potential new therapeutic targets. We used a standardized quantitative immunocytochemical approach with 37 antibodies, based on high-throughput tissue microarrays and image analysis, and analyzed the results with respect to metastatic status after a mean follow-up of 86 months. Complete data were obtained for 586 patients. The predictive value of the markers was first analyzed individually by univariate analysis (log rank test) in 586 node-negative tumors, according to metastatic status during follow-up. Twenty-seven markers had significant prognostic value. ROC curve analysis (logistic regression) was then used to determine the marker combination that best classified the patients with and without metastases. A 15-marker signature (Bcl2, P16, P21, P27, P53, CD34, CA IX, c-kit, FGF-R1, P38, JAK, pSTAT3, CK9, STAT1 and ER) correctly classified 84.8% of the patients (sensitivity 85.5%, specificity 84.6%). When ER, PR and c-erb B2 were excluded from the analysis, a very similar signature, in which CK8-18 replaced ER, correctly classified 83.6% of the patients (sensitivity 84.5%, specificity 83.4%). These results show that quantitative immunoprofiling, independently of ER, PR and c-erb B2 status, can provide a basal-like signature, can properly predict the metastatic risk of node-negative breast carcinomas at diagnostic time. This may be helpful for selecting patients who do not need aggressive adjuvant chemotherapy, and for developing tailored therapies.
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PMID:[Early breast carcinoma profiling based on quantitative immunocytochemistry can help predict the risk of early distant metastasis]. 2066 17

Lymph node involvement is prognostically the most determinant clinical factor for patients with head and neck squamous cell carcinomas (HNSCCs). Ultrasound of the neck and fine-needle aspiration (FNA) cytology is one of the first diagnostic procedures and the most accurate diagnostic staging tool for the neck. Patients with HPV-positive oropharyngeal carcinomas (OPSCC) show a significantly better prognosis when compared with HPV-negative OPSCC. P16 overexpression is accepted as surrogate marker for HPV-positive in OPSCC. These HPV/p16-positive OPSCC are localized either in the palatal tonsils or the base of tongue and frequently present with lymph node metastases. We analyzed the correlation and reliability of p16 expression of the FNA of the lymph node metastasis with the immunohistochemical expression of p16 of the same lymph node metastasis and its corresponding primary tumor, as it could be of importance for determining the localization and different prognosis of the primary tumor. 54 HNSCC patients were evaluated, p16 expression of the primary tumors and their lymph node metastases correlated precisely. In 25 of the 54 HNSCC patients, a FNA of the lymph node metastases was taken before the treatment. The positive cytological and immunohistochemical p16 staining correlated exactly. Of the 17 histologically p16-negative lymph node metastases 15 FNA were p16-negative, whereas two samples were p16-positive. In our view, a cytological p16 analysis of cervical lymph node metastasis can facilitate the correct localization of the primary tumor and discriminate reliably HPV-positive OPSCC from HPV-negative HNSCC with their significantly diverse prognosis.
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PMID:The clinical impact of p16 status in fine-needle aspirates of cervical lymph node metastasis of head and neck squamous cell carcinomas. 2258 95

Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma. This study was undertaken to explore CpG methylation abnormalities in an extended tumor panel and assess possible relationships between metastatic disease and mutation status. CpG methylation was quantified by bisulfite pyrosequencing for selected TSG promoters and LINE1 repeats. Methylation indices above normal reference were observed for DCR2 (TNFRSF10D), CDH1, P16 (CDKN2A), RARB, and RASSF1A. Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome. Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease. Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue. In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival. The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series. Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy.
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PMID:Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation. 2315 31

The reported prevalence for presence of human papillomavirus (HPV) genome in lung cancer varies across the world, and limited data are available for North America. P16 immunostaining is used as a surrogate marker for the presence of HPV in cervical and head and neck cancers. In non-small cell lung carcinoma (NSCLC), the association between P16 protein overexpression and HPV remains unclear. We investigated the presence of HPV genome by in situ hybridization (ISH) and polymerase chain reaction (PCR) and P16 or Rb protein expression by immunohistochemistry (IHC) in 336 surgically resected primary NSCLC: 204 adenocarcinoma (AdC) and 132 squamous cell carcinoma (SqCC). HPV genome was detected in 5 (1.5%) of 336 tumors studied by both ISH and PCR; all of them were typed as HPV16 and found in SqCC (3.8%). Despite being solitary tumors and clinically considered as primary lung cancers, all 5 patients had past history of HPV associated squamous cell carcinomas of other organ sites, thus highly suggestive of being metastases. P16 immunostaining was found in 137 (40.8%) tumors, with 109 (32.4%) showing high level expression. All HPV positive (+) cases showed P16 high expression. P16 and Rb protein expressions were inversely correlated (P<0.001), suggesting that the high P16 expression is largely driven by non-HPV loss of Rb protein expression. We conclude that HPV is not or rarely associated with NSCLC in Canadian and most likely North American patients, and P16 immunostaining is not a surrogate marker for its presence.
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PMID:Human papilloma virus genome is rare in North American non-small cell lung carcinoma patients. 2325 64

Head and neck squamous cell carcinoma (HNSCC) is notorious for local recurrence and metastatic spread to regional lymph nodes. Distant spread is uncommon, and brain involvement is rare. Over the past decade there has been a rising incidence of HPV-related HNSCC, but it is not known if this escalation has had any impact on trends relating to brain involvement. Cases of metastatic squamous cell carcinoma (SCC) to the brain were identified from a computerized search of the surgical pathology files of The Johns Hopkins Hospital between 1985 and 2012. The medical records were reviewed to document primary site of tumor origin, treatment, and patient outcome. P16 immunohistochemistry and HPV in situ hybridization were performed on those metastases arising from the head and neck. Of the 38 metastatic SCCs, 7 (18 %) originated in the head and neck. HPV-16 was detected in 4 (57 %) of the metastatic HNSCCs. All 4 HPV-positive metastases were from oropharyngeal primaries. The time from treatment of the primary to development of the brain metastasis ranged from 19 to 57 months (mean, 45). Following aggressive treatment (surgery and radiation), two patients died of disease progression (7 and 34 months), and two are alive with recurrent brain metastases (4 and 10 months). Although HPV positivity is regarded as a favorable prognostic indicator, it does not safeguard from spread to the brain. In our experience, just over half of the HNSCCs that metastasized to the brain were HPV-related. The potential for developing a brain metastasis long after curative therapy argues for extended patient follow-up. The development of a brain metastasis is an ominous finding signaling rapid clinical deterioration.
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PMID:Metastatic squamous cell carcinoma to the brain: an unrecognized pattern of distant spread in patients with HPV-related head and neck cancer. 2340 86

The aim of this study was to determine the proportion of human papilloma virus (HPV)-positive cases in tonsillar carcinomas and investigate its development over the last decade. Further aim was to show the oncologic results in accord to HPV status and various treatment modalities. A retrospective study was conducted between 2000 and 2012 and included 275 patients treated for tonsillar carcinoma. P16 immunohistochemistry was used as a surrogate marker for HPV-associated carcinogenesis. A total of 101 (36.7%) patients proved to be p16 positive and 174 p16 negative. 80.2% of the p16-positive cases presented with T1-2 tumor. Of the early-stage patients, 79% of the p16-positive and 52.3% of the p16-negative presented with lymph node metastases. The percentage of p16-positive patients increased from 23.2% in the period 2005-2007 to 58.6% in the period 2010-2012 in the whole population and from 30.9% to 76.9% in T1-2 carcinomas. Early T-category p16-positive carcinomas had significantly better disease-specific survival (92.4% vs. 75.5%, P = 0.007) and overall survival (OS, 79.6% vs. 54.3%, P < 0.001) compared to p16-negative tumors. This study showed an increase in the percentage of p16-positive patients in tonsillar carcinoma from 23.2% in the years between 2005 and 2007 to 58.6% between 2010 and 2012. The majority (80.2%) of p16-positive patients presented with early T-category tumor but most of these (79.0%) had also lymph node metastases. Nevertheless, p16-positive patients had excellent oncologic results after surgery and adjuvant radiotherapy and could be considered for de-escalation of treatment.
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PMID:Epidemiology and survival of HPV-related tonsillar carcinoma. 2461 25


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