p16INK4 Gene Research Articles

Tumor p16INK4 gene expression and prognosis in colorectal cancer.

Hypermethylation of the tumor suppressor gene p16INK4 (p16) promoter is associated with worse prognosis in colorectal cancer (CRC). In the present study, it was investigated whether p16 mRNA expression correlates with the methylation of its promoter, and whether it influences prognosis in patients with CRC. DNA and RNA were extracted from 101 resected tumor specimens. A MethyLight assay was used to quantify p16 methylation in terms of percentage of methylated reference (PMR), and the expression of p16 mRNA was measured using reverse transcription‑polymerase chain reaction. Associations between p16 methylation or mRNA expression and patient survival were evaluated using Kaplan‑Meier analysis and Cox proportional hazards regression. p16 methylation was detected in 67 cases (66.3%) and the median PMR value was 0.344 (range, 0.00‑468.6). Using a cut‑off PMR value of 4, high p16 methylation was observed in 18 cases (17.8%). No significant association was observed between p16 methylation level and patient prognosis. As expected, a significant inverse association was observed between p16 methylation and mRNA expression (P=0.034). Amongst the 83 cases with low p16 methylation, a significantly worse outcome was identified in patients expressing high p16 mRNA expression levels (P=0.026). Multivariate analysis identified that p16 mRNA expression was an independent prognostic factor for worse survival (P=0.011). These results suggested a paradoxical association between high levels of p16 mRNA expression in the tumor and worse prognosis in patients with CRC.

Expression of p16 protein in acral lentiginous melanoma

Acral lentiginous melanoma (ALM) is a clinicopathologic subtype of cutaneous malignant melanoma. ALM is the most common type of melanoma amongst Asians, Africans, and patients with mixed ancestry. In Brazil, ALM comprises 10% of cutaneous melanoma. ALM develops on palmar, plantar, and subungual skin, and its biology is different from that of other cutaneous melanomas, where sunlight is the major known environmental determinant. Alterations and inactivation of the p16INK4 gene that encodes a specific inhibitor of cyclin-dependent kinase have been related to melanoma genesis and progression. Few studies, however, have addressed p16 expression in ALM. In order to verify and compare p16 protein expression, 32 paraffin-embedded ALM specimens were subjected to a immunohistochemical technique using a monoclonal anti-p16 antibody. The tumors were classified according to thickness (up to 1.0 mm and thicker than 1.0 mm) and the presence of ulceration. Twenty-five (78%) ALMs displayed positive p16 protein expression: 21 of the 25 (84%) with a thickness of more than 1.0 mm, and four of the seven (57%) with a thickness of 1.0 mm or less. Thirteen of the 17 (76%) nonulcerated lesions and 12 of the 15 (80%) ulcerated lesions displayed positive p16 protein expression. The data obtained suggest that p16 protein expression per se may not represent a marker of retinoblastoma protein (pRb) pathway disturbance in ALM tumorigenesis.

Analysis of the involvement of the tumour suppressor genes TP53, p16INK4, p21WAF1, RB1 and the drugs metabolizing enzymes in the development of bone tumours in children

Several tumor suppressor genes such as p16INK4, TP53, RB1 y p21WAF1 are involved in cell cycle regulation in response to DNA damage and belong to the complex pathway that regulates cell proliferation and/or differentiation. We have investigated the presence of mutations in those genes and polymorphisms of Drug Metabolizing Enzymes that could be involved in the development of pediatric bone tumors or in their outcome. By means of PCR-based techniques, we have analyzed the presence of variations in the coding sequence of p16INK4, TP53, RB1 y p21WAF1 and of the Drug Metabolizing Enzymes in a group of 82 osteosarcomas and 47 Ewing's sarcomas as well as in a control group of 115 healthy children. We detected mutations of the TP53 gene in about 25% of the samples analyzed, most frequently in association with tumors of poor prognosis or reduced survival. The p16INK4 gene was homozygously deleted in 18% of the osteosarcomas, also associated with poor prognosis and unfavourable histologic subtypes; RB1 was altered in 21% of the osteosarcomas. We did not detect relevant associations between polymorphisms of the Drug Metabolizing Enzymes or mutation of the p21WAF1 and development of pediatric bone tumors. Alteration of TP53, p16INK4 and p21WAF1 seems to be involved in the development of pediatric bone tumors and to be an unfavourable prognostic factor in this type of tumors.

MTP22-01: Neuroendocrine tumors

MTP22-01: Neuroendocrine tumors

Dysregulated Expression of Stem Cell Factor Bmi1 in Precancerous Lesions of the Gastrointestinal Tract

It is important to identify the definitive molecular switches involved in the malignant transformation of premalignant tissues. Cellular senescence is a specific characteristic of precancerous tissues, but not of cancers, which might reflect tumorigenesis-protecting mechanisms in premalignant lesions. Polycomb protein Bmi1, which is a potent negative regulator of the p16INK4 gene, suppresses senescence in primary cells and is overexpressed in various cancers. We hypothesized that Bmi1 expression would also be dysregulated in precancerous lesions in human digestive precancerous tissues. Bmi1 expression was investigated in cancerous and precancerous tissues of the digestive tract. The expression of p16, beta-catenin, and Gli1 and the in vivo methylation status of the p16 gene were also analyzed in serial sections of colonic precancerous lesions. Bmi1 was clearly overexpressed across a broad spectrum of gastrointestinal cancers, and the expression of Bmi1 increased in a manner that reflected the pathologic malignant features of precancerous colonic tissues (low-grade dysplasia, 12.9 +/- 2.0%; high-grade dysplasia, 82.9 +/- 1.6%; cancer, 87.5 +/- 2.4%). p16 was also strongly expressed in high-grade dysplasia, but not in cancers. p16 promoter methylation was detected only in some Bmi1-positive neoplastic cells. Bmi1 overexpression was correlated with the malignant grades of human digestive precancerous tissues, which suggests that advanced Bmi1 dysregulation might predict malignant progression. The abnormal Bmi1 expression might link to malignant transformation via the disturbance of orderly histone modification.

Effects of Exogenous Wild-Type P16 Gene Transfection on the Expression of Cell Cycle-Related Proteins in Bladder Cancer Cell Line

Cell cycle regulatory proteins are important indicators in determining progression through the cell cycle. Recent experimental evidence shows that active Cdk4-Cyclin D1 complexes help cells to pass through the R point, a point of no return, after which the cells become committed to a new round of replication. It is widely known that P16INK4a can arrest cells in the G1 phase, but how the expression of exogenous P16INK4 gene can affect the activity of Cdk4-Cyclin D1 remains unclear. In this study, using exogenous wild-type P16 gene, antibodies for P16, Cdk4, Cyclin D1 and Rb proteins, and primers for these genes, we examined the expression of exogenous wild-type P16 gene and the changes of cell cycle regulatory genes (Cdk4, Cyclin D1, and Rb) in human bladder cancer cells. The cell cycle analysis revealed that the proliferation of P16 gene-transfected cancer cells was inhibited after the transfection of exogenous wild P16 gene. The immunocytochemical results indicated that after the transfection of exogenous wild-type P16 gene, the expression of Cdk4, Cyclin D1, and Rb were negative in the nuclei, whereas the expression of P16 significantly increased in the nuclei and the cytoplasm. The RT-PCR results showed that the transcription of P16 gene increased significantly after the transfection, whereas the transcription of Cdk4, Cyclin D1, and Rb decreased. Our results suggest that the transfection of exogenous wild P16 gene induces the bladder cancer cells arrested in G0/G1 phase, and the increasing expression of P16 inhibits the expression of Cdk4, Cyclin D1, and Rb in nuclei. As a consequence, exogenous P16 has negative effects on the malignant proliferation of the bladder cancer cells, and it may be considered as target for potential anticancer drugs.

Effects of Exogenous Wild-Type P16 Gene Transfection on the Expression of Cell Cycle-Related Proteins in Bladder Cancer Cell Line

Cell cycle regulatory proteins are important indicators in determining progression through the cell cycle. Recent experimental evidence shows that active Cdk4-Cyclin D1 complexes help cells to pass through the R point, a point of no return, after which the cells become committed to a new round of replication. It is widely known that P16INK4a can arrest cells in the G1 phase, but how the expression of exogenous P16INK4 gene can affect the activity of Cdk4-Cyclin D1 remains unclear. In this study, using exogenous wild-type P16 gene, antibodies for P16, Cdk4, Cyclin D1 and Rb proteins, and primers for these genes, we examined the expression of exogenous wild-type P16 gene and the changes of cell cycle regulatory genes (Cdk4, Cyclin D1, and Rb) in human bladder cancer cells. The cell cycle analysis revealed that the proliferation of P16 gene-transfected cancer cells was inhibited after the transfection of exogenous wild P16 gene. The immunocytochemical results indicated that after the transfection of exogenous wild-type P16 gene, the expression of Cdk4, Cyclin D1, and Rb were negative in the nuclei, whereas the expression of P16 significantly increased in the nuclei and the cytoplasm. The RT-PCR results showed that the transcription of P16 gene increased significantly after the transfection, whereas the transcription of Cdk4, Cyclin D1, and Rb decreased. Our results suggest that the transfection of exogenous wild P16 gene induces the bladder cancer cells arrested in G0/G1 phase, and the increasing expression of P16 inhibits the expression of Cdk4, Cyclin D1, and Rb in nuclei. As a consequence, exogenous P16 has negative effects on the malignant proliferation of the bladder cancer cells, and it may be considered as target for potential anticancer drugs.

Differences in loss of p16INK4 protein expression by promoter methylation between left- and right-sided primary colorectal carcinomas

The p16INK4 gene, encoding a cyclin-dependent kinase inhibitor, is frequently methylated in colorectal cancer, and a side-specific methylation frequency was suggested. To clarify the frequency of real loss of tumor suppressor function dependent on anatomical localization, we investigated 43 primary colorectal carcinomas by determining aberrant promoter methylation using methylation-specific PCR. In addition, we evaluated the p16INK4 protein expression immunohistochemically. P16INK4 methylation was found in 18 of 43 (41.9%) cases. Fourteen of 43 cases (32.6%) were negative for p16INK4 protein, whereas 10 of these 14 cases showed methylation of the promoter region of the p16INK4 gene. Methylation of the promoter region was significantly correlated with loss of p16INK4 protein (p<0.01). P16INK4 tumor suppressor inactivation was significantly correlated with proximal location (p=0.031 for methylation and p=0.028 for immunostaining). The groups characterized by tumors with and without aberrant promoter methylation or loss of p16INK4 immunostaining showed no significant difference in either Dukes' stage and grade or age and gender. This is further evidence that p16INK4 methylation causes gene silencing. Loss of p16INK4 tumor suppressor function in colorectal tumors was associated with proximal location in the gut.

Expression of Cdk4, Cyclin D1 and Rb in exogenous wild type P16 gene transfected bladder cancer cell line

Cell cycle control plays a key role in the growth of normal mammalian cells. One of the fundamental abnormalities in human tumors is dysregulated cell cycle control. It is generally accepted that active Cdk4–Cyclin D1 complexes help cells to pass through the R point, a point of no return, after which cells become committed to a new round of replication. Accumulated evidences indicate that Cdk4 is the ‘primary sensor’ for driving cells through the R point and it is widely known that P16INK4a can arrest cells in G1.But how can the expression of exogenous P16INK4 gene affect the activity of Cdk4–Cyclin D1 remains unclear. In this study, using exogenous wild type P16 gene and antibodies for P16, Cdk4, Cyclin D1 and Rb proteins, we examined the expression of exogenous wild type P16 gene and the changes of cell cycle regulatory genes-Cdk4, Cyclin D1 and Rb in human bladder cancer cells. The cell growth analysis revealed that the proliferation of P16 gene transfected cancer cells was inhibited after the transfection of exogenous wild P16 gene. The immunocytochemical results indicated that after the transfection of exogenous wild type P16 gene, the expression of Cdk4, Cyclin D1 and Rb were negative in the nuclei while the expression of P16 significantly increased in the nuclei and the cytoplasm. Our results suggest that the transfection of exogenous wild P16 gene induces the inhibition of proliferation of the bladder cancer cells and the increasing expression P16 inhibits the expression of Cdk4, Cyclin D1 and Rb in nuclei, which results in the cell cycle being inhibited at G0/G1 phase. As a consequence, exogenous P16 has negative effects on the malignant proliferation of bladder cancer cells and it may be considered as target for potential anti-cancer drugs.

Adenovirus-mediated p16INK4 gene transfer significantly suppresses human breast cancer growth.

The p16INK4 tumor suppressor gene encodes a protein that inhibits cyclin-dependent kinase 4, and its homologous deletion is common in human breast cancer. p16INK4 gene transfer has been reported to be efficacious in inducing growth inhibition of various human tumors such as brain, lung, prostate, and esophageal cancers. However, the efficiency of the p16INK4 gene with regard to growth inhibition of human breast cancer has not been studied extensively. To examine its tumor-suppressive function and its potential in breast cancer gene therapy, the wild-type p16INK4 gene was expressed in an adenovirus-mediated gene delivery system and introduced into breast cancer cell lines that do not express p16INK4 protein. Expression of the introduced p16INK4 blocked tumor cell entry into the S phase of the cell cycle, induced tumor cell apoptosis, and inhibited tumor cell proliferation both in vitro and in vivo. These results strongly suggest that p16INK4 is a tumor suppressor gene and suggest that it has potential utility in breast cancer gene therapy.

The clinicopathologic significance of the p16 gene expression in primary lung cancer.

To explore the relationship between p16 gene expression and oncogenesis , and development of human lung cancer. Immunohistochemistry was employed to detect the expression of p16 protein in 114 paraffin-embedded primary lung cancer tissues. Loss of p16 INK4 gene exon 2 (E2) was analyzed using PCR technique in 62 cancer samples with p16 protein-negative stain and 14 paracancerous lung tissues. The positive rates of p16 protein expression in squamous cell carcinoma , adenocarcinoma and small cell lung cancer (SCLC) were 43. 3 % , 48. 2 % and 27. 0 % respectively , and no significant difference was found among them ( P > 0. 05) . The expression level of p16 protein was closely correlated with histological grade and lymph node metastasis of lung cancer. The deletion of p16 E2 was 45. 2 % in NSCLC and closely related to lymph node metastasis and histological grade ( P < 0. 05) . No deletion was observed in 37 cases of SCLC and 14 paracancerous lung tissues. Alteration of p16 gene and protein is closely related to the histological grade and lymph node metastasis of NSCLC. It may play an important role in the oncogenesis , development and lymph node metastasis of NSCLC.

Analysis of Tumor Cell Evolution in a Melanoma: Evidence of Mutational and Selective Pressure for Loss of p16ink4 and for Microsatellite Instability

Tumorigenesis and tumor progression can be considered an evolutionary process. In order to deduce information on the mutational and selective pressures during melanoma progression we performed microsatellite analysis at 42 autosomal and two X-linked loci in a microdissected primary melanoma and its nine metastases. Loss of heterozygosity at locus D9S259 was the only genetic change observed in all metastases. The pattern of loss of heterozygosity at loci D9S162 and D9S171 within the region of common loss on chromosome 9p21 which encompasses the tumor suppressor gene p16ink4 enabled the distinction of four genetically different tumor cell populations. Three cell lineages showed homozygous loss of the p16ink4 gene, which evolved independently in each tumor cell population within the primary tumor. Additional allele losses could be demonstrated at markers D14S53 and DXS998. The fourth lineage did not demonstrate loss of heterozygosity at loci D9S162 and D9S171 and contained the wild type p16ink4 gene but was characterized by abundant microsatellite instability. The evolutionary approach towards tumorigenesis and tumor progression used in this study thus confirms the role of p16ink4 inactivation for melanoma progression but not for melanoma initiation; it suggests the existence of additional putative tumor suppressor genes located on 9p as well as on the long arm of chromosome 14 and shows that microsatellite instability may represent an alternative pathway of tumor cell evolution in malignant melanoma.

Alteration of pRb/p16/cdk4 regulation in human osteosarcoma.

Cell-cycle regulation depends on a fine balance between cyclin-cyclin-dependent kinase complexes and a family of kinase inhibitors that bind cyclin-cdk complexes and block their activity. To investigate the role of mechanisms regulating cell-cycle progression in human osteosarcomas (OS), pRb/p16/cdk4 expression was analyzed in 39 high-grade OS; 19 of these developed metastasis during follow-up. Positive reaction for functional pRB was shown by 18/39 (46%) OS, while 21/39 (54%) were negative. A higher probability of metastasis was seen in patients with negative pRb expression (p < 0.05). Furthermore, while functional pRb and D1 expression are inversely associated to metastasis occurrence, the presence of D1/cdk4 complex in our study was related to poor prognosis. We found that 10/18 pRb-positive and 14/21 pRb-negative tumors were p16-positive. No significant correlation was found between pRb and p16 expression. On the other hand, high cdk4 levels in p16-positive tumors as compared with p16-negative tumors resulted in a positive association between p16 and cdk4 expression (Chi squared = 5.98; p = 0.01). No extensive p16INK4A genomic alterations were found in tumors lacking p16-protein expression. To determine which mechanisms are involved in the down-regulation of p16 protein, the methylation status of the p16INK4 gene was evaluated on the 15 p16-negative tumors: 8 samples showed 5' CpG-island methylation; 4/8 had a complete methylation status, while in the remaining 4 the gene was only partially methylated. These data confirm the role of the pRb/p16/cdk4 pathway in OS development.

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma

Carcinoma of the pancreas is the fifth leading cancer in the U.S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma-prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population-based cohort of patients with malignant melanoma. The malignant melanoma patients were identified from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The cohort was followed within the SEER system to ascertain the occurrence of subsequent microscopically confirmed primary carcinoma of the pancreas from January 1973 through December 1993. The time of follow-up was expressed as person-years of observation. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated. There were 43,781 malignant melanoma patients providing 263,528 person-years of follow-up. A nearly 2-fold increased risk of subsequent carcinoma of the pancreas in patients diagnosed with malignant melanoma before age 50 years was observed (SIR = 1.76; 95% CI = 0.80-3.34) and the greatest estimated risk occurred in young white females (SIR = 2.27; 95% CI = 0.73-5.30). These results provide some evidence in support of observations in recent studies that not only a family history of malignant melanoma but also malignant melanoma diagnosed at an early age may be associated with the subsequent development of carcinoma of the pancreas. Further research with larger numbers of melanoma patients is necessary to explore these potential associations.

The risk of subsequent primary carcinoma of the pancreas in patients with cutaneous malignant melanoma

BACKGROUND Carcinoma of the pancreas is the fifth leading cancer in the U. S. and has the poorest survival rate of the major malignancies. Recent studies have reported an increased risk of carcinoma of the pancreas in malignant melanoma-prone kindreds and have suggested a link between malignant melanoma and pancreas carcinoma and mutations in the p16INK4 gene. This study evaluates the risk of carcinoma of the pancreas in a population-based cohort of patients with malignant melanoma. METHODS The malignant melanoma patients were identified from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute. The cohort was followed within the SEER system to ascertain the occurrence of subsequent microscopically confirmed primary carcinoma of the pancreas from January 1973 through December 1993. The time of follow-up was expressed as person-years of observation. Standardized incidence ratios (SIR) and 95% confidence intervals (95% CI) were calculated. RESULTS There were 43,781 malignant melanoma patients providing 263,528 person-years of follow-up. A nearly 2-fold increased risk of subsequent carcinoma of the pancreas in patients diagnosed with malignant melanoma before age 50 years was observed (SIR = 1.76; 95% CI = 0.80-3.34) and the greatest estimated risk occurred in young white females (SIR = 2.27; 95% CI = 0.73-5.30). CONCLUSIONS These results provide some evidence in support of observations in recent studies that not only a family history of malignant melanoma but also malignant melanoma diagnosed at an early age may be associated with the subsequent development of carcinoma of the pancreas. Further research with larger numbers of melanoma patients is necessary to explore these potential associations. Cancer 1998;82:1672-6. © 1998 American Cancer Society.

P16INK4 gene mutations are relatively frequent in ampullary carcinomas.

A high incidence of gene mutations or deletions of P16INK4, a cell cycle regulator which inhibits the activity of cyclin‐dependent kinase 4/cyclin D complex and blocks the Gl‐to‐S transition, has been reported in pancreato‐biliary tract cancers. In order to investigateP16INK4 gene alterations in sporadic ampullary carcinomas, 17 sporadic ampullary carcinomas were examined. After histological diagnosis, DNA samples extracted separately from both cancerous and normal paraffin‐embedded tissues were investigated. Loss of heterozygosity (LOH) was investigated utilizing 3 microsatellite markers on 9p21‐22, and a mutationsl analysis was performed by cloning and sequencing. LOH was observed in 3 cases (17.6%) and somatic mutations with retention of heterozygosity were found in 7 cases (41.2%). Of note was that two mutations resulted in truncated incomplete proteins and one was a point mutation at the consensus site in the conserved ankyrin repeats, which would be crucial for function. Although two‐hit inactivation was not evident in any of the mutation cases and further investigation would be needed to elucidate the role of altered p16INK4, these results suggest that the pl6INK4 gene mutations are relatively frequent and its inactivation might be important in ampnllary carcinogenesis.

Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15ink4B/p16ink4 gene inactivation in childhood acute lymphoblastic leukaemia.

Seventy-four patients with acute lymphoblastic leukaemia (ALL) were analysed with limited allelotyping to detect loss of heterozygosity on chromosome segments 6q, 9p, 12p and 13q in order to detect patterns of genetic alteration. In the case of chromosome 9, analyses were also performed to detect inactivation of the p15ink4B and p16ink4 genes by Southern blot and sequencing techniques. The deletion data from these chromosomes were correlated to each other and to clinical features including prognosis. Allelic loss of these chromosomal regions could be detected in 24% (6q), 15% (12p) and 10% (13q) of the patients respectively, whereas aberrations involving 9p were detected in approximately 50% of the cases. There was an inverse correlation between loss of heterozygosity (LOH) for chromosome 12 and inactivation of the p16ink4 gene. This finding may suggest that a leukaemogenic event on chromosome 12p affects the same pathway of cell-cycle control as p16ink4 inactivation or, alternatively, reflects the fact that these mutations tend to occur in cells of different lineages.

Loss of expression of thep16INK4/CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage

The G1/S checkpoint of the cell cycle is regulated by p16, p53 and RB tumor suppressor genes. Loss of expression of the p16INK4 tumor suppressor protein, the product of the CDKN2 gene, has been associated with a wide variety of human malignancies. Mutations, loss of heterozygosity and deletions of the CDKN2 locus have been reported in sporadic and familial cutaneous malignant melanomas (CMM). To investigate the role of the alterations of p16 expression in melanoma, we evaluated by immunohistochemistry the p16 expression and cell proliferation in 79 primary CMM and 10 benign melanocytic nevi (BMN). Forty-six melanomas (58%) and all BMN were found to be p16 positive; 33 melanomas (42%) were considered p16 negative. The extent of invasion according to Clark was significantly higher in p16-negative tumors than in p16-positive tumors. Cell proliferation as expressed by the proportion of positive cells in Ki-67 immunostaining was found to be significantly higher in p16-negative tumors than in p16-positive tumors, although there was no significant difference in the mitotic index between p16-positive and p16-negative tumors. In p16-positive tumors, the number of Ki-67-positive cells correlated with the mitotic index; in p16-negative tumors, there was no correlation between these parameters. Our data suggest that loss of p16 expression is more common in advanced melanomas, and that G1/S checkpoint regulation is disrupted in p16-negative melanomas. Our results show that loss of p16 expression is a common event in primary melanomas, which further substantiates the role of p16 as a major tumor suppressor.

Germ-line mutations of the p16INK4(MTS1) gene occur in a subset of patients with hepatocellular carcinoma.

The molecular mechanisms of hepatocarcinogenesis are poorly understood. Only very recently has there been a suggestion of familial hepatocellular carcinoma (HCC). We have analyzed the status of the p16INK4(MTS1) gene, a cyclin-dependent kinase inhibitor, in 26 patients with HCC of different etiologies. Four patients carried hemizygous germ-line point mutations of the p16INK4(MTS1) gene, suggesting the existence of familial HCC involving this gene. The wild-type allele was lost in the tumor in 2 of these 4 patients. Three of the patients carrying a germ-line mutation had non-cirrhosis-associated HCC. No somatic mutations of p16INK4(MTS1) were observed in the 26 cases of HCC. The most common somatic alteration of the p16INK4(MTS1) gene in HCC was de novo methylation, which was detected in 48% of the cases. Low levels (21%) of p16INK4(MTS1) gene allele loss were observed. Altogether, these results indicate that alteration of the p16INK4(MTS1) gene plays an important role in the genesis of HCC.

Informative MspI polymorphism adjacent to exon 3 of the p16 INK4(MTS1) gene

No abstract