The transcription of the mts1 gene putatively involved in the control of tumor metastasis was studied in three human lymphoma cell lines: MOLT-4, CEM and Jurkat.
The identical nature of mutations observed in primary tumours and metastases derived from the same patient provides strong evidence that inactivation of p16 function was an in vivo event.
The mts1 (S100A4) gene, encoding a Ca(2+)-binding protein of the S-100 subfamily, is involved in the control of tumor metastasis in some murine tumor cell lines.
To shed light on the role of these alterations in the development and progression of sporadic melanoma, 12 primary melanomas and 9 corresponding metastases were analyzed for CDKN2 and CDK4 gene mutations.
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.
This paper reviews the current literature on p16 expression in melanoma and pancreatic cancer, explores factors that place patients with these cancers in categories of high risk for metastases or recurrence, and addresses whether aberrant gene expressions should influence awareness of and current recommendations for the management of these aggressive cancers.
Tumor suppressor gene MTS1/p16 (cyclin-dependent kinase-4 inhibitor) and a putative tumor metastasis suppressor gene nm23 (nucleoside diphosphate A kinase) have been identified in a variety of human tumors but have not been well studied in mesenchymal neoplasms.
P14ARF expression was investigated by immunohistochemical staining of 32 tissue samples of benign melanocytic nevi (n=14), melanomas (n=12) and melanoma metastases (n=6).
Furthermore, enhancement of c-MYC:CDKN2A was associated with a shorter disease-free interval as marked by the development of recurrences or metastases (P = 0.014; Log-rank test).
The results revealed that nuclear expression of beta-catenin, p16 and c-myc was quantitatively increased from normal mucosa to premalignant adenoma, primary carcinoma and lymph node metastatic carcinoma; the frequency of nuclear overexpression of beta-catenin and p16 in lymph node metastases was significantly higher than that in distant metastases (p < 0.05).
To investigate whether alterations in Cyclin D1, p14, CDK4 and Rb are associated with tumour cell proliferation, tumour progression and patient survival in malignant melanoma, we examined 202 vertical growth phase tumours and 68 corresponding metastases for expression of Cyclin D1, p14, CDK4 and Rb, and compared the results with Ki-67 expression, p16 and p53 expression, clinico-pathological variables, and survival data.
In conclusion, molecular analysis using a combination of p53 and INK4a-ARF mutation analysis can identify the corresponding primary skin tumor in case of CSCC metastases in the majority of cases.
Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases.
A much higher proportion of methylated p16 was detected in GCs with metastases (local or distant) than without metastases (14.76 vs 2.61%; t-test P=0.014).
P16 expression also correlated with site of tumor origin: 13 of 19 oropharyngeal metastases were p16 positive, whereas only 1 of 46 non-oropharyngeal metastases was p16 positive (68% versus 2%; P < 0.0001).
Diffuse (>75% positive tumor cells) moderate to strong p16 expression is a sensitive (100%) and specific (97%) marker for identifying HPV-related endocervical adenocarcinomas metastatic to the ovary among the primary ovarian tumors and metastatic adenocarcinomas from other sites that are in the differential diagnosis of ovarian tumors having mucinous and/or endometrioid/endometrioidlike differentiation. p16 is useful as part of a panel of immunohistochemical markers for distinguishing primary ovarian tumors from metastases and, when diffusely positive, can suggest the cervix as a potential primary site for metastatic adenocarcinomas of unknown origin.
Also, inactivation of the p16 gene (CDKN2A) was absent in naevi and present at steadily increasing rates moving from primary melanomas (7% early lesions to 17% advanced lesions) to melanoma metastases (62%) (P=0.004).
The genetic comparison of 15 primary ECs and their paired metastases revealed that in most of the cases the deleted region of p16 gene remains the same or becomes larger during the progression from primary tumor to its corresponding metastases.