Prevalence Of RAS Mutations Research Articles

Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations.

The follicular variant (FV) of papillary thyroid carcinoma is characterized by a follicular growth pattern and cytologic features of papillary carcinoma. ret/PTC rearrangements are common in classic papillary thyroid carcinoma (PTC) and PAX8-PPAR gamma and ras mutations in follicular thyroid carcinoma. Their prevalence in FV has not been established. We studied these genetic alterations and clinical-pathologic features in 30 FV cases and compared those with 46 non-FV papillary carcinomas. FV cases revealed 1 ret/PTC rearrangement (3%) and 13 ras mutations (43%). Non-FV cases harbored 13 ret/PTC (28%) (P = .006) and no ras mutations (P = .0002). No PAX8-PPAR gamma was found in either group. FV cases demonstrated a significantly higher prevalence of tumor encapsulation, angiovascular invasion, and poorly differentiated areas and a lower rate of lymph node metastases. These data indicate that the FV of papillary carcinoma has a distinct set of molecular alterations and is characterized by a high frequency of ras point mutations.

Ki-ras oncogene mutations in chronic pancreatitis: which discriminating ability for malignant potential?

Ki-ras mutations are found in the majority of pancreatic adenocarcinomas (85-100%). Ki-ras analysis was increasingly used in ERCP samples in order to differentiate between chronic pancreatitis and pancreatic cancer. However, its sensitivity was recently reported to be low due to a high prevalence of ras mutations in patients with chronic pancreatitis (25-37%). Detection of Ki-ras mutations in microdissected pancreata confirmed their high frequency (55-83%) in pancreatic intraductal lesions (PILs) observed in chronic pancreatitis specimens and in the vicinity of invasive pancreatic carcinoma. There is now molecular evidence that PILs can be precursors of invasive carcinoma, since they can harbor genetic alterations identical to those of the adjacent carcinoma. Similarly, we observed 2 patients with chronic pancreatitis who developed pancreatic cancer 18 and 24 months after the evidence of Ki-ras mutations in pancreatic brushings. However, besides these findings, ras mutations were also identified in nondiseased pancreata coming from autopsy series. The current data on ras analysis in pancreatic juice and brushings or in microdissected pancreata suggest that PILs with Ki-ras mutations do not inevitably lead toward invasive carcinoma. Ki-ras mutations probably have a low discriminating ability for malignant potential and their detection in pancreatic juice is not justified routinely for differentiating between benign and malignant pancreatic diseases. However, prospective follow-up of patients with chronic pancreatitis harboring a mutant ras is probably of major interest by combining the search for other genetic markers that have the ability to characterize patients with the greater risk of malignant transformation.

Prevalence of Ras mutations in thyroid neoplasia.

Mutations at codons 12, 13 or 61 of ras which result in constitutive activation occur frequently in human malignancies. There have been varied reports on their prevalence and hence their likely significance in the pathogenesis of primary thyroid neoplasia. To address this, we have examined a large series of benign and malignant thyroid tumours for ras mutations. Genomic DNA was analysed for the presence of mutations at codons 12, 13 and 61 of H-ras, K-ras and N-ras by allele-specific oligonucleotide hybridization. Direct DNA sequencing was used to confirm the mutations. A total of 90 samples with benign (66) and malignant (24) thyroid disease were investigated. A total of 14/90 (15.5%) samples had a ras mutation. All mutations were at codon 61 of either N-ras or K-ras. The positive cases were 1/25 (4%) nodular goitre, 7/38 (18%) follicular adenoma, 4/9 (44%) follicular carcinoma, 1/1 anaplastic carcinoma, 1/1 follicular variant of papillary carcinoma, and 1 metastatic follicular carcinoma in which the primary tumour had the same mutation. Our data demonstrate a relatively low overall prevalence of ras mutations in thyroid neoplasia, with a predominance in follicular neoplasms. Their presence in follicular adenomas suggests that they may have an early aetiological role in the development of thyroid neoplasia.

Farnesyltransferase inhibitors:a cell signalling approach to the design of efficacious anticancer agents

The emergence of farnesyltransferase (FTase) as an intensely investigated target for anticancer drug development was largely based on the potential of FTase inhibitors to effectively retard the growth of ras transformed tumours. Indeed, it has been well-established that Ras is readily prenylated by FTase and that inhibition of this reaction has functional consequences for the transformed phenotype of cells that express oncogenic Ras. Therefore, it has been envisioned that FTase inhibitors could potentially fulfil the huge therapeutic need existing for drugs that will effectively control the growth of colon and pancreatic tumours. While the prevalence of ras mutations is generally in the range of 30% across tumour types, colon and pancreatic cancers harbour ras mutations at a particularly high rate (50 and 90%, respectively). The medical need has not diminished since farnesyltransferase emerged onto the drug development scene. However, we now know that FTase inhibitors may well have significantly broader therapeutic activity than that first predicted. The ability of FTase inhibitors to effectively slow the growth of tumours that do not express oncogenic Ras has been an agreeable surprise. Indeed, the existence of multiple protein substrates for FTase should serve as a reminder that the true target under consideration is not Ras, but rather farnesyltransferase. Compounds from this therapeutic class are just beginning to enter the clinical arena. Thus, many years of preclinical investigation into the therapeutic potential of farnesyltransferase is now being put to the ultimate test. During the next two or three years, we are likely to get an answer to the question of whether this approach to signalling intervention will result in FTase inhibitors truly representing a new generation of anticancer drugs.

Prevalence of activating ras mutations in morphologically characterized thyroid nodules.

Ras proteins are signal-transducing proteins that share common properties with membrane-anchored G proteins. Mutations at codon 12/13 or codon 61 alter GTP-binding or GTPase activity, respectively. Such activating mutations are present in nearly 30-50% of various malignancies including colon, breast, and lung carcinomas. There are conflicting data regarding the prevalence of ras mutations in the thyroid and their possible pathogenetic role in the different tumor types. To address this question, we examined 45 morphologically characterized thyroid carcinomas, adenomas, and hyperplastic nodules using a highly sensitive single-stranded conformation polymorphism (SSCP) approach combined with DNA-sequencing. DNA from cell lines with known mutations served as controls. A G to A H13 codon substitution replacing an Asp for a Gly residue was detected in 1 papillary carcinoma. Although no H12 or H61 codon substitutions were identified, 2 discrete alterations were identified in codons H17 and 22. No N12/13 codon substitutions were identified. N61 codon substitutions of A to G resulting in a Gly to Arg substitution were detected in 2 papillary carcinomas; the same mutation was also found in one follicular adenoma. Interestingly, K12/13 and K61 ras mutations were not present in any of the tumors examined. These data establish a low prevalence of mutations in all ras gene family members in human thyroid neoplasms. This difference from neoplasms of other organs may explain the relatively indolent biologic behavior of many thyroid tumors and supports an alternate early genetic mutation that is more characteristic of these neoplasms.

Increased prevalence of K-ras oncogene mutations in lung adenocarcinoma: Mills NE, Fishman CL, Rom WN, Dubin N, Jacobson DR. Research Service 151, New York V.A. Hospital, 423 E. 23 St., New York, NY 10010. Cancer Res 1995;55:1444–1447

Reported estimates of ras mutation prevalence in lung adenocarcinoma of 15-24% may be underestimates because of the insensitivity of the assays used. We have devised a rapid, non-radioactive assay for ras mutations, which detects 1 mutant allele/10(3) normal alleles and have used it to study DNA isolated from 53 lung tumor samples (including 28 adenocarcinomas) previously analyzed by PCR/allele specific oligonucleotide hybridization, which is less sensitive. We detected mutations in 13 of 28 samples, including 7 not detected by PCR/allele specific oligonucleotide hybridization. We also found ras mutations in 14 of 25 previously unstudied samples (56%). Our results indicate that the prevalence of K-ras codon 12 mutations in lung adenocarcinoma is higher than previously reported; thus, ras mutations may be more clinically useful as molecular markers for lung cancer than has been appreciated.

G→A mutations in p53 and Ha‐ras genes in esophageal papillomas induced by N‐nitrosomethylbenzylamine in two strains of rats

In human esophageal cancers, no ras gene mutations but a relatively high prevalence of p53 gene mutations have been reported. We found a high prevalence of point mutations in Ha-ras and p53 genes in N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumors in two strains of rats (BD VI and F344). Our analysis showed the point mutation GGA-->GAA (expected from the known mechanisms of action of NMBA) at Ha-ras codon 12 in 22 of 46 (48%) and 22 of 38 (58%) papillomas from BD VI and F344 rats, respectively. There was no significant difference in the prevalence of ras mutations in tumors induced by high doses (5.0 mg/kg) and low doses (2.5 mg/kg) of NMBA. Eleven papillomas from each strain were analyzed for p53 mutations. The prevalent mutations found were G-->A and C-->T transitions. The frequency of p53 mutation was 36% (four of 11) for each strain. No apparent hot-spot codon or exon was found in the p53 gene, and two papillomas contained double mutations in this gene. The high prevalence of G-->A mutations in the rat Ha-ras gene contrasts with that in the human gene, in which no ras mutations have been found in primary tumors, and suggests either that the biology of esophageal carcinogenesis differs in humans and rats or that nitrosamines are not the major etiological risk factor for human esophageal cancers.