Kirsten Ras* oncogene: Significance of its discovery in human cancer research

The KRAS/ K-RAS oncogene is crucially involved in human cancer. The term "oncogene" - i.e., a gene able to transform a normal cell into a tumor cell - was introduced in 1969, but the word was not used in the human carcinogenesis literature until much later. Transforming Kras and Hras oncogenes from the Kirsten and Harvey sarcoma viruses were not identified until the early 1980s due to the complicated structures of the viral genomes. Orthologs of these viral oncogenes were then found in transforming DNA fragments in human cancers in the form of mutated versions of the HRAS and KRAS proto-oncogenes. Thus, RAS genes were the first human oncogenes to be identified. Subsequent studies showed that mutated KRAS acted as an in vivo oncogenic driver, as indicated by studies of anti-EGFR therapy for metastatic colorectal cancers. This review addresses the historical background and experimental studies that led to the discovery of Kirsten Ras as an oncogene, the role of mutated KRAS in human carcinogenesis, and recent therapeutic studies of cancer cells with KRAS mutations

Gliomas: Genetic alterations, mechanisms of metastasis, recurrence, drug resistance, and recent trends in molecular therapeutic options

Glioma is the most common intracranial tumor with poor treatment outcomes and has high morbidity and mortality. Various studies on genomic analyses of glioma found a variety of deregulated genes with somatic mutations including TERT, TP53, IDH1, ATRX, TTN, etc. The genetic alterations in the key genes have been demonstrated to play a crucial role in gliomagenesis by modulating important signaling pathways that alter the fundamental intracellular functions such as DNA damage and repair, cell proliferation, metabolism, growth, wound healing, motility, etc. The SPRK1, MMP2, MMP9, AKT, mTOR, etc., genes, and noncoding RNAs (miRNAs, lncRNAs, circRNAs, etc.) were shown mostly to be implicated in the metastases of glioma. Despite advances in the current treatment strategies, a low-grade glioma is a uniformly fatal disease with overall median survival of ∼ 5-7 years while the patients bearing high-grade tumors display poorer median survival of ∼ 9-10 months mainly due to aggressive metastasis and therapeutic resistance. This review discusses the spectrum of deregulated genes, molecular and cellular mechanisms of metastasis, recurrence, and its management, the plausible causes for the development of therapy resistance, current treatment options, and the recent trends in malignant gliomas. Understanding the pathogenic mechanisms and advances in molecular genetics would aid in the novel diagnosis, prognosis, and translation of pathogenesis-based treatment opportunities which could pave the way for precision medicine in glioma

Single nucleotide polymorphism rs17849071 G/T in the PIK3CA gene is inversely associated with follicular thyroid cancer and PIK3CA amplification.

The proto-oncogene PIK3CA has been well studied for its activating mutations and genomic amplifications but not single nucleotide polymorphism (SNP) in thyroid cancer. We investigated SNP rs17849071 (minor allele G and major allele T) in PIK3CA in thyroid tumors in 503 subjects by PCR and sequencing of a region of intron 9 carrying this SNP. This SNP was found in both normal and thyroid tumor tissues as well as in different generations of a studied family, confirming it to be a germline genetic event in thyroid tumor patients. In comparison with normal subjects, a dramatically lower prevalence of the heterozygous genotype G/T at rs17849071 was found in patients with follicular thyroid cancer (FTC). Specifically, rs17849071G/T was found in 15% (18/117) normal subjects vs. 1.3% (1/77) FTC patients, with an odds ratio of 0.07 (95% CI 0.01-0.55; P = 0.001). This represents a 93% risk reduction for FTC with this SNP. In contrast, no difference was seen with benign thyroid neoplasms in which the prevalence of rs17849071G/T was 13.1% (17/130), with an odds ratio of 0.83 (95% CI 0.40-1.69; P = 0.72). There was a trend of lower prevalences of rs17849071G/T and odds ratio in other types of thyroid cancer without statistical significance. We also found an interesting inverse relationship of rs17849071G/T with PIK3CA amplification. With copy number ≥4 defined as copy gain, 2.9% (1/34) rs17849071G/T vs. 19.0% (67/352) rs17849071T/T cases displayed PIK3CA amplification (P = 0.01). Conversely, 1.5% (1/68) cases with PIK3CA amplification vs. 10.4% (33/318) cases without PIK3CA amplification harbored rs17849071G/T (P = 0.01). This provides an explanation for the reciprocal relationship of rs17849071G/T with FTC, since PIK3CA amplification is an important oncogenic mechanism in thyroid cancer, particularly FTC. Thus, the present study uncovers an interesting phenomenon that rs17849071G/T is protective against FTC possibly through preventing PIK3CA amplifications

Heterozygous rs17849071G/T of the <i>PIK3CA</i> Gene in Normal Subjects and Various Thyroid Tumors (Odd Ratio in comparison with normal population).

<p>Heterozygous rs17849071G/T of the <i>PIK3CA</i> Gene in Normal Subjects and Various Thyroid Tumors (Odd Ratio in comparison with normal population).</p

Inverse relationship of heterozygous genotype GT at rs17849071 with <i>PIK3CA</i> amplification in thyroid tumors.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049192#pone-0049192-g002" target="_blank">Figure 2A</a> shows that in the subjects with heterozygous genotype GT at rs17849071very few cases were positive for <i>PIK3CA</i> amplification and, correspondingly, a large number of cases were negative for <i>PIK3CA</i> amplification, whereas, in contrast, a large number of subjects with homozygous genotype TT harbored <i>PIK3CA</i> amplification. Comparison of the difference between <i>PIK3CA</i> amplification-positive and -negative subjects of the GT group with that of the TT group showed a high significance (P = 0.01). Conversely, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0049192#pone-0049192-g002" target="_blank">Figure 2B</a> shows that in the subjects with <i>PIK3CA</i> amplification very few cases harbored heterozygous genotype GT at rs17849071 and, correspondingly, a large number of cases harbored homozygous TT, whereas, in contrast, a large number of subjects without <i>PIK3CA</i> amplification harbored heterozygous GT. Comparison of the difference between GT and TT subjects of the <i>PIK3CA</i> amplification-positive group with that of the <i>PIK3CA</i> amplification-negative group showed a high significance (P = 0.01).</p