Molecular biology in colorectal cancer

Cancer is a genetic disease. Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis. However, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis. High-penetrance mutations confer predispoition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in theAPC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer. Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but mainly due to the implementation of association studies, are increasingly being detected and characterized. The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies. Supported by an unrestricted educational grant by Bristol-Myers Squibb.     

Molecular biology in the development of colorectal cancer

In 1988, Vogelstein and colleagues published a paper entitled "Genetic alterations during colorectal-tumor development." This marked the beginning of a series of advances in our understanding of how colorectal cancer develops. This paper also provided evidence for the adenoma-carcinoma sequence. Furthermore, the importance of DNA mismatch repair genes in hereditary nonpolyposis colorectal cancer has been recognized. We herein discuss the development of colorectal cancer on the basis of molecular biology, including specific abnormalities of related genes.     

Molecular biology of ovarian cancer

It has been suggested that the accumulation in multiple steps of gene abnormality is related to the malignant transformation of the normal cell. Understanding such abnormalities would be useful in the establishment of effective measures for the early detection and treatment of cancers with poor prognoses. In gynecological malignancies, the prognosis for epithelial ovarian cancer is poor even though great numbers of patients are treated with multimodal therapy. Uncovering the genes associated with the epithelial ovarian cancer crisis could lead to the identification of high risk cases, and accurate screening could open the way to early detection. Among the genes searched to date for abnormalities related to ovarian cancer, BRCA1 is thought to be the most likely candidate for having a causal relation with the familial ovarian cancer syndrome.     

Molecular biology of breast cancer

Although Breast Cancer (BC) has been considered for many years as a single entity with a common management and treatment, it is actually a extremely heterogeneous disease which includes at least 4 or 5 very different subtypes. The first step in the recognition of the heterogeneity of BC was the demonstration of the presence of functional hormonal receptors (HR) in nearly two thirds of breast cancer specimens. This finding, which established a first classification of BC in two clear subtypes (HR-positive and HR-negative) was followed by the demonstration of many other differential features. The her2/neu gene alteration, present in nearly 20% of BC tumors, is probably the most relevant of them, but certainly not the only one. The development of new technologies and, in particular, the use of complementary DNA (cDNA) microarrays will allow us now the simultaneous analysis of thousands of genes and the establishment of new, more refined BC subtypes based on gene expression profiles/genetic fingerprints. This review discusses the practical applications of molecular analysis of BC, which can be classified in four categories: 1. Establishment of a new molecular taxonomy of breast cancer. 2. Definition of prognostic factors/prognostic indexes based on molecular/genetic peculiarities. 3. Prediction of response to diverse antitumoral treatments. 4. Identification of molecular targets that allows the development of new tailored antitumor treatments.     

Molecular biology of gastric cancer

Abstract Despite its decreasing incidence overall, gastric cancer is still a challenging disease. Therapy is based mainly upon surgical resection when the tumour remains localised in the stomach. Conventional chemotherapy may play a role in treating micrometastatic disease and is effective as palliative therapy for recurrent or advanced disease. However, the knowledge of molecular pathways implicated in gastric cancer pathogenesis is still in its infancy and the contribution of molecular biology to the development of new targeted therapies in gastric cancer is far behind other more common cancers such as breast, colon or lung. This review will focus first on the difference of two well defined types of gastric cancer: intestinal and diffuse. A discussion of the cell of origin of gastric cancer with some intriguing data implicating bone marrow derived cells will follow, and a comprehensive review of different genetic alterations detected in gastric cancer, underlining those that may have clinical, therapeutic or prognostic implications. *Supported by an unrestricted educational grant from Sanofi-Aventis.     

食管癌分子生物学研究进展

分子生物学研究显示食管癌的发生发展过程中有许多基因及蛋白发生改变.与食管癌癌前病变相关的分子事件主要有p53基因突变及蛋白的过表达、一些基因位点的杂合性丢失及DNA甲基化及一些染色体非整倍体的出现;与食管癌治疗及预后密切相关的生物标志物主要有P53蛋白、表皮生长因子受体(EGFR)、趋化因子受体-4(CXCR-4)等.     

Molecular biology of bladder cancer

Bladder cancer is a major cause of health expenses and it presents formidable clinical challenges. Two types of tumors have been identified, papillary and non-papillary. The former are mainly characterized by FGFR3 and chromosome 9 alterations and a low frequency of Tp53 alterations. The latter are characterized by a high frequency of alterations in genes in the p53 and Rb pathways. Chromosome 9 alterations, specially in 9q, are crucial to bladder cancer development and occur in both types of tumors. Progression of some superficial tumors (mainly TaG3 and T1G3) to high-grade, invasive, carcinomas provides evidence of some overlap between the two pathways. Distinct gene expression profiles have been identified in superficial and invasive tumors. The stage is now ready for the clinical application of this knowledge. *Supported by an unrestricted educational grant from Sanofi-Aventis.     

Molecular biology of esophageal cancer

Squamous cell carcinoma (ESCC) is the most frequent histological subtype in esophageal cancer, although the incidence of esophageal adenocarcinoma (EAC) is increasing faster than any other malignancy in the western world. New developments in the understanding of molecular mechanisms in esophageal cancer comprise analysis of the genetic tumor profiles by CGH (comparative genomic hybridization), the detection of tumor suppressor gene inactivation, and the analysis of proto-oncogenes. Especially the inactivation of the p53 gene proved to be of particular importance for the development of esophageal cancer. Also p15 and p16 have been identified to be involved in the pathogenesis of esophageal cancer by influencing the cyclin kinase inhibitor cascade and DNA mismatch repair processes. Amplification of cyclin D1 results in growth advantage for tumor cells and enhances tumorigenesis; gene amplification and overexpression of cyclin D1 were frequently demonstrated especially in ESCC. Regarding the dysplasia-metaplasia-carcinoma sequence of Barrett's esophagus, inhibition of apoptosis by overexpression of bcl-2 proteins occurs as an early event.     

Molecular biology of gastric cancer

Gastric cancer is one of the leading causes of cancer mortality in the world. Gastric adenocarcinomas account for more than 95% of gastric tumors, whereas gastrointestinal stromal tumors (GISTs) are the most common neoplasms of the rare gastric mesenchymal tumors. Although the incidence of mid-distal gastric adenocarcinomas is decreasing, the incidence of gastroesophageal junctional tumors and Barrett's adenocarcinomas is increasing for unknown reasons. The majority of gastric tumors are sporadic in nature. However, there are rare, inherited gastric cancer predisposition traits, such as germline p53 (Li-Fraumeni syndrome) as well as E-cadherin (CDH1) alterations in familial diffuse gastric cancers. Gastric cancer has been observed to be part of the spectrum of neoplasms associated with germline mismatch repair gene (MMR) alterations that give rise to the hereditary nonpolyposis colorectal cancer (HNPCC) entity. Comparative genomic hybridization analyses have identified several amplifications and losses of DNA copy numbers in gastric cancers. Loss of heterozygosity (LOH) studies have shown several chromosomal loci with significant allelic loss, thus indicating the possibility of harboring a tumor suppressor gene important in gastric tumorigenesis. Microsatellite instability (MIS) and associated alteration of the TGF-bIIR, IGFRII, BAX, E2F-4, hMSH3, and hMSH6 genes are found in a subset of gastric carcinomas. Cell adhesion molecule abnormalities such as those involving CDH1 may play an important role in diffuse-type gastric cancer development. Although, multiple somatic alterations have been described in gastric carcinomas at the molecular level, the significance of these changes in gastric tumorigenesis remains to be established in most instances. The critical molecular alterations in gastric cancers that may lead to advances in our armamentarium to combat this lethal disease remain to be fully characterized.     

Molecular biology of pancreatic cancer

Pancreatic cancer is a leading cause of cancer death. This devastating disease has the horrible honour of close to equal incidence and mortality rates. Late diagnosis and a constitutive resistance to every chemotherapy approach are responsible for this scenario. However, molecular biology tools in cooperation with translational efforts have dissected several secrets that underlie pancreatic cancer. Progressive acquisition of malignant, invasive phenotypes from pre-malignant lesions, recent revelations on core signalling pathways and new targeted designed trials offer a better future for pancreatic cancer patients. This review will summarise recent advances in the molecular biology of pancreatic cancer.     

Molecular biology of cervical cancer

Cervical cancer is a virus-induced disease that is caused by the integration of high-risk infecting human papillomaviruses (HPV) in the host genome. For this reason, the carcinogenesis process of cervical cancer is associated to the expression of the viral oncogenic proteins E6 and E7. These proteins are capable of inactivating p53 and pRb, which induces a continuous cell proliferation with the increasing risk of accumulation of DNA damage that eventually leads to cancer. Moreover, cervical cancer can be prevented by prophylactic HPV vaccines; their molecular characteristics and mechanism of action are reviewed. Ultimately, new molecular targets for cervical cancer like proteasome, the EGFR family and IGF family are exposed. Supported by an unrestricted educational grant from Sanofi-Aventis.     

Molecular biology in gastric cancer

In gastric cancer, the process of carcinogenesis is thought to occur as a stepwise accumulation of genetic abnormalities. However, the mechanisms of the process of multistage carcinogenesis is still unknown for gastric cancer. Gene abnormalities seen in gastric cancer, including ras, myc, c-erbB-2, met, K-sam and cript are summarized herein. Abnormalities of cancer suppressor genes, including p53, RB and APC are also described. In our studies, the biological malignancy of patients with c-erbB-2 amplification was higher than that of patients without amplification. Moreover, the cases with amplification of c-erbB-2 were found to be highly correlated with distant organ metastasis. However, very little is currently known of the molecular abnormalities leading to gastric cancer. In order to clarify the multiple gene abnormalities in gastric cancer, we used the method of restriction landmark genomic scanning (RLGS). RLGS provides a useful method for genomic analysis of gastric cancer. In the future, new analytical methods that will permit screening of all gene abnormalities at once promise to improve our understanding of the mechanisms of gastric cancer.     

Molecular biology in prostate cancer

Summary Genes involved in cancer generation are usually tumor suppressors and oncogenes. Progressive genetic alterations in these genes are involved in the mechanisms of tumorigenesis. In prostate cancer, additionally several chromosomal loci that should harbor mutated genes have been proposed. Some genes have been found altered in prostate cancer, such as PTEN, TP53, AR, RNASEL (HPC1), ELAC2 (HPC2), CDKN2A and MSR1 and those can be natural targets for new strategies of treatment. Besides, gene therapy has been suggested to be suitable for prostate cancer treatment. This approach includesex vivo corrective therapy, suicide, and antisense therapy.     

Molecular biology of bladder cancer.

Recent studies have provided the first clues as to the molecular mechanisms responsible for bladder carcinogenesis. Cytogenetic and molecular studies have demonstrated nonrandom changes of chromosomes 1, 5, 7, 9, 11, and 17. The finding of monosomy of chromosome 9 in early noninvasive lesions has initiated a search for a bladder-specific gene responsible for bladder oncogenesis. Activation of ras and erbB oncogenes has been reported, although the role that these changes play in bladder cancer is not yet understood. Inactivation of two well-characterized tumor suppressor genes, p53 and Rb, also appears to be important in the pathogenesis of bladder cancer, and evidence suggests that inactivation of p53 correlates with the acquisition by bladder cancer cells of the invasive phenotype. Although the picture is far from complete, it is clear that for the first time an understanding of the molecular events responsible for bladder cancer is possible, and that this information will have clinical impact on patients in the near future.     

Molecular biology of ovarian cancer.

This minireview, which due to the limitations of space cannot claim to be exhaustive, summarizes major advances in molecular biologic research on ovarian surface epithelial (adeno)carcinomas communicated approximately between the beginning of April 1990 through the end of March 1991. We focus primarily on studies of oncogenes, peptide hormone growth factors and their receptors, steroid hormone receptors, cytogenetics and flow cytometry, and resistance to therapy with cytotoxic agents.     

Molecular biology of exocrine pancreatic cancer

Exocrine pancreatic cancer is one of the neoplasias with a worse prognosis, with conventional treatments having little impact on disease outcome. Research and genomic high-throughput technology is continuously expanding our knowledge of pancreas cancer biology. Characterization of genetic and epigenetic alterations in pancreatic tumors has allowed a better understanding of the progression model of the disease at the molecular level. The development of new therapeutic approaches with target-oriented agents is been tested in the preclinical and clinical settings. This review updates the current available data on pancreatic cancer molecular biology. Supported by an unrestricted educational grant by Bristol-Myers Squibb.     

Molecular biology of thyroid cancer initiation

Thyroid cancers stand out among solid tumours because many of the tumour-initiating genetic events have been identified. Mutations leading to constitutive activation of MAP kinase effectors -the tyrosine receptor kinase RET and the intracellular signalling effectors RAS and BRAF- are essential for the pathogenesis of papillary thyroid carcinoma (PTC). Similarly, there is increasing evidence demonstrating that mutations leading to activation of the phosphatidylinositol 3- kinase (PI3K)/AKT effectors -PTEN and PI3KCa- are essential for the pathogenesis of follicular thyroid carcinoma (FTC). Besides this strong relationship between the histological phenotype and the pathway predominantly activated, the nature of the genetic event seems to determine the biological behaviour of the tumour and the ultimate clinical outcome of the patient. In this review we will summarise and discuss the main genetic events related to thyroid cancer initiation, the contribution of genomics and the convenience of using a new molecular classification of thyroid cancer, complementary to the clinicopathological classification. This may help us to predict more faithfully the clinical outcome of patients with thyroid cancer and to select more appropriately candidates for targeted therapies.     

Molecular prognostics in colorectal cancer

Conventional staging of colorectal cancer does not account for the marked variability in outcome that exists within each stage. Certain populations of patients with early recurrence, resistance to chemotherapy and decreased survival cannot be predicted utilizing common histopathologic criteria. As the molecular mechanisms underlying colorectal carcinogenesis are elucidated, putative molecular prognostic factors are identified. A comprehensive review of various molecular markers and their roles as prognostic factors in colorectal cancer is presented.