Invasion and metastasis markers in cancers

Over 90% of all adults human cancers are of epithelial origin comprising mainly of skin and aero-digestive tract cancers. A significant proportion of our discipline's workload consists of management of these cancers. This review article is to provide clinicians with a summary of the current research findings in invasion and metastasis of epithelial cancers and the translation of some of this information to clinical use particularly related to skin and head and neck cancers (HNSCC). Metastasis is the leading cause of death in cancer patients. Although surgical resection of isolated metastases is beneficial for some patients, the overall efficacy of surgery, chemotherapy or radiotherapy is limited. Clearly, with today's advances in surgery a majority of these primary cancers are resectable and a cure attainable if surgeons could control or inhibit metastasis.

Spontaneous and UV radiation-induced multiple metastatic melanomas in Cdk4(R24C/R24C)/TPras mice

Human melanoma susceptibility is often characterized by germ-line inactivating CDKN2A (INK4A/ARF) mutations, or mutations that activate CDK4 by preventing its binding to and inhibition by INK4A. We have previously shown that a single neonatal UV radiation (UVR) dose delivered to mice that carry melanocyte-specific activation of Hras (TPras) increases melanoma penetrance from 0% to 57%. Here, we report that activated Cdk4 cooperates with activated Hras to enhance susceptibility to melanoma in mice. Whereas UVR treatment failed to induce melanomas in Cdk4(R24C/R24C) mice, it greatly increased the penetrance and decreased the age of onset of melanoma development in Cdk4(R24C/R24C)/TPras animals compared with TPras alone. This increased penetrance was dependent on the threshold of Cdk4 activation as Cdk4(R24C/+)/TPras animals did not show an increase in UVR-induced melanoma penetrance compared with TPras alone. In addition, Cdk4(R24C/R24C)/TPras mice invariably developed multiple lesions, which occurred rarely in TPras mice. These results indicate that germ-line defects abrogating the pRb pathway may enhance UVR-induced melanoma. TPras and Cdk4(R24C/R24C)/TPras tumors were comparable histopathologically but the latter were larger and more aggressive and cultured cells derived from such melanomas were also larger and had higher levels of nuclear atypia. Moreover, the melanomas in Cdk4(R24C/R24C)/TPras mice, but not in TPras mice, readily metastasized to regional lymph nodes. Thus, it seems that in the mouse, Hras activation initiates UVR-induced melanoma development whereas the cell cycle defect introduced by mutant Cdk4 contributes to tumor progression, producing more aggressive, metastatic tumors.

Use of community genetic screening to prevent HFE-associated hereditary haemochromatosis

HFE-associated hereditary haemochromatosis is a recessive, iron-overload disorder that affects about one in 200 north Europeans and that can be easily prevented. However, genetic screening for this disease is controversial, and so we assessed whether such screening was suitable for communities. Cheek-brush screening for the Cys282Tyr HFE mutation was offered to individuals in the workplace. Outcomes were assessed by questionnaires before and after testing. 11307 individuals were screened. We recorded no increase in anxiety. in individuals who were homozygous for the Cys282Tyr mutation or non-homozygous. Self-reported tiredness before testing was significantly higher in homozygous participants than in non-homozygous participants (chi(2) test, p=0.029). Of the 47 homozygous individuals identified, 46 have taken steps to treat or prevent iron accumulation. Population genetic screening for HFE-associated hereditary haemochromatosis can be practicable and acceptable.

The molecular genetics of breast cancer: The contribution of comparative genomic hybridization

Comparative genomic hybridization (CGH) has been the technique of choice over the last 10 years for mapping DNA copy number changes in human tumors. Here we review the literature to demonstrate how CGH has contributed to the comprehension of molecular aspects of breast tumorigenesis. At least two distinct molecular pathways of breast cancer have been characterized that show a strong correlation with histological grade. It seems that grade I invasive ductal carcinomas (IDCs) arise from well-differentiated ductal carcinoma in situ (DCIS), whereas grade III IDCs come from poorly differentiated DCIS. In addition, dedifferentiation from a low- to a high-grade breast cancer has proven an unlikely phenomenon. CGH has been instrumental in dissecting distinct molecular pathways toward breast malignancy and in establishing a direct relationship between genotype and clinical pathological features. (C) 2005 Elsevier GrnbH. All rights reserved.

Sox genes and cancer

Sox genes encode transcription factors belonging to the HMG ( High Mobility Group) superfamily. They are conserved across species and involved in a number of developmental processes. In vitro studies have shown at least one Sox gene to be capable of inducing oncogenic transformation of fibroblast cells. In addition, overexpression and/or amplification of Sox genes are associated with a large number of tumour types in vivo. We review here the available evidence linking Sox gene expression and cancer, and show that this link is supported by extensive EST database analysis. This work provides a basis for further studies aimed at investigating the possible role of Sox genes in the oncogenic process. Copyright (C) 2004 S. Karger AG, Basel.

Will nicotine genetics and a nicotine vaccine prevent cigarette smoking and smoking-related diseases?

This paper briefly explains why it would be unwise to use genetic and neurobiological knowledge to prevent cigarette smoking and tobacco-related disease. However implausible these uses may seem to those who are well informed about the genetics of tobacco use or tobacco-control policy, it is the preventive uses of genetic information and nicotine vaccines that most excite the interest of the media and the public. The major challenges that these approaches face need to be widely understood if we are to prevent these superfi cially attractive but controversial uses from undermining effective control policies and the development of better methods of helping smokers to quit.

Altered cell surface expression of human MC1R variant receptor alleles associated with red hair and skin cancer risk

The human melanocortin-1 receptor gene (MC1R) encodes a G-protein coupled receptor that is primarily expressed on melanocytes, where it plays a key role in pigmentation regulation. Variant alleles are associated with red hair colour and fair skin, known as the RHC phenotype, as well as skin cancer risk. The R151C, R160W and D294H alleles, designated 'R', are strongly associated with the RHC phenotype and have been proposed to result in loss of function receptors due to impaired G-protein coupling. We recently provided evidence that the R151C and R160W variants can efficiently couple to G-proteins in response to alpha-melanocyte stimulating hormone. The possibility that altered cellular localization of the R151C and R160W variant receptors could underlie their association with RHC was therefore considered. Using immunofluorescence and ligand binding studies, we found that melanocytic cells exogenously or endogenously expressing MC1R show strong surface localization of the wild-type and D294H alleles but markedly reduced cell surface expression of the R151C and R160W receptors. In additional exogenous expression studies, the R variant D84E and the rare I155T variant, also demonstrated a significant reduction in plasma membrane receptor numbers. The V60L, V92M and R163Q weakly associated RHC alleles, designated 'r', were expressed with normal or intermediate cell surface receptor levels. These results indicate that reduced receptor coupling activity may not be the only contributing factor to the genetic association between the MC1R variants and the RHC phenotype, with MC1R polymorphisms now linked to a change in receptor localization.

Risk of non-small cell lung cancer and the cytochrome P4501A1 Ile462Val polymorphism

Objective: The Ile462Val substitution in the cytochrome P450 1A1 gene (CYP1A1) results in increased enzymatic activity. Preliminary data suggesting a link between this polymorphism and lung cancer risk in Caucasians are inconsistent, reflecting small sample sizes and the relatively low frequency of the variant. Methods: The data set consisted of 1050 primary non-small cell lung cancer cases and 581 controls, a large homogenous population designed specifically to address previous inconsistencies. Patients were genotyped using a PCR-RFLP technique. Results: Carriers of the valine allele, CYP1A1*2C, (Ile/Val or Val/Val genotypes) were significantly over-represented in non-small cell lung cancer compared to controls (OR=1.9; 95% CI=1.2-2.9; p=0.005) when adjusted for confounders, particularly in women (OR=4.6; 95% CI=1.7-12.4; p=0.003). The valine variant was statistically significantly over-represented in cases of lung cancer younger than the median age (64 years) (OR=2.5; 95% CI=1.3-4.8; p=0.005) and cases with less than the median cumulative tobacco-smoke exposure (46 pack-years) (OR=2.4; 95% CI=1.3-4.7; p=0.007). Conclusions: These new data establish an association between the CYP1A1 Ile462Val polymorphism and the risk of developing non-small cell lung cancer, especially among women.