UV damage, DNA repair and skin carcinogenesis.

Skin cancer is unique among human cancers in its etiology, accessibility and the volume of detailed knowledge now assembled concerning its molecular mechanisms of origin. The major carcinogenic agent for most skin cancers is well established as solar ultraviolet light. This is absorbed in DNA with the formation of UV-specific dipyrimidine photoproducts.

Richard B. Setlow, a commentary on seminal contributions and scientific controversies.

Richard B. Setlow inspired the field of DNA repair. His demonstration that photoproducts could be quantified within cells and their excision examined experimentally pioneered the identification of nucleotide excision repair.

Genome scanning with array CGH delineates regional alterations in mouse islet carcinomas.

Carcinomas that develop in the pancreatic islets of transgenic mice expressing the SV40 T-antigens (Tag) under transcriptional control of the rat insulin II promoter (RIP) progress through well-characterized stages that are similar to aspects of human tumor progression, including hyperplastic growth, increased angiogenesis and reduced apoptosis. The latter two stages have been associated with recurrent loss of heterozygosity (LOH) and reduced genome copy number on chromosomes 9 (LOH9) and 16 (LOH16), aberrations which we believe contribute to these phenotypes. Earlier analyses localized LOH9 to approximately 3 Mb and LOH16 to approximately 30 Mb (both syntenic with human 3q21-q25) but were limited by low throughput and a lack of informative polymorphic markers.

Genetic changes in paired atypical and usual ductal hyperplasia of the breast by comparative genomic hybridization.

Purpose: Breast cancer is thought to develop from noninvasive precursor lesions, although the earliest steps of neoplastic transformation are still undefined. Usual ductal hyperplasia (UDH) is considered to represent a benign proliferation of ductal epithelial cells, whereas atypical ductal hyperplasia (ADH) may represent the first clonal neoplastic expansion of these cells. The aim of this study was to examine genetic alterations in UDH and ADH and to determine the relationship between these lesions in the same breast biopsy.

Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival.

We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify a relationship between abnormalities at two loci and the mutational status of p53.

Proliferation, cell cycle and apoptosis in cancer.

Beneath the complexity and idiopathy of every cancer lies a limited number of 'mission critical' events that have propelled the tumour cell and its progeny into uncontrolled expansion and invasion. One of these is deregulated cell proliferation, which, together with the obligate compensatory suppression of apoptosis needed to support it, provides a minimal 'platform' necessary to support further neoplastic progression. Adroit targeting of these critical events should have potent and specific therapeutic consequences.

Nucleotide excision repair "a legacy of creativity".

The first half of the 20th century has seen an enormous growth in our knowledge of DNA repair, in no small part due to the work of Dirk Bootsma, Philip Hanawalt and Bryn Bridges; those honored by this issue. For the new millennium, we have asked three general questions: (A) Do we know all possible strategies of nucleotide excision repair (NER) in all organisms? (B) How is NER integrated and regulated in cells and tissues? (C) Does DNA replication represent a new frontier in the roles of DNA repair? We make some suggestions for the kinds of answers the next generation may provide. The kingdom of archea represents an untapped field for investigation of DNA repair in organisms with extreme lifestyles.

Caspase-8 in apoptosis: the beginning of "the end"?

Caspase-8 is a member of the cysteine proteases, which are implicated in apoptosis and cytokine processing. Like all caspases, caspase-8 is synthesized as an inactive single polypeptide chain zymogen procaspase and is activated by proteolytic cleavage, through either autoactivation after recruitment into a multimeric complex or trans-cleavage by other caspases. Thus, ligand binding-induced trimerization of death receptors results in recruitment of the receptor-specific adapter protein Fas-associated death domain (FADD), which then recruits caspase-8.

Comparison of genetic changes in schistosome-related transitional and squamous bladder cancers using comparative genomic hybridization.

The development of bladder tumors has been associated with a number of causative agents, including schistosomiasis. Schistosome-related cancers show different clinical and pathological features compared with non-schistosome-related bladder cancers, occurring in younger patients, and being predominantly of squamous cell type. This study addresses the difference between squamous and transitional tumor types in the presence of schistosome infection as a measure of the relationship between tumor genotype and phenotype.

Morphological similarity: a 3D molecular similarity method correlated with protein-ligand recognition.

Recognition of small molecules by proteins depends on three-dimensional molecular surface complementarity. However, the dominant techniques for analyzing the similarity of small molecules are based on two-dimensional chemical structure, with such techniques often outperforming three-dimensional techniques in side-by-side comparisons of correlation to biological activity. This paper introduces a new molecular similarity method, termed morphological similarity (MS), that addresses the apparent paradox.

Common pathways for ultraviolet skin carcinogenesis in the repair and replication defective groups of xeroderma pigmentosum.

The human disease xeroderma pigmentosum (XP) involves DNA repair and replication deficiencies that predispose homozygous individuals to a 1000-fold increase in nonmelanoma and melanoma skin cancers. Two major forms of XP are known with different biochemical defects: one form lacks nucleotide excision repair (NER); the other lacks the capacity to replicate damaged DNA. Since the clinical symptoms of both kinds of patients are almost the same, the different cellular defects must be reconciled with common clinical outcomes.

Genome changes and gene expression in human solid tumors.

Genome-wide analysis techniques such as chromosome painting, comparative genomic hybridization, representational difference analysis, restriction landmark genome scanning and high-throughput analysis of LOH are now accelerating high-resolution genome aberration localization in human tumors. These techniques are complemented by procedures for detection of differentially expressed genes such as differential display, nucleic acid subtraction, serial analysis of gene expression and expression microarray analysis. These efforts are enabled by work from the human genome program in physical map development, cDNA library production/sequencing and in genome sequencing.

Carcinogenesis in mouse and human cells: parallels and paradoxes.

It has been known since the last century that genetic changes are important in carcinogenesis [Boveri,T. (1914) Zur Frage der Erstehung Maligner Tumoren. Gustav Fischer, Jena].

Chromosomal alterations in ductal carcinomas in situ and their in situ recurrences.

Background: Ductal carcinoma in situ (DCIS) recurs in the same breast following breast-conserving surgery in 5%-25% of patients, with the rate influenced by the presence or absence of involved surgical margins, tumor size and nuclear grade, and whether or not radiation therapy was performed. A recurrent lesion arising soon after excision of an initial DCIS may reflect residual disease, whereas in situ tumors arising after longer periods are sometimes considered to be second independent events. The purpose of this study was to determine the clonal relationship between initial DCIS lesions and their recurrences.

Signalling networks that cause cancer.

Cancer is caused by the stepwise accumulation of mutations that affect growth control, differentiation and survival. The view that mutations affect discrete signalling pathways, each contributing to a specific aspect of the full malignant phenotype, has proved to be too simplistic. We now know that oncogenes and tumour suppressors depend on one another for their selective advantage, and that they affect multiple pathways that intersect and overlap.

Confluence-induced alterations in CpG island methylation in cultured normal human fibroblasts.

Growth constraint of bacterial and human cells has been shown to trigger genetic mutation. We questioned whether growth constraint might also trigger epigenetic mutation in the form of CpG island methylation. Logarithmically growing normal human fibro-blasts (NHF) displayed little (0-15%) CpG methylation in select regions of three CpG islands [estrogen receptor (ER), E-cadherin (ECAD) and O (6)-methylguanine-DNA methyltransferase (MGMT)] examined.

A summary of mutations in the UV-sensitive disorders: xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy.

The human diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy are caused by mutations in a set of interacting gene products, which carry out the process of nucleotide excision repair. The majority of the genes have now been cloned and many mutations in the genes identified. The relationships between the distribution of mutations in the genes and the clinical presentations can be used for diagnosis and for understanding the functions and the modes of interaction among the gene products.

Difluoromethylornithine chemoprevention of epidermal carcinogenesis in K14-HPV16 transgenic mice.

To be informative for chemoprevention, animal models must both closely emulate human disease and possess surrogate endpoint biomarkers that facilitate rapid drug screening. This study elucidated site-specific histopathological and biochemical surrogate endpoint biomarkers of spontaneous epidermal carcinogenesis in K14-HPV16 transgenic mice and demonstrated that the incidence and severity of these markers were decreased by the ornithine decarboxylase (ODC) inhibitor difluoromethylornithine (DFMO). The cumulative incidence of visible epidermal cancers in 127 untreated transgenic mice was 42% by 52 weeks of age, most frequently affecting the chest as flat lesions in association with chronic ulcers, or in the ear as protuberant masses.