Jarle Breivik

Different genetic pathways to proximal and distal colorectal cancer influenced by sex-related factors

Mutations in the k‐ras and TP53 genes, as well as microsatellite instability (MIN), are frequent genetic alterations in colorectal carcinomas and represent 3 different mechanisms in the carcinogenic process. Both the incidence of colorectal cancer and the frequency of genetic alterations in such tumours have been related to different clinico‐pathological variables, including age and gender of the patient and location of the tumour. A number of studies have also reported associations between different types of genetic alterations. We therefore wanted to explore the relationship between these genetic and clinico‐pathological variables using multivariate analysis on material from 282 colorectal carcinomas. Three logistic regression models were constructed: 1) the presence of K‐ras mutations was dependent on MIN and age and gender of patient, with an especially low frequency among younger males and in tumours with MIN (overall p = 0.0003); 2) the presence of TP53 mutations was only dependent on tumour location, with a positive association to cancers occurring distally (p = 0.002); and 3) the presence of MIN was dependent on age, gender and K‐ras and TP53 mutations, as well as on tumour location. MIN was most frequent among younger male and older female patients, was rare in tumours with K‐ras or TP53 mutations and was found almost exclusively in the proximal colon (overall p < 0.0001). Our data confirm that different genetic pathways to colorectal cancer dominate in the proximal and distal segments of the bowel and suggest that the K‐ras‐ and MIN‐dependent pathways are influenced by different sex‐related factors. Int. J. Cancer 74:664–669, 1997.© 1997 Wiley‐Liss, Inc.

Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation

Mutations in codon 12 of K-RAS are frequently found in pancreatic adenocarcinomas. T-cell responses specific for individual RAS mutations can be elicited in vitro by stimulation of peripheral blood mononuclear cells with synthetic peptides. Mutant ras peptides are therefore a candidate vaccine for specific immunotherapy in pancreatic carcinoma patients. When vaccinated with a synthetic ras peptide representing the K-RAS mutation in their tumours, a transient ras-specific T-cell response was induced in two of five patients treated. The vaccination protocol involved multiple infusions of large amounts of peptide-pulsed antigen-presenting-cells obtained by leucapheresis. These results indicate that specific T-cell responses against mutations uniquely harboured in tumour cells can be induced in cancer patients by vaccination.

K-ras mutation in colorectal cancer: Relations to patient age, sex and tumour location

DNA from 251 primary tumours obtained from 123 male and 125 female Norwegian patients with colorectal carcinoma was analysed for the presence of K-ras point mutations at codons 12 and 13. Mutations were found in 99 (39%) of the samples. The frequency of K-ras mutations was significantly related to age and sex of the patients, and to the location of the tumours (overall: P = 0.008). K-ras mutations were much less frequent in colonic tumours from male than female patients at younger ages (< 40 years, odds ratio < 0.014). The low frequency might indicate that a different, ras-independent, pathway to neoplasia is dominating in the colon of younger males. In contrast, older men had more mutations than older women (e.g. 90 years, odds ratio = 5.8). An inverse but less pronounced relationship was seen for rectal tumours. The type of mutation was found to be associated to sex of patient and location of tumour. G-->C transversions accounted for 35% of the mutations in rectal tumours from females, in contrast to only 2.5% in the rest of the material (P = 0.0005). This may indicate that there are specific carcinogens acting in this location.

Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: Results of a phase I/II study

In a pilot phase I/II study we have tested synthetic ras peptides used as a cancer vaccine in 5 patients with advanced pancreatic carcinoma. The treatment principle used was based on loading professional antigen‐presenting cells (APCs) from peripheral blood with a synthetic ras peptide corresponding to the ras mutation found in tumour tissue from the patient. Peptide loading was performed ex vivo and the next day APCs were re‐injected into the patients after washing to remove unbound peptide. Patients were vaccinated in the first and second week and thereafter every 4–6 weeks. In 2 of the 5 patients treated, an immune response against the immunising ras peptide could be induced. None of the patients showed evidence of a T‐cell response against any of the ras peptides before vaccination. The treatment was well tolerated and could be repeated multiple times in the same patient. Side effects were not observed even if an immunological response against the ras peptide was evident. We conclude that ras peptide vaccination according to the present protocol is safe and may result in a potentially beneficial immune response even in patients with advanced malignant disease.

Don't stop for repairs in a war zone: Darwinian evolution unites genes and environment in cancer development

Cancer development is an evolutionary process involving replication, variation, and selection within the body of an organism (1). Therefore, just as species are shaped by the surrounding habitat, the properties of cancer cells should mirror their somatic environment. Based on this Darwinian perspective, and a large amount of circumstantial evidence, G. Gaudernack and I (2) recently proposed a general explanation for the elevated mutation rate that drives carcinogenesis. Bardelli et al. (3) have now tested this hypothesis in an elegant set of experiments, and in this issue of PNAS they present evidence for direct evolutionary relationships between carcinogenic environments and specific types of genetic instability.

Self-Organization of Template-Replicating Polymers and the Spontaneous Rise of Genetic Information

Living systems imply self-reproducing constructs capable of Darwinian evolution. How such dynamics can arise from undirected interactions between simple monomeric objects remains an open question. Here we circumvent difficulties related to the manipulation of chemical interactions, and present a system of ferromagnetic objects that self-organize into template-replicating polymers due to environmental fluctuations in temperature. Initially random sequences of monomers direct the formation of complementary sequences, and structural information is inherited from one structure to another. Selective replication of sequences occurs in dynamic interaction with the environment, and the system demonstrates the fundamental link between thermodynamics, information theory, and life science in an unprecedented manner.

K-ras mutations and HLA-DR expression in large bowel adenomas.

A total of 72 sporadic colorectal adenomas in 56 patients were studied for the presence of point mutations in codons 12 and 13 of the K-ras gene and for HLA-DR antigen expression related to clinicopathological variables. Forty K-ras mutations in 39 adenomas were found (54%): 31 (77%) in codon 12 and nine (23%) in codon 13. There was a strong relationship between the incidence of K-ras mutations and adenoma type, degree of dysplasia and sex. The highest frequency of K-ras mutations was seen in large adenomas of the villous type with high-grade dysplasia. Fourteen out of 15 adenomas obtained from 14 women above 65 years of age carried mutations. HLA-DR positivity was found in 38% of the adenomas, large tumours and those with high-grade dysplasia having the strongest staining. Coexpression of K-ras mutations and HLA-DR was found significantly more frequently in large and highly dysplastic adenomas, although two-way analysis of variance showing size and grade of dysplasia to be the most important variable. None of the adenomas with low-grade dysplasia showed both K-ras mutation and HLA-DR positivity (P = 0.004). K-ras mutation is recognised as an early event in colorectal carcinogenesis. The mutation might give rise to peptides that may be presented on the tumour cell surface by class II molecules, and thereby induce immune responses against neoplastic cells.

Resolving the evolutionary paradox of genetic instability: a cost-benefit analysis of DNA repair in changing environments.

Loss of genetic stability is a critical phenomenon in cancer and antibiotic resistance, and the prevailing dogma is that unstable cells survive because instability provides adaptive mutations. Challenging this view, we have argued that genetic instability arises because DNA repair may be a counterproductive strategy in mutagenic environments. This paradoxical relationship has also been confirmed by explicit experiments, but the underlying evolutionary principles remain controversial. This paper aims to clarify the issue, and presents a model that explains genetic instability from the basic perspective of molecular evolution and information processing.

Frame that gene. A tool for analysing and classifying the communication of genetics to the public.

Enabling the public to understand scientific concepts and advances, and the issues they raise, is an increasingly important challenge for scientists and politicians alike. Public opinion—received via polls and elections—can influence scientific policy‐making, and hence affect the funding and even the nature or focus of research itself. The fierce dispute over genetically modified crops in Europe, and the sometimes bitter debates about research using human embryonic stem cells in both Europe and the USA, highlight the enormous importance of public opinion on scientific issues. A greater awareness of the ethical, technical and philosophical issues surrounding research, as well as a better understanding of the science itself, could lead to more rational debates and outcomes—at least, that is what many scientists hope. The media therefore has a central role in furthering or modifying the public understanding of, and engagement with, scientific issues: it is the main source of information for many people, even more so than politicians, educators or scientists. > A greater awareness of the ethical, technical and philosophical issues surrounding research […] could lead to more rational debates and outcomes… No single scientific concept is more fundamental to the understanding of life science than ‘the gene’. The gene has also become a key term in public discourse, and hardly a day goes by without some mention of genes in the media (Petersen, 2002). So, what is a gene in the eyes of the public? Several studies have highlighted the tendency of the mass media to present genes as deterministic causes of human behaviour or disease, as exemplified by headlines such as ‘The infidelity gene’ or ‘Drunk? Its in your genes’ (Hubbard & Wald, 1993; Nelkin & Lindee, 1995; Condit et al , 1998; Conrad, 2001; Condit, 2007). On the basis of an analysis of popular discourse in …

Quantitative Frame Analysis of How the Gene Concept Is Presented in Tabloid and Elite Newspapers

Tabloid and elite newspapers differ in journalistic style and address different socioeconomic segments of society. Few studies have systematically investigated how these differences influence science communication, and the issue of genetics is particularly relevant. In this study, we performed a quantitative frame analysis of genetic discourse in 12 national newspapers that address different audiences. We found that tabloid and elite newspapers use different frames when communicating the gene concept. The differences were related to the use of expert writers and choice of topics, and we discuss how framing of the gene concept is related to the newspapers’ editorial profiles.