Papers by Walter F Bodmer
Academia Oncology, Nov 28, 2024
It is now generally recognised that cancer is a somatic evolutionary process driven by stepwise s... more It is now generally recognised that cancer is a somatic evolutionary process driven by stepwise selection for single genetic mutations or stable epigenetic changes caused by specific DNA methylations. It is these changes that are potential druggable targets for cancer treatment. The extraordinary developments in DNA sequencing applied to very large numbers of different types of cancers have already revealed most of the mutations that drive any give type of cancer. The number of genes whose changes in levels of expression have been shown convincingly to be due to stable methylation rather than mutation is so far much less than the identified number of mutated genes. The poor prognosis of undifferentiated adenocarcinomas has long been recognised. This strongly suggests that selection against differentiation is one of the most powerful drivers of cancer progression. Changes in the expression levels of genes that control differentiation may often involve methylation changes or effects of DNA coded functional RNAs. This suggests that the future search for driver genetic changes should be based mainly on studying gene expression control by methylation and DNA coded functional RNAs, rather than just mutations in protein coding genes. This search needs to be extended beyond just searching for altered methylation of coding gene promoter regions. The ultimate challenge will be to develop general treatments that can reverse inhibition of expression by, for example, reversing methylation of a given DNA sequence or the use of small inhibitory RNAs.
BMJ, Jan 28, 1989
For letters on scientific subjects we normally reserve our correspondence columns for those relat... more For letters on scientific subjects we normally reserve our correspondence columns for those relating to issues discussed recently (within six weeks) in the BMJ. * We do not routinely acknowledge letters. Please send a stamped addressed envelope ifyou would like an acknowledgment. * Because we receive many more letters than we can publish we may shorten those we do print, particularly when we receive several on the same subject.
Heredity, May 1, 1959
IN a previous paper Bodmer and Parsons (1959) have outlined a comprehensive analysis of x2 for da... more IN a previous paper Bodmer and Parsons (1959) have outlined a comprehensive analysis of x2 for data from balanced multi-point linkage tests. By drawing an analogy with factorial experimentation, it was possible to obtain components measuring genic viability effects and interactions, recombination effects, parental heterozygote effects and possible interactions between these three sources of variation. These components were obtained from a corresponding analysis of variance on the assumption that, at least to a good approximation, the various effects were additive, whereas the usual treatment assumes a multiplicative set of effects (Fisher, xç; Parsons, If these are large, departure from additivity may be severe and should be detectable in a difference between the interactions as measured on an additive or a multiplicative scale. If we take logarithms, we can turn a multiplicative system into an
Research Square (Research Square), Apr 14, 2023
The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent 1 , provides a unique ... more The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent 1 , provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5 +) in NMRs over time in their native in vivo state, we show adaptations to living in near-anaerobic 2 , fooddeprived 3 subterranean environment, has necessitated an expanded pool of Lgr5 + cells, which exhibit slower division rates compared to short-lived mice, but have similar turnover as humans. Unlike human LGR5 + cells at the crypt base (LGR5 +CBC) that slow down their division rates by entering quiescence(G0) 4 , NMR Lgr5 +CBC cells in both the small intestine and the colon transit slowly through the active cell cycle (G1 to M) by prolonging arrest at G1 and/or G2. The inverse correlation between ASC division rates and lifespan appears to be speci c to Lgr5 +CBC /LGR5 +CBC cells as this relationship is not seen for cells outside the crypt base. Our data provide an explanation for the observed anticorrelation between somatic mutation rates and longevity in mammals 5 , with ASC lineages in longer-lived organisms turning over slowly to possibly mitigate ASC exhaustion and reduce mutation rates for long-term tissue maintenance. Finally, we also observe an expanded pool of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment e ciently, triggering a robust anti-proliferative, pro-apoptotic response within the stem cell zone.
Genetics, Aug 1, 1968
HE buffering effect of cross migration on random genetic drift in partially isolated populations ... more HE buffering effect of cross migration on random genetic drift in partially isolated populations was first studied in a very simple model which SEWALL
Proceedings of the National Academy of Sciences of the United States of America, Mar 16, 2015
American Journal of Pathology, Mar 1, 2002
Genetics, Oct 12, 1967
Introduction. 1. The general model. 2. The condition for the existence of a nontrivial equilibriu... more Introduction. 1. The general model. 2. The condition for the existence of a nontrivial equilibrium with D = 0. 3. The additive viability model. 4. The multiplicative viability model. 5. A general necessary condition for the stability of a nontrivial equilibrium with D = 0. 6. A general symmetric viability model. 6.1 Derivation of equilibrium solutions. 6.2 Conditions for stability of the equilibria. 7. Conditions for the increase of a new allele linked to a polymorphic locus. 8. Conditions for the simultaneous increase of new alleles at each of two linked loci. 9. A general condition for stable linkage disequilibrium when r is sufficiently small. IO. Sufficient conditions for the existence of a two-locus polymorphism. Discussion. Summary. Literature cited.
Frontiers in Immunology, Jun 5, 2019
Ruggero Ceppellini, who died at the age of 71 in 1988, was one of the most stimulating and origin... more Ruggero Ceppellini, who died at the age of 71 in 1988, was one of the most stimulating and original human geneticists of his generation (1). Ceppellini's outstanding contributions to the genetics of the human blood groups, immunoglobulin allotypes and the HLA system epitomize the study of immunogenetics. By using his considerable skills and insights to unravel the interpretation of the serological data, he made significant contributions to immunology. He is remembered especially for his incisive contributions to the development of the genetics of the HLA system and its nomenclature, including, in particular, his introduction of the term "haplotype," now widely used by geneticists throughout the world, most of whom are unlikely to be aware of its origins.
Journal of the Royal Society Interface, May 1, 2022
Epidermal growth factor (EGF) signalling regulates normal epithelial and other cell growth, with ... more Epidermal growth factor (EGF) signalling regulates normal epithelial and other cell growth, with EGF receptor (EGFR) overexpression reported in many cancers. However, the role of EGFR clusters in cancer and their dependence on EGF binding is unclear. We present novel single-molecule total internal reflection fluorescence microscopy of (i) EGF and EGFR in living cancer cells, (ii) the action of anti-cancer drugs that separately target EGFR and human EGFR2 (HER2) on these cells and (iii) EGFR-HER2 interactions. We selected human epithelial SW620 carcinoma cells for their low level of native EGFR expression, for stable transfection with fluorescent protein labelled EGFR, and imaged these using single-molecule localization microscopy to quantify receptor architectures and dynamics upon EGF binding. Prior to EGF binding, we observe pre-formed EGFR clusters. Unexpectedly, clusters likely contain both EGFR and HER2, consistent with co-diffusion of EGFR and HER2 observed in a different model CHO-K1 cell line, whose stoichiometry increases following EGF binding. We observe a mean EGFR : EGF stoichiometry of approximately 4 : 1 for plasma membrane-colocalized EGFR-EGF that we can explain using novel time-dependent kinetics modelling, indicating preferential ligand binding to monomers. Our results may inform future cancer drug developments.
Gut, Sep 1, 1998
Aims-To investigate the association between immunohistochemical expression of Bcl-2 and p53 in co... more Aims-To investigate the association between immunohistochemical expression of Bcl-2 and p53 in colorectal cancer and tumour recurrence following surgery. Methods-Sixty six cases of Dukes' B colorectal carcinoma were studied. All tumours were moderately diVerentiated and were shown to be histologically clear of the resection margins. Immunohistochemistry was performed on formalin fixed paraYn wax embedded tissue using monoclonal antibodies for p53 and Bcl-2. The Bcl-2 staining was assessed separately for relative intensity of staining and percentage of positive tumour cells and given a final score which combined the two factors. The p53 staining was assessed on number of positive tumour cells only. The patterns of immunostaining of those cases in which there had been tumour recurrence were compared with those cases in which there was no tumour recurrence (controls). Results-A statistically significant inverse association was found between Bcl-2 score and tumour recurrence (median Bcl-2 score of 6 (interquartile range (IQR) 2-9) in patients with recurrent disease; median Bcl-2 score of 8 (IQR 6-10) in those without recurrence; p=0.03). When examined separately, both the intensity of expression and percentage of positive tumour cells were significantly associated with tumour recurrence (p=0.04 in each case). There was no association between p53 staining and tumour recurrence. Conclusion-Results suggest that, when controlled for diVerentiation, Bcl-2 expression is a prognostic marker and may be useful as an adjunctive test in clinical decision making.
Proceedings of the National Academy of Sciences of the United States of America, Jul 1, 1989
The expression of HLA-A,B,C antigens and lymphocyte function-associated antigen 3 in human colore... more The expression of HLA-A,B,C antigens and lymphocyte function-associated antigen 3 in human colorectal adenomas and adenocarcinomas was studied by immunohistochemistry. None of 10 adenomas and only 1 of 30 carcinomas had lost expression of all HLA-A,B,C molecules. On the other hand, focal loss of an HLA-B product was seen in 2 of the adenomas, and complete losses of tumor cell HLA-A2 (in 7 of 13 cases), HLA-Bw4 (in 4 of 13 cases), and HLA-A3 (in 1 of 6 cases) were seen in the carcinomas. No complete losses of HLA-A1 (in 6 cases) or HLA-Bw6 (in 22 cases) occurred in the carcinomas. In addition, 1 of 20 adenocarcinomas totally lacked lymphocyte function-associated antigen 3. Because a loss of tumor cell HLA-A,B,C antigen or lymphocyte functionassociated antigen 3 could be selected for through an advantage in escape from cytotoxic T-lymphocyte attack, our results suggest that immunoselection may be a more important mechanism in tumor progression than has previously been assumed.
Anticancer Research, Oct 27, 2020
Background/Aim: Interactions between colorectal cancer (CRC) cells and myofibroblasts govern many... more Background/Aim: Interactions between colorectal cancer (CRC) cells and myofibroblasts govern many processes such as cell growth, migration, invasion and differentiation, and contribute to CRC progression. Robust experimental tests are needed to investigate the nature of these interactions for future anticancer studies. The purpose of the study was to design and validate in vitro assays for studying the communication between myofibroblasts and CRC epithelial cell lines. Materials and Methods: The influence of co-culture of myofibroblasts and CRC cell lines is discussed using various in vitro assays including direct co-culture, transwell assays, Matrigel-based differentiation and cell invasion experiments. Results: The results from these in vitro assays clearly demonstrated various aspects of the crosstalk between myofibroblasts and CRC cell lines, which include cell growth, differentiation, migration and invasion. Conclusion: The reported in vitro assays provide a basis for investigating the factors that control the myofibroblastepithelial cell interactions in CRC in vivo. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy globally (1). The approach to studying the treatment and related molecular basis of CRC has evolved over the years. Rather than focusing only on neoplastic cells, there has been more emphasis on studying the role of the tumour microenvironment in driving CRC progression (2-4). This stems from widely reported definition of tumour as a combination of heterogenous and interdependent populations of cancer cells and tumour microenvironment (known as stroma) (5). The tumour microenvironment drives the progression of most solid tumours, especially the epithelialbased carcinomas. Major cellular components of tumour microenvironment include myofibroblasts, cancer-associated fibroblasts (CAFs), macrophages and endothelial cells, that may interact with the extracellular matrix (ECM) (6, 7). Myofibroblasts have been described as a phenotypic variant of many mesenchymal, fibroblastic cell types (8). They can be characterized by specific markers, in particular amine oxidase, copper containing 3 (AOC3) and NK2 homeobox 3 (NKX2-3) (9). Accumulation of myofibroblasts around adenomatous colorectal polyps and primary CRC tumour sites have been associated with a higher rate of recurrence and advanced stage of cancer (10, 11). These activated myofibroblasts, characterized by positive expression of alpha smooth muscle actin (α-SMA) make up CAFs which are abundantly found in solid tumours (12). The prominent role of CAFs in carcinogenesis is evidently indicated by the up-regulated expression of genes associated with poor prognosis for CRC predominantly found within the CAF population, not in tumour cells (13). Myofibroblasts drive tumour progression through interplay with cancer cells, facilitated by various secretomes. Activated forms of myofibroblasts are reported to promote tumour invasion and migration, stimulate cancer cell proliferation, supress cancer killing function of T-cells and support the stemness of cancer stem cells (14-17). Despite many studies conducted on the bi-directional communication between myofibroblasts and CRC tumour cells, there is poor understanding on the nature and exact mechanisms involved in this myofibroblast-cancer cell interaction. This is significantly attributed to lack of robust in vitro experimental methods to recapitulate the biological processes that occur in cancer niche in vivo.
Proceedings of the National Academy of Sciences of the United States of America, Apr 1, 1983
Three sets of cosmid clones-containing the HLA-DRa chain gene and two additional related genes-we... more Three sets of cosmid clones-containing the HLA-DRa chain gene and two additional related genes-were isolated from human genomic DNA libraries by using a cDNA probe for the HLA-DRa chain. Southern blot analysis using DNA from somatic cell hybrids indicated that all of the clones mapped to chromosome 6. Partial sequence analysis showed that the two additional related genes were highly homologous to each other, and to the HLA-DRa chain, in parts of the exon that encoded the a2 domain but were more divergent in intron sequences. One of the genes corresponds to the HLA-DR-related DC series. DNA probes made from this gene revealed marked restriction enzyme polymorphism when hybridized to genomic DNA from HLA-DR typed homozygous cell lines. The patterns obtained from a number of homozygous and heterozygous cell lines correlated with the HLA-DR crossreactive serotypes and also indicated that there is a further sequence in the haploid human genome that is closely homologous with the DCa chain sequence. One family was studied and showed the expected HLA-DR-associated inheritance of restriction enzyme patterns. No polymorphism has yet been demonstrated in restriction enzyme fragments that include the other cloned sequence, which may correspond to the SBa chain gene or to a novel HLA-DR-related gene. These experiments indicate that there are at least three sequences in the human genome related, but not identical, to the HLA-DRa chain gene.
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Papers by Walter F Bodmer