Molecular Genetics of Cancer 2nd edition

Several years ago, a cytogeneticist made the comment to me that nothing we had gleaned from molecular genetics had made a clinical or therapeutic contribution over and above simple cytogenetics. This is no longer the case. The rapid technological changes seen in this area have exponentially increased the rate at which predisposition and progression genes can be identified and a greater basic understanding of the mode of action of these genes is moving the field towards therapeutic application. The contribution made by the human genome has already been significant and will be overwhelming in the years to come. And so it is appropriate to review where we are with cancer genetics.

This contribution is a second edition released as part of the IOS/Academic Press Human Molecular Genetics series. As with the first edition, there is an introductory chapter dealing with the basic techniques of cancer genetics, including positional cloning, loss of heterozygosity and mutation detection. This is followed by chapters dealing with individual types of cancer (breast/ovarian, gastric, melanoma, colorectal, lung, prostatic, liver, brain, bladder) including some cancer syndromes such as MEN1 and 2, NF1 and 2, Tuberous Sclerosis and von Hippel Lindau. The only exceptions to this organ-based presentation are a chapter on TP53 (chapter 9) and one on telomeres and ageing (chapter 21), each with an emphasis on application of our understanding of these genes. Once again, each of the chapters has been written by an expert in that particular type of cancer and each chapter gives a basic but up-to-date overview of what is known about the genetics of that condition.

Considerably larger than the first edition (10 chapters, 245 pages in first edition; 21 chapters, 518 pages in second edition) due to the progress made in the area, this edition readdresses all the topics covered in the first edition and then adds on. The advantage of taking an organ-based approach and re-covering all previous ground is that it produces a very accessible reference manuscript for the clinician, clinical scientist or student. The disadvantage is that overarching concepts such as disruption to repair mechanisms (chapter 10, colorectal cancer, briefly addresses the mismatch repair genes), reiteration of developmental processes and the role of gatekeepers are somewhat lost, making this book less useful for the basic scientist.

This manuscript could well have been entitled the ‘Molecular Genetics of Solid Tumours’ as the book does not deal with any of the leukemias (nor the lymphomas). As explained in the introduction, this was because they alone would merit a separate tome. The introduction also justifies the omission of Blooms syndrome, Ataxia telangiectasia or Fanconi’s anemia due to their common mode of radiation induction and recent media interest generating other publications.

While no book can cover all that is now known about cancer genetics, there were a few marked omissions that were disappointing. The first of these was basal cell carcinoma, the most common tumour in the world. The patched (PTCH) gene was identified as the predisposition gene for the inherited basal cell carcinoma syndrome, Gorlin syndrome, in 19961 and in the same year it was demonstrated that this TSG is also lost/mutated in sporadic BCC2. PTCH has subsequently been shown to be mutated in 15% of medulloblastomas3, an observation that is briefly mentioned in this context in the chapter dealing with brain tumours (chapter 16). The omission of basal cell carcinoma was not only disappointing because of the prevalence of this form of cancer, but because of the classic example that PTCH and the hedgehog signalling pathway, for which PTCH is the receptor molecule, provide for the involvement of developmentally important genes in human cancer. There are very few organs and systems not affected by this signalling pathway in some way during vertebrate development and in addition to its role in tumorigenesis, dysregulation of hedgehog signalling results in an array of dysmorphologies.

The other disappointment was the lack of a chapter dealing directly with the impact expression profiling techniques are having on cancer genetics. Here, the timing may have been tight as this is clearly an area of rapid expansion. However, there have now been many seminal contributions to the global analysis of cancer genetics using EST and oligo microarrays both for identification/subcategorisation of tumour types4 and analysis of regions of gene loss5. The application of this technology to cancers is now reaching a fine art with the combination of RNA expression profiling to identify prognostic markers which are then be verified using tissue arrays6,7 to the analysis of DNA from biopsy specimens to replace CGH approaches5. These technological advances will be what brings cancer genetics out of the realm of the basic scientist and into the realm of the clinic faster than any other molecular advance to date. Roll on Edition Three and may it make the leap from what has been to what is about to unfold.

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