AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore

PL02-05 

All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

Patterns of Somatic Mutation in Human Cancer Genomes

Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Complex biological systems and cellular networks may underlie most genotype to phenotype relationships. Here, we review basic concepts in network biology, discussing different types of interactome networks and the insights that can come from analyzing them. We elaborate on why interactome networks are important to consider in biology, how they can be mapped and integrated with each other, what global properties are starting to emerge from interactome network models, and how these properties may relate to human disease.

Interactome networks and human disease

Currently microorganisms are best identified using 16S rRNA and 18S rRNA gene sequencing. However, in recent years matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has emerged as a potential tool for microbial identification and diagnosis. During the MALDI-TOF MS process, microbes are identified using either intact cells or cell extracts. The process is rapid, sensitive, and economical in terms of both labor and costs involved. The technology has been readily imbibed by microbiologists who have reported usage of MALDI-TOF MS for a number of purposes like, microbial identification and strain typing, epidemiological studies, detection of biological warfare agents, detection of water- and food-borne pathogens, detection of antibiotic resistance and detection of blood and urinary tract pathogens etc. The limitation of the technology is that identification of new isolates is possible only if the spectral database contains peptide mass fingerprints of the type strains of specific genera/species/subspecies/strains. This review provides an overview of the status and recent applications of mass spectrometry for microbial identification. It also explores the usefulness of this exciting new technology for diagnosis of diseases caused by bacteria, viruses, and fungi.

MALDI-TOF mass spectrometry: an emerging technology for microbial identification and diagnosis.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/wps.20204

Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome is a rare multisystem disorder. Overproduction of vascular endothelial growth factor (VEGF) by plasmocytoma could be responsible for the symptoms. The authors treated four patients with high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Within 6 months, symptoms associated with rapid normalization of serum VEGF levels improved.

Autologous peripheral blood stem cell transplantation for POEMS syndrome.

Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare multi-system disorder associated with plasma-cell dyscrasia. Several case series and reports have suggested that high-dose chemotherapy with autologous peripheral blood stem-cell transplantation is efficacious treatment, but this transplantation is not indicated for elderly patients and patients with renal failure. Objective: To investigate the effects of thalidomide treatment for POEMS syndrome. Methods: Nine patients, who were not indicated for high-dose chemotherapy, were treated with thalidomide. Neurological disability scores, nerve conduction studies and serum levels of vascular endothelial growth factor (VEGF) were prospectively examined. VEGF levels were measured by an enzyme-linked immunosorbent assay. Results: During follow-up periods of 8–23 months (mean, 15 months), all patients showed substantial clinical improvement (n = 6) or stabilisation of symptoms (n = 3). Serum VEGF levels decreased in all patients and were normalised in five patients. Nerve conduction velocities in the median nerve increased in seven patients. There were no serious adverse effects, including thalidomide neuropathy. Conclusion: Thalidomide treatment should be further studied as a treatment for POEMS syndrome, particularly for patients who are not indicated for transplantation therapy.

https://jnnp.bmj.com/content/jnnp/79/11/1255.full.pdf

Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome

Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia There is increasing evidence that high-dose chemotherapy with autologous peripheral blood stem cell transplantation (Auto-PBSCT) is an efficacious treatment Objective: To elucidate the extent and time course of neurologic improvement after Auto-PBSCT in patients with POEMS syndrome Methods: Clinical and electrophysiologic findings in nine patients were reviewed The median follow-up period was 20 months (range, 8 to 49 months) Serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA Results: Serum VEGF levels rapidly decreased a month after Auto-PBSCT Within 3 months, neurologic improvement began, and all the patients showed substantial neurologic recovery during the next 3 months Particularly, three initially chairbound patients regained ability to walk at 6 months Nerve conduction studies showed significant increases in conduction velocities and amplitudes within 6 months of treatment At the end of follow-up periods, neuropathy was still improving, and no patients had recurrence of symptoms Conclusion: Autologous peripheral blood stem cell transplantation results in obvious neurologic improvement within 6 months, presumably by extensive axonal regeneration and remyelination This therapy could be considered as a first line treatment for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome with younger onset even if they are tetraplegic

Motoi Nishimura

Papers

Autologous peripheral blood stem cell transplantation for POEMS syndrome.

Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome

Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome.

Highly sensitive detection of SARS-CoV-2 RNA by multiplex rRT-PCR for molecular diagnosis of COVID-19 by clinical laboratories.

Direct application of MALDI-TOF mass spectrometry to cerebrospinal fluid for rapid pathogen identification in a patient with bacterial meningitis.