Begell House Inc.
Critical Reviews™ in Oncogenesis
CRO
0893-9675
14
1
2008
Lynch Syndrome and Related Familial Colorectal Cancers
1-22
10.1615/CritRevOncog.v14.i1.10
Paivi
Peltomaki
Department of Medical Genetics, University of Helsinki, Helsinki, Finland
Wael M.
Abdel-Rahman
Department of Medical Laboratory Technology, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) refers to autosomal dominant predisposition to colorectal, endometrial, and a spectrum of other cancers. The syndrome is due to heterozygous germ line mutations in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Amsterdam I and II criteria for clinical diagnosis and Bethesda guidelines for molecular testing of suspected patients usually point out additional families in which there is no evidence of mismatch repair deficiency even after screening by microsatellite instability analysis and/or immunohistochemistry for mismatch repair proteins. Hence, the term "Lynch syndrome" should be restricted to those families with germ line mutations in one of the mismatch repair genes. Familial colorectal tumors with no evidence of mismatch repair deficiency were shown to be clinically and molecularly distinct from classical Lynch syndrome tumors and, therefore, were designated "familial colorectal cancer type X" (FCC-X). The predisposing gene(s) to FCC-X is as yet unknown, but extensive research is currently underway to delineate its etiology. Given the above distinctions, the term hereditary nonpolyposis colorectal cancer (HNPCC), which was formerly used to refer to clinically diagnosed colorectal cancer families that might or might not have mismatch repair deficiency, is being replaced by one of the more informative names: Lynch syndrome and FCC-X.
Commentary on Lynch Syndrome and Related Familial Colorectal Cancers
23-31
10.1615/CritRevOncog.v14.i1.20
Henry T.
Lynch
Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, NE, USA
Stephen J.
Lanspa
Internal Medicine: Gastroenterology, Creighton University School of Medicine, Omaha, NE, USA
Hereditary colorectal cancer-prone syndromes provide ideal models for cancer control. For success, the physician must obtain a comprehensive cancer family history, which includes all anatomic sites; know the syndrome's natural history; and whenever possible be aware of likely cancer-causing molecular genetic mutations. For examples, mutations in MMR genes, namely MLH1, MSH2, MSH6, or PMS2, are exceedingly important for diagnosing the Lynch syndrome (LS), the most common hereditary colorectal cancer syndrome since, with the exception of the Muir-Torre syndrome and its cutaneous findings, phenotypic features are not present. Familial adenomatous polyposis (FAP), on the other hand, harbor striking phenotypic features, particularly multiple colonic adenomas. It is perhaps better known than Lynch syndrome due to this phenotype. Knowledge of FAP's molecular genetics, namely the APC mutation, will help in its diagnosis, particularly when there is a paucity of colonic adenomas such as observed in FAP's attenuated FAP counterpart, which is also attributable to the APC germline mutation.
Tumor Protein D52 Overexpression and Gene Amplification in Cancers from a Mosaic of Microarrays
33-55
10.1615/CritRevOncog.v14.i1.30
Mona
Shehata
The University of Sydney Discipline of Paediatrics and Child Health, Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead,
Judith
Weidenhofer
Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia
Keerthi
Thamotharampillai
The University of Sydney Discipline of Paediatrics and Child Health, Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia
Jayne R.
Hardy
Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia
Jennifer A.
Byrne
The University of Sydney Discipline of Paediatrics and Child Health, Molecular Oncology Laboratory, Oncology Research Unit, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, NSW, Australia
The tumor protein D52 gene is increasingly recognized to be overexpressed in different cancer types, frequently through gain of the corresponding locus at chromosome 8q21.13. This review summarizes the literature identifying D52 overexpression and/or gene amplification in different cancers, as well as recent publications directly analyzing D52 functions. Since D52 overexpression is increasingly being identified in tumors of different cellular origins, this is likely to perturb fundamental cell properties common to different cell types. Furthermore,since increased D52 expression occurs at different stages of tumorigenesis and progression, this could contribute to these processes through multiple mechanisms. Although functions are beginning to emerge from targeted studies, the pathways through which D52 overexpression contributes to cell transformation and the molecular interactions required remain undefined. In summary, while targeting D52 overexpression could provide therapeutic benefits in many cancer types, this will require an improved understanding of D52's cellular and molecular functions.
Role for the cAMP-Protein Kinase A Signaling Pathway in Suppression of Antitumor Immune Responses by Regulatory T Cells
57-77
10.1615/CritRevOncog.v14.i1.40
Sheraz
Yaqub
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo; and Department of Gastroenterological Surgery, Akershus University Hospital, N-1478 Lørenskog, Norway
Kjetil
Tasken
The Biotechnology Centre of Oslo and Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo, Norway
CD4+CD25+ regulatory T (Treg) cells are engaged in the maintenance of immunological self-tolerance and suppressive control of excessive immune responses to foreign antigens. Furthermore, Treg cells infiltrate tumor tissues and may impede immune surveillance against cancer and hamper the development of an effective antitumor immunity. Depletion of Treg cells in animal models has been demonstrated to provoke tumor immunity. Attenuation of Treg-mediated suppression is therefore an interesting strategy to enhance antitumor responses. We recently found that adaptive Treg cells express COX-2 and suppress responder T cells in a PGE2-cAMP-dependent manner, which can be reversed by COX-2 inhibitors or EP-receptor antagonists. The same mechanism also appeared to be operative in patients with colorectal cancer where treatment with COX-inhibitor or cAMP-antagonist enhanced antitumor immune responses to the same extent as depletion of Treg cells. This provides mechanism-based opportunities for pharmacological intervention to interfere with Treg immunosuppression. In this review we will discuss key mechanisms used by Treg cells to suppress antitumor immunity, with emphasis on the cAMP-PKA pathway. We will also highlight some of the roles of Treg cells in cancer.
NEW DOCTORIAL CANCER RESEARCH:Proteomic Studies of Hepatocytic Autophagosomes
81-83
10.1615/CritRevOncog.v14.i1.50
Anders
Overbye
Department of Cell Biology, Institute of Cancer Research, Norwegian Radium Hospital, Rikshospitalet University Hospital, Montebello, 0310 Oslo, Norway
With the relaunch of Critical Reviews in Oncogenesis, a special section called "New Doctorial Cancer Research" was introduced. Here, we provide new Ph.Ds. with the opportunity to present themselves and their work, preferentially followed by a commentary of a senior scientist with knowledge of the study, and as such, attention is also drawn to the work of the research group. In the current issue of CRO, we present two new Ph.Ds. Keep this opportunity in mind when new Ph.Ds. have fulfilled their dissertations. Instructions for submission to the "New Doctorial Cancer Research" section can be found in the general Instructions to Authors of CRO (www.begellhouse.com).
Metachronous and Recurrent Cancer Development in Colorectal Neoplasia: Clinical Aspects, Molecular Biomarkers, and Proteomic Patterns in Surveillance and Risk Evaluation
85-88
10.1615/CritRevOncog.v14.i1.60
Kjetil
Soreide
Stavanger University Hospital and University of Bergen, Norway