Molecular Genetics Of Cancer Research Articles

Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling.

SummaryAnti-androgens are a common therapy in prostate cancer (PCa) targeting androgen receptor (AR) signaling. However, these therapies fail due to selection of highly aggressive AR-negative cancer cells that have no therapeutic options available. We demonstrate that elevating endogenous ceramide levels with administration of exogenous ceramide nanoliposomes (CNLs) was efficacious in AR-negative cell lines with limited efficacy in AR-positive cells. This effect is mediated through reduced de novo sphingolipid synthesis in AR-positive cells. We show that anti-androgens elevate de novo generation of sphingolipids via SPTSSB, a rate-limiting mediator of sphingolipid generation. Moreover, pharmacological inhibition of AR increases the efficacy of CNL in AR-positive cells through de novo synthesis, while SPTSSB knockdown limited CNL's efficacy in AR-negative cells. Alluding to clinical relevance, SPTSSB is upregulated in patients with advanced PCa after anti-androgens treatment. These findings emphasize the relevance of AR regulation upon sphingolipid metabolism and the potential of CNL as a PCa therapeutic.

Molecular Genetics of Cancer

Cancer is an unchecked cellular proliferation. It develops from a single cell with gene mutations, causing tumor growth and propagation. The genetic changes persist in the progeny of the initial cancer stem cell. Recent research has uncovered some of the mechanisms involved in the development and progression of cancer. Understanding the mechanisms of genetic mutations and their actions allows scientists to interrupt these aberrant genetic pathways and treat these diseases. This review briefly discusses evolution of knowledge in the field, technologies involved, molecular changes caused by the aberrant cancer genes, and pathways of therapeutic interventions.International Journal of Human and Health Sciences Vol. 02 No. 04 October’18. Page : 199-208

Building the Global Cancer Workforce: Assessing the Cancer Research and Control Progress of Low- and Middle-Income Country Participants in the National Cancer Institute Summer Curriculum in Cancer Prevention

Abstract 48 Background: The National Cancer Institute (NCI) Summer Curriculum in Cancer Prevention, hosted by NCI’s Cancer Prevention Fellowship Program, has provided interdisciplinary training to physicians, scientists, nurses, and other cancer health care professionals in the principles and practice of cancer prevention, control, and molecular biology and genetics. Since 1998, the summer curriculum has enrolled an increasing number of international participants, with many nominees from All-Ireland NCI Cancer Consortium and the International Atomic Energy Agency’s Programme of Action for Cancer Therapy. NCI’s Center for Global Health selects meritorious international participants, specifically from low- and middle-income countries (LMICs), and has offered limited travel and subsistence scholarships. In spring 2016, the Center for Global Health conducted an evaluation of LMIC participants from 1999 to 2015 to assess the impact of the summer curriculum on participants’ engagement and activities in cancer research and control, including peer-reviewed publications, grants received, scientific presentations, cancer control planning, and advocacy. Methods: We surveyed participants about these topics by using an electronic survey system (Questionnaire Design Studio, v3.0) and analyzed responses in SPSS (SPSS, Chicago, IL) and Excel (Microsoft, Redmond, WA). Results: Of 427 LMIC participants from 1999 to 2015, 357 were surveyed via e-mail invitations to an online survey link, of which 156 responded (44%) during a 4-week study period with follow-up. Overall, 97% report using the knowledge and skills acquired frequently or sometimes, and 80% reported training at least one other person in course content. Nearly 50% reported publishing and 27% reported receiving research funding, of which 84% had not received a grant before participation. Conclusion: Participation of international attendees at the NCI Summer Curriculum builds a global cancer community, utilizing the expertise of Cancer Prevention Fellowship Program in training the cancer health care workforce. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST No COIs from either author.

Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment.

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis.

Molecular Genetics of Cancer

Cancer involves an accumulation of genetic alterations that result in a stepwise progression toward unregulated growth and invasion. Understanding the evolution of a normal cell to its neoplastic state, including knowledge of the precipitating genetic defects, is vital to the development of potential treatments to combat unregulated growth. This review discusses the accession of specific critical properties underlying neoplastic transformation. Specifically, the cell cycle, the primary characteristics of cancer (continuous growth signaling, insensitivity to growth inhibition, evasion of apoptosis, angiogenic potential, immortalization, and invasion or metastasis), and cancer therapeutics are described. Figures show a simplified schematic of the cell cycle, cyclin-CdK complex function during the cell cycle, growth factor binding receptors, the mechanism of oncogene production, various transmembrane tyrosine kinases, the translocation of Ig heavy and light chains to the Myc locus on chromosome 8 in Burkitt lymphoma, a translocation observed in chronic myelogenous leukemia, the INK4A locus, and the apoptotic pathway. Tables include nonexhaustive lists of oncogenes in human malignancies and selected tumor suppressor genes associated with inherited susceptibility. This review contains 9 figures, 2 tables, and 186 references.

Clinically relevant genetic characterization of prostate tumors: how close are we to the goal?

Substantial efforts are being made in research on the molecular genetic characterization of prostate cancer. The number of fundamental research programs in prostate cancer molecular biology and genetics is overwhelming. However, a significant gap appears to exist between the huge number of studies on the genetic characterization of prostate cancer, which often have limited translation into clinical practice or simply were not conceived to be so translated, and clinical practice. From a clinical point of view, this balance should be urgently shifted towards rapid translation into urological practice. However, prostate cancer is characterized by prominent genetic heterogeneity, which could be a very difficult barrier to overcome. In this review, we discuss the possible clinical applications of scientific data from fundamental studies of prostate cancer genetics, the main problems with the translation of these data to clinics, and future perspectives.

Research progress on bladder cancer molecular genetics.

Bladder cancer is a common malignant urinary tumor with a high rate of recurrence and quick progression, which threats human health. With the research on bladder cancer molecular genetics, the knowledge of gene modification and the development of molecular detection methods, more tumor markers have been discovered, which may have potential for early diagnosis, clinical examination and prognosis. This article reviews the research progress on bladder cancer molecular genetics.

Plasmacytoid Urothelial Carcinoma, a Chemosensitive Cancer with Poor Prognosis, and Peritoneal Carcinomatosis

Plasmacytoid urothelial carcinoma is a rare variant histology with poorly defined clinical behavior. We report clinical outcome information on patients with predominant plasmacytoid urothelial carcinoma. We retrospectively analyzed treatments and outcomes in patients with predominant plasmacytoid urothelial carcinoma seen at our institution from 1990 through 2010. The Kaplan-Meier method was used to calculate overall and progression-free survival. We identified 31 patients with a median age of 63.5 years, of whom 83.3% were male. TNM stage was cT1N0 in 4 patients, cT2N0 in 7, cT3b-4aN0 in 5 and cT4b, N+ or M+ in 15. Median overall survival was 17.7 months (stage I-III vs IV 45.8 vs 13.3). Five of the 16 patients with potentially surgically resectable plasmacytoid urothelial carcinoma (pT4aN0M0 or less) received neoadjuvant chemotherapy, 10 underwent initial surgery and 1 was treated only with transurethral resection of bladder tumor. Despite pathological down staging in 80% of the patients who received neoadjuvant chemotherapy, relapses were common. There was no survival difference between patients treated with neoadjuvant chemotherapy or initial surgery, although 7 received adjuvant chemotherapy. Surgical up staging with positive margins was also common for surgery alone. The most common site of recurrence was in the peritoneum (19 of 23 patients) with relapses even in those with a pathological complete response at surgery. In patients who presented with metastatic disease and were treated with chemotherapy median survival was 12.6 months. Plasmacytoid urothelial carcinoma is an aggressive subset with overall poor outcomes. Although down staging is seen with neoadjuvant chemotherapy, there are few long-term survivors. There is a strong predilection for recurrence along the peritoneal lining.

Thyroid cancer genetics: how close are we to personalizing clinical management?

Author for correspondence: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Thyroid Cancer Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Genetics, & CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA Tel.: +1 216 444 3440 Fax: +1 216 636 0655 engc@ccf.org Thyroid cancer genetics: how close are we to personalizing clinical management?

Molecular Genetics of Cancer

The uncontrolled clonal expansion of a cell, which often leads to invasion of surrounding tissues and metastatic spread, produces cancer. A clear histologic and molecular genetic evolution from precancerous lesions to frankly malignant and invasive cancer has been defined for some tumors (e.g., colon and bladder cancers). In rare cases, mutations may occur and be passed on in the germline, resulting in genetic predisposition to cancer (i.e., familial cancer syndromes). Environmental factors are also thought to contribute to the development of cancer. Interactions between environmental factors and subtle germline genetic variations that distinguish individuals may in some cases constitute an important determinant of cancer risk within the general population. Finally, viral infection has been linked to the development of specific cancers. Oncogenes and proto-oncogenes, and germline genetic analysis and cancer risk assessment are covered. Also discussed are genetic alterations and abnormalities, tumor suppressor genes, tumor progression, genetic mechanisms of treatment sensitivity and resistance, and emerging trends in cancer genomics and risk assessment. Figures illustrate activation of proto-oncogenes, the Knudsen two-hit model of tumor initiation, allelic losses in tumors, the retinoblastoma gene (RB1) cell cycle pathway, the p53 cellular stress and DNA damage response pathway, microsatellite instability and DNA mismatch repair, multiple oncogenes and tumor suppressors, tumor progression, cellular senescence and telomerase activation, tumor angiogenesis, chemotherapy drug resistance, targeting of oncogenic proteins by imatinib mesylate, analysis of expression profiles using high-density microarrays, and the spectrum of risk alleles for breast cancer predisposition. Tables outline oncogene and tumor suppressor gene mutations. This chapter contains 119 references.

Abstract SY15-02: Comprehensive analysis of genetic and epigenetic factors contributing to tumorigenesis in retinoblastoma

Abstract Decades of research on tumor cell biology has led to consensus that most cancers can be defined in terms of a small number of shared biological properties or hallmarks. Tumor cells activate growth-signaling pathways, evade cell death and senescence, acquire limitless replicative potential, sustain angiogenesis and may eventually invade surrounding tissues and metastasize. Molecular genetic studies have provided important examples of the direct connection between genetic lesions in tumor suppressor genes or proto-oncogenes and the corresponding pathways that are deregulated during tumorigenesis. For example, TP53 mutations allow cancer cells to evade cell death and senescence while RB1 mutations promote limitless replicative potential. We sought to simplify the integration of cancer genetics with the hallmarks of cancer by focusing on a simple, homogeneous tumor type that progresses rapidly and initiates with a common genetic lesion. Retinoblastoma is a rare cancer of the retina that begins during fetal development and is diagnosed in the first years of life. Virtually all retinoblastomas are believed to initiate with biallelic RB1 gene inactivation, which is rate-limiting for tumorigenesis. Here we present comprehensive genetic and epigenetic analysis of 4 primary retinoblastomas, their matched peripheral blood and an orthotopic xenograft derived from one of the primary tumors. Genetic or epigenetic inactivation of both copies of the RB1 gene was confirmed in all 4 primary tumors. Overall, our data suggest that epigenetic mechanisms may be playing a more important role in retinoblastoma tumorigenesis than previously appreciated. In addition, the orthotopic xenograft retained genomic stability through multiple passages in animals. Therefore, our orthotopic retinoblastoma xenograft provides an ideal experimental system to begin to directly connect the molecular genetics of cancer with sensitivity to novel chemotherapeutic agents. Recent advances in high-throughput sequencing technologies have allowed researchers to produce comprehensive profiles of the mutations and chromosomal lesions in individual tumors for the first time. This is important because in theory, the complete spectrum of genetic lesions in a particular tumor can now be directly mapped to each of the corresponding biological hallmarks of that tumor. Eventually, such analyses could be used to select the most appropriate treatment regimens for individual patients based on the spectrum of genetic lesions in their tumor and our understanding of how those lesions relate to the functional properties of the tumor cells themselves. However, cancer genome analysis has proven to be more complex than previously anticipated. In particular, the magnitude and complexity of the genetic lesions in some human cancers has made it difficult to unambiguously assign individual genetic lesions to the corresponding pathways that contribute to the hallmarks of cancer. For example, in a recent paired genome sequence analysis of a tumor from a lung cancer patient, 530 single nucleotide variants were identified in the tumor from 392 different coding regions. In addition, this tumor contained 43 large-scale structural variations. This genetic complexity is further complicated by difference across tumor types, differences among individual tumors for a particular tumor type and in some cases, lack of a clear understanding of the order of genetic lesions during tumorigenesis. Moreover, in tumors such as the aforementioned lung tumor, with high rates of genome instability that may take decades to be diagnosed, it is difficult to definitively separate those lesions that directly promote tumorigenesis from those that play no role in cancer initiation or progression. In this study, we sought to simplify the integration of cancer genetics with the hallmarks of cancer by focusing on a simple, homogeneous tumor type that progresses rapidly and initiates with a common genetic lesion. We performed whole genome and transcriptome sequence analysis of human retinoblastoma. There are several advantages to using retinoblastoma for this type of study. First, retinoblastomas are relatively homogeneous developmental tumors with little if any difference in incidence across gender, race or region. Second, all retinoblastomas are believed to initiate with the same genetic lesion_RB1 gene inactivation. This simplifies the cancer genetics tremendously because we do not need to parse out subgroups that initiate with different lesions. Third, RB1 gene inactivation is rate-limiting for tumorigenesis suggesting that the secondary and tertiary mutations occur rapidly as a direct or indirect result of RB1 inactivation. This may help us with our analysis because the time for initiating genetic lesion to tumor diagnosis is rapid and may minimize the accumulation of mutations or chromosomal lesions that do not contribute to tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY15-02. doi:10.1158/1538-7445.AM2011-SY15-02

Population genetics meets cancer genomics

There is a broad consensus that genetic alterations of normal body cells are the basis of cancer progression. Throughout the lifetime of an individual, her or his cells have to divide often, which is associated with occasional genetic changes. Some of the changes lead to uncontrolled cell proliferation and, at later stages of cancer progression, to blood vessel formation in the tumor tissue and distribution of tumor tissue across the body. The molecular genetics of cancer is a very advanced field: Many genetic alterations that predispose an individual to a certain cancer have been identified, and specific genetic pathways of cancer development have been elucidated (1). More recently, studies have been conducted on the scale of the entire genome to identify cancer-associated mutations (2–5). However, our understanding of the population genetic aspects of cancer development, that is, those aspects that relate to the dynamics of cancer cell replication, survival, and evolution, have not yet caught up with the advances in molecular genetics. A study by Bozic et al. (6) in PNAS brings the understanding of the population genetics of cancer cells closer to the edge defined by recent studies of the molecular genetics and genomics of various cancers.

The importance of molecular and anatomic pathology in cancer management

Cancers are routinely classified on anatomic and histologic criteria. Over the past 20 years, the impact of molecular classifications have become more and more fundamental to accurate diagnosis and prognosis, and increasingly, to selection of therapeutic options. The next 20 years are likely to see the development of sophisticated molecular characterisation of tumours, paralleled by access to a broad range of molecularly targeted therapeutic agents. It is already clear that the response to such agents is predicated on a full understanding of the molecular genetics of cancer. In this presentation, I will discuss the impact of molecular biology on cancer classification and treatment, with a special emphasis on sarcomas.

The first 20 years of the Department of Molecular Genetics of the National Institute of Oncology (NIO)

Molecular cancer genetics has developed during the last three decades as an independent discipline. Recent technological advances and discoveries in genomic and molecular research, including genome-wide analyses, provided unprecedented amount of knowledge on the aetiology of human cancer, and offered a framework for applying the novel results to clinical studies and the rapidly evolving field of molecular oncology. The Department of Molecular Genetics at NIO was established in 1986. Our group has played a pioneering role in molecular cancer research in Hungary and the region. This article overviews the achievements of our Department generated over the last two decades with a focus on cancer (susceptibility) genes.

Making Waves in Cancer Research: New Models in the Zebrafish

The zebrafish (Danio rerio) has proven to be a powerful vertebrate model system for the genetic analysis of developmental pathways and is only beginning to be exploited as a model for human disease and clinical research. The attributes that have led to the emergence of the zebrafish as a preeminent embryological model, including its capacity for forward and reverse genetic analyses, provides a unique opportunity to uncover novel insights into the molecular genetics of cancer. Some of the advantages of the zebrafish animal model system include fecundity, with each female capable of laying 200-300 eggs per week, external fertilization that permits manipulation of embryos ex utero, and rapid development of optically clear embryos, which allows the direct observation of developing internal organs and tissues in vivo. The zebrafish is amenable to transgenic and both forward and reverse genetic strategies that can be used to identify or generate zebrafish models of different types of cancer and may also present significant advantages for the discovery of tumor suppressor genes that promote tumorigenesis when mutationally inactivated. Importantly, the transparency and accessibility of the zebrafish embryo allows the unprecedented direct analysis of pathologic processes in vivo, including neoplastic cell transformation and tumorigenic progression. Ultimately, high-throughput modifier screens based on zebrafish cancer models can lead to the identification of chemicals or genes involved in the suppression or prevention of the malignant phenotype. The identification of small molecules or gene products through such screens will serve as ideal entry points for novel drug development for the treatment of cancer. This review focuses on the current technology that takes advantage of the zebrafish model system to further our understanding of the genetic basis of cancer and its treatment.

Inhibitors of growth factor signalling

The therapeutic utility of trastuzumab ('Herceptin') in breast cancer patients with tumours that overexpress erbB2 established the principle that targeted inhibition of specific signal transduction pathways can provide a new approach to cancer treatment. The ErbB family of protein tyrosine kinases, in particular the epidermal growth factor receptor (EGFR), are commonly overexpressed in many solid human tumours and EGFR was the initial target for a drug discovery programme seeking small molecule inhibitors of the EGFR tyrosine kinase (TK) enzyme activity. The description of the anilinoquinazoline class of potent and selective TK inhibitors led to several candidate drugs from this chemical class, for example gefitinib ('Iressa') and erlotinib ('Tarceva'), which are being evaluated in breast cancer patients. Rapid advances in cancer molecular genetics have identified numerous potential drug targets associated with abnormal control of cell division either downstream of the ErbBs, for example Ras and MEK, or in erbB-associated signalling networks, like Src kinase, which affect the tumour cell motility and invasiveness. Candidate drugs for several of these targets are currently being evaluated; for example, the prenylation inhibitor AZD3409, a mimetic of the CAAX box of K-Ras, inhibits protein farnesyl and geranylgeranyl tranferases and a novel, selective, orally active Src kinase inhibitor AZD0530 have entered Phase I clinical trials and may have utility in breast cancer therapy.

Bases génétiques de la radiosensibilité des cancers du sein

Local-regional radiation therapy is one of the major therapeutic means in the management of breast cancer. Three questions however arise from the important advances achieved in this domain in the past years. The first question concerns the possibilities to identify and overcome the radioresistance of a subset of tumours. The second question is how to recognize women likely to benefit from adjuvant radiation therapy, and therefore to diminish treatment indications in other groups. Finally, the third question is how to identify subjects at high risk for long term injury following breast irradiation, in order to adapt techniques and indications in such populations. The major advances of breast cancer molecular genetics in the past years should provide clinicians with tools to answer these important questions. In this paper, we review the molecular germline (BRCA1, BRCA2, ATM, ...) and somatic (p53, tyrosine kinase receptors, as well as actors of cell cycle, signal transduction, apoptosis, DNA repair ...) main bases of breast cancer radiosensitivity. Recent methods of exploration of the genetic background of both the host and the tumours (gene and protein expression profiles) are also reviewed as major tools of breast cancer management in the next few years.

Well Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) accounts for 98 % of thyroid cancer, with neoplasms arising from the follicular cells (papillary, follicular and Hurthle cell thyroid cancer) and parafollicular cells (medullary thyroid cancer). This paper will focus on the well-differentiated thyroid cancers arising from the follicular epithelial cells. By retaining the differentiated features of normal thyrocytes, these tumors usually retain their ability to produce thyroglobulin and to concentrate and organify iodine. Such features facilitate diagnosis, surveillance and treatment of this disease. There is ongoing debate over the management of DTC with respect to the extent of thyroid resection, indications for radioactive iodine treatment and the extent of thyroid hormone suppression therapy. New elements in cancer screening, diagnosis and treatment continue to evolve with the knowledge gained from ongoing research in thyroid cancer molecular genetics, clinical trials for medical treatments and retrospective studies on recurrence, survival and clinical outcomes of current treatment modalities.

Allelic imbalance studies of chromosome 9 suggest major differences in chromosomal instability among nonmelanoma skin carcinomas.

Loss of heterozygosity in the 9p21-p22 region, has been frequently described in a wide range of human malignancies, including familial melanomas. Also, losses and gains in other regions of chromosome 9 have frequently been observed and may indicate additional mechanisms for basal cell tumorigenesis. To investigate allelic imbalance in the 9p21-p22 region, among basal cell carcinomas. Microsatellite analysis. Two dermatology services of public universities in São Paulo and the Laboratory of Cancer Molecular Genetics of Universidade Estadual de Campinas (Unicamp). 13 patients with benign skin lesions consecutively referred to the outpatient dermatology clinics of Unicamp and Universidade Estadual de São Paulo (Unesp) and 58 with malignant skin tumours. MEAN MEASUREMENTS: We examined 13 benign cases including four of solar keratosis, three keratoachanthomas, three melanocytic nevi, two of Bowen's disease and one of neurofibroma, and 58 malignant skin tumors: 14 of squamous cell, 40 basal cell carcinomas and four melanomas. Participating patients had the main tumor and a normal portion of non-adjacent skin surgically removed. DNA was extracted from the tumor and matching normal tissue. We used four sets of primers to amplify polymorphic microsatellite repeats on chromosome 9, two of them targeting the 9p21-p22 region. We identified eight cases (20%) of allelic imbalance among basal cell carcinomas, two cases of loss of heterozygosity and six cases of microsatellite instability in the 9p21-p22 region. Additional markers were also involved in three of these tumors. No events were detected among the benign or the other malignant cases. This phenotype dependency suggests that there is a major distinction between the two most important forms of nonmelanoma skin cancers in their tendency to present microsatellite instability in chromosome 9. Since the CDKN2a/p16INK4a, p19ARF and p15INK4b tumor suppressor genes do not appear to be responsible for the observed abnormalities, other genes at 9p21-p22 may be involved in the pathogenesis and progression pathway of basal cell carcinomas.

Frontiers of hormone research (series editor: A.B. Grossman), volume 28: genetic disorders of endocrine neoplasia

This is a short multi-author monograph on the hereditary disorders of endocrine neoplasia. It comprises seven chapters, spanning 218 pages with 17 figures. There are two introductory chapters that briefly review the basic concepts of clinical and molecular cancer genetics and the principles of gene identification for the inherited cancer syndromes. These are followed by a further five chapters that attempt to cover in detail the clinical and molecular features of the multiple endocrine neoplasia syndromes: MEN1 and MEN2, Von Hippel-Lindau (VHL) disease and the hamartoma/lentiginosis syndromes. The references for each chapter are extensive and up to date for the year 2000. The text layout is clear and the indexing and crossreferencing to other sections is good. All but one of the contributors is based in North America and most have been directly involved in disease gene identification for these conditions. As expected for a multi-author book, there are significant variations in the quality of the contributions. I found the chapters on MEN1 and VHL particularly readable. This is not a book that will be of primary interest for novices to this field or for clinicians with a “passing interest”. For instance, we are informed that there are internationally agreed “operational criteria” for the diagnosis of Cowden’s syndrome (CS) but not what these criteria actually are. Later on in the same chapter, “CS” is also used as an abbreviation for Cushing’s syndrome during a discussion of the features of Carney’s syndrome. The clinical descriptions are also quite brief and opinions about management are sometimes too didactic. We are recommended that initial parathyroid surgery in MEN1 should extend to thymectomy and total parathyroidectomy, due to the small risk of thymic carcinoid, as well as that of supernumary parathyroid glands. This may well be the optimal approach but the authors give us no evidence to support their contention or discussion of the weaknesses of other strategies. A useful opportunity to illustrate some of the characteristic skin lesions (angiofibroma, lichen amyloidosis and various patterns of lentiginosis) found in these various conditions, some of which are rare, has also been missed.