Epstein-barr virus and gastric cancer: Data and unanswered questions

Sixty-five unselected cases of gastric cancer have been analysed for EBV DNA by polymerase chain reaction, in situ hybridization and immunohistochemistry for CD21 antigen expression. Four cases were found EBV-positive by PCR, while ISH yielded positive results in 3 of these cases, demonstrating EBV in the nuclei of cancerous cells. CD21 antigen was expressed in cancerous cells in all 3 ISH-positive cases. All the EBV-positive cancers of the present series were poorly to moderately differentiated adenocarcinomas with prominent lymphoid infiltration. These results are discussed also on the basis of the literature.     

Hereditary diffuse gastric cancer: association with lobular breast cancer

Hereditary diffuse gastric cancer (HDGC) has been shown to be caused by germline mutations in the gene CDH1 located at 16q22.1, which encodes the cell–cell adhesion molecule, E-cadherin. Not only does loss of expression of E-cadherin account for the morphologic differences between intestinal and diffuse gastric cancer (DGC) variants, but it also appears to lead to distinct cellular features which appear to be common amongst related cancers that have been seen in the syndrome. As in most hereditary cancer syndromes, multiple organ sites may be commonly affected by cancer, in HDGC, lobular carcinoma of the breast (LBC) and possibly other organ sites have been shown to be associated with the familial cancer syndrome. Given the complexity of HDGC, not only with regard to the management of the DGC risk, but also with regard to the risk for other related cancers, such as LBC, a multi-disciplinary approach is needed for the management of individuals with known CDH1 mutations.     

Hereditary diffuse gastric cancer: updated clinical practice guidelines

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that is characterised by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is largely caused by inactivating germline mutations in the tumour suppressor gene CDH1, although pathogenic variants in CTNNA1 occur in a minority of families with HDGC. In this Policy Review, we present updated clinical practice guidelines for HDGC from the International Gastric Cancer Linkage Consortium (IGCLC), which recognise the emerging evidence of variability in gastric cancer risk between families with HDGC, the growing capability of endoscopic and histological surveillance in HDGC, and increased experience of managing long-term sequelae of total gastrectomy in young patients. To redress the balance between the accessibility, cost, and acceptance of genetic testing and the increased identification of pathogenic variant carriers, the HDGC genetic testing criteria have been relaxed, mainly through less restrictive age limits. Prophylactic total gastrectomy remains the recommended option for gastric cancer risk management in pathogenic CDH1 variant carriers. However, there is increasing confidence from the IGCLC that endoscopic surveillance in expert centres can be safely offered to patients who wish to postpone surgery, or to those whose risk of developing gastric cancer is not well defined.     

Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy

BACKGROUND: A subset of patients with diffuse gastric cancer harbor deleterious cancer-causing germline mutations in the type 1 E-cadherin (epithelial) gene (CDH1), which predisposes to the autosomal dominantly inherited hereditary diffuse gastric cancer (HDGC) syndrome. These mutations are associated with a 70% life-time risk for diffuse gastric cancer (DGC) and an additional 40% risk for lobular breast cancer in women. Management options for unaffected mutation carriers include prophylactic total gastrectomy. METHODS: Four HDGC pedigrees from a cohort of 56 CDH1 mutation-positive families were subjected to further analysis. Cancer diagnoses, whenever possible, were verified with pathology reports and/or slides/tissue block review. Genetic counseling for family members covered the natural history of HDGC, the pros and cons of mutation testing, the lack of effective screening procedures available to CDH1 mutation-positive individuals, and the option for them of prophylactic total gastrectomy. RESULTS: Within the 4 families, carrier testing for mutations in the CDH1 gene was carried out on 52 individuals, including 25 individuals who were positive for mutation. Prophylactic gastrectomies were performed on a total of 17 individuals from 3 of the families, including 11 first cousins from 1 of the families. Occult DGC was diagnosed in gastrectomy specimens from 13 of 17 individuals (76.5%). During follow-up questioning, each of the 11 cousins stated that the decision for the prophylactic procedure was the "right one" for them. CONCLUSIONS: Unaffected mutation carriers from HDGC families face difficult decisions and can be assisted best through education and interactions with counseling by an informed multidisciplinary team.     

Breast cancer racial disparities: unanswered questions

Breast cancer is the most common noncutaneous cancer diagnosed in women in the United States and is second only to lung cancer as the leading cause of cancer-related mortality. Although mortality rates have been dropping steadily due to a variety of factors including improved treatment modalities and screening, substantial racial differences in outcome between blacks and whites persist. Although differences in health care utilization and access, tumor biology, and cancer management have been elucidated as possible reasons for disparities seen, it is likely that other interactions exist. The purpose of this review is, therefore, to present a comprehensive overview of the literature on racial disparities in breast cancer outcome and highlight potential causative factors that may contribute to disparities seen among blacks and whites with breast cancer. In addition, we make research recommendations by discussing some of the remaining gaps in knowledge that may lead to further understanding of disparities and consequently improved outcomes for all women with breast cancer.     

Hereditary diffuse gastric cancer: What the clinician should know

Hereditary diffuse gastric cancer (HDGC) is an inherited autosomal dominant syndrome with a penetrance of up to 80% affecting diverse geographic populations. While it has been shown to be caused mainly by germline alterations in the E-cadherin gene (CDH1), problematically, the genetic diagnosis remains unknown in up to 60% of patients. Given the important knowledge gaps regarding the syndrome, asymptomatic carriers of CDH1 mutations are advised for a prophylactic total gastrectomy. Intensive annual endoscopic surveillance is the alternative for carriers who decline gastrectomy. As HDGCs have a prolonged indolent phase, this provides a window of opportunity for surveillance and treatment. Recent findings of other gene defects in CTNNA1 and MAP3K6, as well as further characterization of CDH1 mutations and their pathogenicity will change the way HDGC patients are counselled for screening, surveillance and treatment. This review will bring the reader up to date with these changes and discuss future directions for research; namely more accurate risk stratification and surveillance methods to improve clinical care of HDGC patients.     

Hereditary diffuse gastric cancer: A manifestation of lost cell polarity

Hereditary diffuse gastric cancer is a cancer syndrome caused by germline mutations in the gene for the cell adhesion protein E-cadherin ( CDH1 ). E-cadherin plays a central role in the maintenance of cell polarity and its loss during tumorigenesis is associated with poorly differentiated cancers and a poor prognosis. Hereditary diffuse gastric cancer is dominated by diffuse-type gastric adenocarcinoma, often with signet ring cell morphology. Large numbers of stage T1a signet ring cell carcinomas exist in the stomachs of CDH1 mutation carriers from a young age, and these foci sometimes show enrichment to the transition zone between the body and antrum. Generally these signet ring cell carcinomas are hypoproliferative, lack Wnt pathway activation, and are relatively indolent. However, a small proportion of the T1a foci contain cells that are poorly differentiated, display mesenchymal features, and express activated c-Src and its downstream targets. These same features are observed in more advanced stages of hereditary diffuse gastric cancer progression, suggesting that an epithelial–mesenchymal transition is required for tumor invasion beyond the muscularis mucosae. Hereditary diffuse gastric cancer initiation requires somatic down-regulation of the second CDH1 allele, which in most cases is caused by DNA promoter hypermethylation. Subsequent to CDH1 down-regulation, lost polarity in gastric stem or progenitor cells would be predicted to interfere with mitotic spindle orientation and the segregation of cell fate determinants. We predict that this disruption of cell division results in daughter cells being deposited in the lamina propria where their population expands and partially differentiates, resulting in the formation of foci of signet ring cells. ( Cancer Sci 2009; 100: 1151–1157)     

Hereditary diffuse gastric cancer and lost cell polarity: a short path to cancer

The mechanisms that underlie the initiation of human cancer are poorly understood. Here, we describe the development of hereditary diffuse gastric cancer and argue that it arises from the disruption of the regenerative processes that are inherent to all epithelial tissues. This model supports the cancer stem cell hypothesis, in which tumors contain a subpopulation of cells with the key stem cell characteristics of capacity for self renewal, differentiation and limitless replication. We argue that epigenetic modifications induced by common environmental and physiological pressures are able to initiate this disruption. The carcinogenic effects of these modifications are potentially reversible through the use of epigenetic therapies such as DNA demethylating agents and histone deacetylation inhibitors.     

Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice

Hereditary diffuse gastric cancer (HDGC) is the only known cancer syndrome that is dominated by gastric adenocarcinoma. HDGC is caused by germline mutation of the CDH1 gene that encodes the cell adhesion protein E-cadherin. Mutation carriers have a more than 70% lifetime risk of developing DGC and an elevated risk of lobular breast cancer. Intestinaltype gastric cancer is not part of the syndrome. Clinical management of HDGC involves predictive genetic testing beginning at or near 16 years of age. It is recommended that mutation carriers undergo prophylactic gastrectomy after about 20 years of age. Anatomical mapping has demonstrated that mutation carriers develop multifocal stage T1a signet ring cell carcinomas, with up to several hundred foci being observed in single stomachs. These foci develop following the somatic inactivation of the second CDH1 allele by mechanisms that include DNA promoter hypermethylation.     

Pregnancy protection of breast cancer: new insights reveal unanswered questions

The recent paper by Meier-Abt and colleagues on pregnancy protection of breast cancer development takes a different approach to the problem and focused on the effect of parity on the cell subpopulations of the mouse mammary gland. Their results demonstrate that parity decreases the cell number of the hormone receptor-positive luminal cells (that is, luminal Sca1+) but not the basal stem/progenitor cells (CD24lo/CD49hi). Additionally, microarray studies demonstrate that wnt4 expression from the luminal Sca1+ cells is markedly reduced as is the wnt signaling pathway in basal cells. One important implication from these results is that targeting the wnt signaling pathway might be a feasible prevention approach in humans.     

Thoracic radiation therapy for limited-stage small-cell lung cancer: unanswered questions

The role of thoracic radiation therapy (RT; TRT) is now established in the management of limited-stage small-cell lung cancer (SCLC). There is increasing evidence in the literature in favor of early concurrent chemoradiation therapy, and a gold standard of care for patients with a good performance status is twice-daily TRT (45 Gy in 3 weeks) with concurrent cisplatin/etoposide. Five-year survival rates > 20% can be expected with this combined-modality approach. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies for the disease, essential questions related to the optimization of TRT remain unanswered. In particular, the optimal RT dose, fractionation, and treatment volume have not been defined. This review highlights the need for well-designed multinational trials aimed at the optimization and standardization of RT for limited-stage SCLC. These trials should integrate translational research studies to investigate the molecular basis of RT resistance and to develop biomarker profiles of prognosis.     

Neoadjuvant chemotherapy for advanced ovarian cancer: overview of outcomes and unanswered questions

Neoadjuvant chemotherapy for advanced ovarian cancer was initially administered as an alternative treatment for patients not suitable for primary debulking surgery (PDS) because of unresectable tumor or poor performance status. Accumulation of favorable outcomes of this treatment compared with standard treatment starting with PDS made this strategy a candidate for prospective, randomized Phase III studies without limiting the subjects to patients who were unsuitable for PDS. Among the four Phase III studies to date, the earliest study from the European Organization for Research and Treatment of Cancer (EORTC) has revealed noninferior survival with less-serious morbidity in the neoadjuvant chemotherapy arm. These data suggest that neoadjuvant chemotherapy followed by surgical cytoreduction is an acceptable management strategy for patients with advanced ovarian cancer. In this article, we review the treatment outcomes and discuss some unanswered questions, as well as possible future research in this area.     

Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions

A multitude of laboratory and clinical research studies of ulcerative oral mucositis induced by cytotoxic cancer therapies have been reported during the past decade. However, a comprehensive understanding of oral mucositis pathogenesis, together with a clear definition of risk factors for development and severity of the lesion, remain under investigation. The literature presents sometimes divergent data regarding these issues, which in turn restrict efforts to develop a unified approach for management of this morbid condition. The current review summarizes these controversies and highlights the need for strategies for stratification of patients enrolled in clinical trials, in relation to both pathophysiologic and associated risk factors.     

Hereditary diffuse gastric cancer and E-cadherin: description of the first germline mutation in an Italian family.

AIMS: Germline mutation of the E-cadherin gene (CDH1) accounts for the Hereditary Diffuse Gastric Cancer (HDGC) syndrome. Fourteen pedigrees with Diffuse Gastric Cancer that fulfilled the International Gastric Cancer Linkage Consortium (IGCLC) criteria were selected and screened for CDH1 germline mutations. METHODS: The entire coding region of the CDH1 gene and all intron-exon boundaries were analyzed by direct sequencing in the 14 families fulfilling the IGCLC criteria. E-cadherin immunohistochemical expression was evaluated on tumour as well as normal formalin-fixed paraffin embedded tissues. RESULTS: A novel germline missense mutation was found. It was a single C-->T substitution in exon 8, resulting in a transition of CCG-->CTG (C1118T; Pro373Leu) demonstrated in the proband and her brother. At immunohistochemical analysis, the staining intensity was reduced and considered weakly positive (15%). CONCLUSIONS: The first CDH1 germline mutation of an Italian family is herein reported. The present missense mutation has never been described so far.     

Hereditary diffuse gastric cancer in a Japanese family with a large deletion involving CDH1

Hereditary diffuse gastric cancer (HDGC), characterized by susceptibility to gastric signet ring cell carcinomas (SRCCs) and caused by CDH1 germline mutations, is rare in the Japanese. We present here a Japanese family with HDGC identified by comparative genomic hybridization (CGH) analysis. A 55-year-old woman was treated with completion gastrectomy for multiple SRCCs, and pathological examination revealed approximately 200 foci of SRCC with loss of E-cadherin expression. Her 30-year-old son had surveillance endoscopy and was found to have multiple SRCCs. He underwent total gastrectomy, and 32 foci of SRCC with loss of E-cadherin expression were histologically found. Although no point mutations were detected in CDH1 by sequencing, CGH revealed a 275-kb deletion involving exons 7–16 of CDH1 in both patients. While only a few HDGCs have been reported in East Asia, patients with multiple SRCC may need to be offered appropriate genetic counseling and testing in this area.     

Metabolic reprogramming in glioblastoma: the influence of cancer metabolism on epigenetics and unanswered questions

A defining hallmark of glioblastoma is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. Altered metabolic enzymes and their metabolites are oncogenic and not simply a product of tumor proliferation. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field.