International Agency for Research on Cancer

About: International Agency for Research on Cancer is a government organization based out in Lyon, France. It is known for research contribution in the topics: Population & Cancer. The organization has 2989 authors who have published 9010 publications receiving 929752 citations. The organization is also known as: IARC.

Hereditary breast cancer : pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage

Abstract: BACKGROUND The purpose of this investigation was to determine if there are pathobiologic differences between BRCA1-related and BRCA2-related hereditary breast cancer (HBC) and non-HBC. METHODS On the basis of linkage to chromosomes 17q or 13q and/or the presence of ovarian and male breast cancer, HBC families were classified as either “BRCA1-related” (26 families, 90 breast cancer pathology cases) or “Other” (26 families, 85 cases), in which most BRCA2 cases were likely to reside. Cases were compared with 187 predominantly non-HBC cases. Tumors were assessed for histologic type, grade, and ploidy and S-phase fraction by quantitative DNA flow cytometry. Clinical presentation and available follow-up data were obtained. RESULTS BRCA1-related and Other HBC patients each presented at lower stage (P = 0.003) and earlier age than non-HBC patients (mean, 42.8 years and 47.1 years vs. 62.9 years, P < 0.0001). Compared with non-HBC, invasive BRCA1-related HBC had a lower diploidy rate (13% vs. 35%; P = 0.002), lower mean aneuploid DNA index (1.53 vs. 1.73; P = 0.002), and strikingly higher proliferation rates (mitotic grade 3; odds ratio [OR] = 4.42; P = 0.001; aneuploid mean S-phase fraction 16.5% vs. 9.3%, P < 0.0001). Other HBC patients, including patients in two BRCA2-linked families, had more tubular-lobular group (TLG) carcinomas (OR = 2.56, P = 0.007). All trends were independent of age. A nonsignificant trend toward better crude survival in both HBC groups was age- and stage-dependent. Compared with Other HBC, BRCA1-related HBC patients had fewer recurrences (P = 0.013), a trend toward lower specific death rates, and fared no worse than breast cancer patients at large. Other HBC patients, despite neutral prognostic indicators, fared worse. CONCLUSIONS BRCA1-related HBCs are more frequently aneuploid and have higher tumor cell proliferation rates compared with Other HBC. Despite these adverse prognostic features, BRCA1-related HBC patients have paradoxically lower recurrence rates than Other HBC patients. The excess of TLG cancers in the “Other” HBC group may be associated with BRCA2 linkage. Cancer 1996; 697-709.

NORDCAN - A Nordic tool for cancer information, planning, quality control and research

Abstract: The NORDCAN database and program (www.ancr.nu) include detailed information and results on cancer incidence, mortality and prevalence in each of the Nordic countries over fi ve decades and has lately been supplemented with predictions of cancer incidence and mortality; future extensions include the incorporation of cancer survival estimates. Material and methods . The data originates from the national cancer registries and causes of death registries in Denmark, Finland, Iceland, Norway, Sweden, and Faroe Islands and is regularly updated. Presently 41 cancer entities are included in the common dataset, and conversions of the original national data according to international rules ensure comparability. Results. With 25 million inhabitants in the Nordic countries, 130 000 incident cancers are reported yearly, alongside nearly 60 000 cancer deaths, with almost a million persons living with a cancer diagnosis. This web-based application is available in English and in each of the fi ve Nordic national languages. It includes comprehensive and easy-to-use descriptive epidemiology tools that provide tabulations and graphs, with further user-specifi ed options available. Discussion. The NORDCAN database aims to provide comparable and timely data to serve the varying needs of policy makers, cancer societies, the public, and journalists, as well as the clinical and research community.

A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma

Abstract: So far, no common environmental and/or phenotypic factor has been associated with melanoma and renal cell carcinoma (RCC). The known risk factors for melanoma include sun exposure, pigmentation and nevus phenotypes; risk factors associated with RCC include smoking, obesity and hypertension. A recent study of coexisting melanoma and RCC in the same patients supports a genetic predisposition underlying the association between these two cancers. The microphthalmia-associated transcription factor (MITF) has been proposed to act as a melanoma oncogene; it also stimulates the transcription of hypoxia inducible factor (HIF1A), the pathway of which is targeted by kidney cancer susceptibility genes. We therefore proposed that MITF might have a role in conferring a genetic predisposition to co-occurring melanoma and RCC. Here we identify a germline missense substitution in MITF (Mi-E318K) that occurred at a significantly higher frequency in genetically enriched patients affected with melanoma, RCC or both cancers, when compared with controls. Overall, Mi-E318K carriers had a higher than fivefold increased risk of developing melanoma, RCC or both cancers. Codon 318 is located in a small-ubiquitin-like modifier (SUMO) consensus site (ΨKXE) and Mi-E318K severely impaired SUMOylation of MITF. Mi-E318K enhanced MITF protein binding to the HIF1A promoter and increased its transcriptional activity compared to wild-type MITF. Further, we observed a global increase in Mi-E318K-occupied loci. In an RCC cell line, gene expression profiling identified a Mi-E318K signature related to cell growth, proliferation and inflammation. Lastly, the mutant protein enhanced melanocytic and renal cell clonogenicity, migration and invasion, consistent with a gain-of-function role in tumorigenesis. Our data provide insights into the link between SUMOylation, transcription and cancer.

Activation and Caspase-mediated Inhibition of PARP: A Molecular Switch between Fibroblast Necrosis and Apoptosis in Death Receptor Signaling

Abstract: Death ligands not only induce apoptosis but can also trigger necrosis with distinct biochemical and morphological features. We recently showed that in L929 cells CD95 ligation induces apoptosis, whereas TNF elicits necrosis. Treatment with anti-CD95 resulted in typical apoptosis characterized by caspase activation and DNA fragmentation. These events were barely induced by TNF, although TNF triggered cell death to a similar extent as CD95. Surprisingly, whereas the caspase inhibitor zVAD prevented CD95-mediated apoptosis, it potentiated TNF-induced necrosis. Cotreatment with TNF and zVAD was characterized by ATP depletion and accelerated necrosis. To investigate the mechanisms underlying TNF-induced cell death and its potentiation by zVAD, we examined the role of poly(ADP-ribose)polymerase-1 (PARP-1). TNF but not CD95 mediated PARP activation, whereas a PARP inhibitor suppressed TNF-induced necrosis and the sensitizing effect of zVAD. In addition, fibroblasts expressing a noncleavable PARP-1 mutant were more sensitive to TNF than wild-type cells. Our results indicate that TNF induces PARP activation leading to ATP depletion and subsequent necrosis. In contrast, in CD95-mediated apoptosis caspases cause PARP-1 cleavage and thereby maintain ATP levels. Because ATP is required for apoptosis, we suggest that PARP-1 cleavage functions as a molecular switch between apoptotic and necrotic modes of death receptor-induced cell death.