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Contains fulltext : 110453.pdf (Publisher’s version ) (Closed access) CDH1 mutation carriers have a strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). Clinical data of GC cases and surgical and histological data of prophylactic gastrectomies and mastectomies of all 10 Dutch CDH1 mutation families were collected. In vitro functional assays were performed to analyze the nature of the newly found missense mutation c.1748T>G (p.Leu583Arg). Ten different CDH1 mutations were found. Functional assays gave strong arguments for the pathogenic nature of the p.Leu583Arg mutation. The pedigrees comprised 36 GC cases (mean age 40 years, range 20-72 years) and one LBC case. Twenty-nine/37 carriers alive, aged 18-61 years, underwent prophylactic gastrectomy. Invasive GC-foci and premalignant abnormalities were detected in 2 and 25 patients, respectively. In four patients GC/signetring cell (SRC) foci were diagnosed at preoperative gastroscopy. Long-standing presence of SRCs without progression to invasive carcinoma was shown in two others. Multifocal LBC/LCIS was found in the two prophylactic mastectomy specimens. Clefts of lip and/or palate (CL/P) were reported in seven individuals from three families. The age at onset and aggressiveness of GC is highly variable, which has to be included in counseling on planning prophylactic gastrectomies. The incidence of LBC is expected to increase and prophylactic mastectomy needs to be considered. The relationship between CL/P and CDH1 needs further study to inform future parents from hereditary diffuse gastric cancer (HDGC) families adequately.

Patients with carcinoma of unknown primary (CUP) present with metastatic disease for which the primary site cannot be found, despite extensive standard investigation. Here, we describe the development and implementation of the first clinically available microarray-based test for this cancer type (CUPPrint), based on 633 individual tumors representing 30 carcinoma and 17 noncarcinoma classes. Tissue of origin prediction for either fresh frozen or paraffin-embedded tumor samples is achieved with the use of a custom 8-pack 1.9k microarray and robust classification algorithm. An expression profile of 495 genes was used to predict tumor origin by applying a k-nearest neighbor algorithm. Internal cross-validation and analysis of an independent, previously published, 229-sample dataset revealed that clinically informative predictions were made for up to 94% of samples analyzed. Analysis of 13 previously published CUP specimens yielded predicted tumor origins that supported the clinical suspicion in 12 cases (92%). Microarray profiling presents a promising tool to assist in the identification of the primary tumor and might direct a more tailored treatment for CUP patients.

We aimed to investigate whether biological factors related to radiosensitivity and chemosensitivity have prognostic significance in non-small-cell-lung-cancer (NSCLC) patients treated with daily low doses of cisplatin and radiotherapy. We treated 27 NSCLC patients with concomitant daily low-dose cisplatin and radiotherapy between 1993 and 1995. Tumour specimens were analyzed for p53 and bcl-2 expression, and for cell proliferation using antibodies against ki-67. In addition, apoptosis was measured by an end-labeling technique (TUNEL). Finally, cisplatin-induced DNA modification in buccal cells was assessed immunocytochemically using a specific anti-serum. Univariate and multivariate analyses were performed to assess the association between the different variables and survival. The median follow-up was 41 months, and 21 patients (78%) have died. In a univariate analysis, age, tumour stage and cisplatin-DNA-adduct staining were the only factors significantly associated with survival (p < 0.05, log-rank test). p53, bcl-2, Ki-67 and apoptosis showed no relationship with outcome. Multivariate analysis revealed that cisplatin-DNA-adduct staining remained an independent prognostic factor (hazard ratio, 0.10, 95% CI, 0.02-0.49), with shorter survival times for patients with low adduct staining.

The genetic control of susceptibility to radiation-induced tumors in mice has been tested using the series of 20 CcS/Dem (CcS) Recombinant Congenic Strains, each carrying a different random set of 12.5% of genes of the resistant strain STS/A (STS) on the genetic background of the susceptible strain BALB/cHeA (BALB/c). Two classes of tumors were frequently observed: tumors of the haematopoietic system (lymphomas, myelocytic leukemias) and lung tumors. The results indicate that the genes controlling various aspects of tumor development were segregated in the CcS strain series. Large inter-strain differences were observed in the incidence of lung tumors. With lymphomas and leukemias, we not only observed strain differences in the incidence of tumors and in the latency of their development but also in the type of tumors (T- vs. B-cell lymphomas, myelocytic tumors) and in the frequency of their localized or disseminated (leukemic) form. Surprisingly, the myelocytic tumors, which occur very rarely or not at all in the parental strains BALB/c and STS or in their crosses, developed with high frequency in one of the CcS strains (CcS-2), indicating a unique combination of genes in this strain, which facilitates the development of myelocytic tumors. The effect of these genes is suppressed in the genetic composition of the parental strains. Tests of crosses of the resistant-strain CcS-13 with BALB/c indicated a suggestive linkage of a susceptibility gene for lymphomas to chromosome 5. These tests of the CcS strains illustrate the genetic complexity of the control of radiation-induced tumors in mice and suitability of these model systems to study their different facets.