Only a small proportion of cancers result from familial cancer syndromes with Mendelian inheritance. Nonfamilial, 'sporadic' cancers, which represent most cancer cases, also have a significant hereditary component, but the genes involved have low penetrance and are extremely difficult to detect. Therefore, mapping and cloning of quantitative trait loci (QTLs) for cancer susceptibility in animals could help identify homologous genes in humans. Several cancer-susceptibility QTLs have been mapped in mice and rats, but none have been cloned so far. Here we report the positional cloning of the mouse gene Scc1 (Susceptibility to colon cancer 1) and the identification of Ptprj, encoding a receptor-type protein tyrosine phosphatase, as the underlying gene. In human colon, lung and breast cancers, we show frequent deletion of PTPRJ, allelic imbalance in loss of heterozygosity (LOH) and missense mutations. Our data suggest that PTPRJ is relevant to the development of several different human cancers.

Results of individualized therapy guided by mutational tumor profile of patients with non-small-cell lung cancer are presented. After confirming the importance of epidermal growth factor receptor (EGFR) and KRAS mutations for (non)response on gefitinib in a retrospective series of patients, EGFR mutations were looked for before--and were a condition for--treatment with gefitinib or erlotinib. To increase the chance to find such a mutation, we selected patients on the basis of smoking status, gender and histopathology. Out of 41 patients selected, 13 (32%) were found to harbor an EGFR mutation. In nine of them it concerned deletions in exon 19 and in none of them KRAS mutations were detected. All nine patients with an exon 19 deletion had a favorable and continuing response to tyrosine kinase inhibitors (TKIs), while four other patients with point mutations responded less favorably: stable disease or a response of short duration. These observations confirm the potential role of EGFR and KRAS mutations in predicting (non)response to TKIs. Exon 19 deletions that are associated with the best responses might be used for first-line treatment selection, while KRAS mutations could play a role in excluding patients from treatment with TKIs.

Continuous dosing of R115777 is feasible with an acceptable toxicity profile at a dose of 300 mg bid.

The results suggest that goblet cell carcinoids should be regarded as a separate entity. The formerly used term 'crypt cell carcinoma' may be more appropriate because it reflects the more aggressive clinical behaviour of these tumours as well as their greater similarity to adenocarcinomas rather than to carcinoids.

Patients with advanced lung adenocarcinoma who harbor a ras mutation may have major responses to chemotherapy and have similar progression-free and overall survival as patients with ras mutation-negative tumors. K-ras mutations may represent one of several ways in which early tumors are enabled to metastasize to distant sites.

IntroductionWith currently available treatment protocols, a complete first remission can be obtained in approximately 70% of diffuse large B-cell lymphoma (DLBCL) patients. Long-term disease-free survival can be achieved in about 40% of the patients as a whole group. 1 Most relapses occur within the first 2 to 3 years after diagnosis. 2 Relapses after 4 years or more do occur but are rare. Relapse after 24 months after diagnosis is reported at a rate of about 2.2% per year. 3 One of the most important questions regarding late relapses is whether they represent true, clonally related disease or de novo unrelated second, possibly therapy-induced, malignancy. Except for a few case reports and isolated cases in larger series, [3][4][5][6] no systematic data are available on this issue.In terms of clinical follow-up strategies after treatment for DLBCL, it would be relevant to identify a subgroup of patients who are at risk for late relapse and who could be considered to have relapsed disease with a long first remission. Development of a second de novo non-Hodgkin lymphoma might be an indication of a (genetic) predisposition for B-cell lymphoma and may guide treatment choice in these patients. Study design Patients and histologic assessmentFrom the clinical files of The Netherlands Cancer Institute, 13 cases of patients with DLBCL who presented with a relapse after a disease-free interval of more than 4 years after treatment since 1983 and of whom suitable histological material for immunohistochemical and molecular studies from both episodes was available were retrieved. The slides of all study samples and other relevant biopsy material were reassessed and reclassified according to the World Health Organization classification, 7 and clinical data were collected (Table 1). ImmunohistochemistryImmunohistochemistry on paraffin-embedded biopsy samples was performed using standard antigen retrieval methods and included MIB-1, CD20, CD79a, CD3, CD21, bcl-2, bcl-6 (all from DAKO, Glostrup, Denmark), and CD5 and CD10 (from Novacastra, Newcastle upon Tyne, United Kingdom). Preparation of DNA from paraffin-embedded samples, amplification, and sequencing of IgH genesAfter DNA isolation from representative biopsy samples of the initial episode and the relapse, immunoglobulin heavy (IgH) chain gene CDR3 and CDR2 regions were amplified and analyzed on a 3700XL capillary ABI Prism Sequencer (Applied Biosystems, Foster City, CA). 8 Monoclonal rearranged products were isolated from agarose gels and sequenced using the ABI Prism BigDyePrimer Cycle Sequencing Ready Reaction Kit (Applied Biosystems). The most closely related immunoglobulin heavy chain variable (VH), diversity (DH), and joining (JH) genes were identified as compared to germ line sequences (VBASE) to record the patterns of shared and ongoing mutations.Bcl-2/IgH polymerase chain reaction (PCR) assays for translocations in the bcl-2 major breakpoint region (MBR) and minor cluster region (MCR) regions were performed. 8,9 LOH analysis DNA from lymphoma tissue and noninvolved ...

Recently, conflicting results have been reported on the incidence of RAS mutations in primary testicular germ cell tumors of adults (TGCTs). In four studies a low incidence of mutations (less than 15%) in a variety of TGCTs or derived cell lines was found, whereas in two other studies a high incidence of N- or KRAS mutations (over 40%) was shown. A total of 62 testicular seminomas (SE) and 34 nonseminomatous TGCTs (NS) were studied thus far. The largest series consisted of 42 TGCTs, studied on paraffin embedded tissue. We present the results of analysis for the presence of N- and KRAS mutations, in codons 12, 13, and 61, in snap frozen samples of 100 primary TGCTs, comprising 40 SE and 60 NS. Using the polymerase chain reaction (PCR) and allele specific oligonucleotide hybridization (ASO), mutations were found in five SE (three in NRAS and two in KRAS, all codon 12), and in one NS (KRAS, codon 12). To exclude underestimation of the incidence of RAS mutations in TGCTs due to the presence of an excess of wild type alleles in the analyzed sample, a PCR technique preferentially amplifying KRAS alleles with a mutation in codon 12 was applied to all SE. This approach, allowing a 250 times more sensitive assay, resulted in the detection of only one additional SE with a mutation. Based on a critical analysis of published data and on our results from the largest series of frozen samples investigated thus far, we conclude that N- or KRAS mutations are rare and apparently not essential for initiation or progression of TGCTs.

The classification of multifocal myxoid/round cell liposarcoma, which is defined as tumor presentation in at least two separate sites before manifestation in the lungs, as either metastasis or as a second primary tumor, has essential clinical consequences. Genetically, myxoid/round cell liposarcoma is characterized by t(12; 16)(q13;p11) or t(12;22)(q13;q12), and various exon fusion transcripts are described with varying incidences, which permits their use as markers for clonality. Moreover, in solid tumors, analysis of loss of heterozygozity is valuable for clonality analysis. Therefore, fifteen multifocal myxoid/round cell liposarcoma patients with two to five metachronous (n ‫؍‬ 12) or synchronous (n ‫؍‬ 3) localizations were investigated. Using RT-PCR, the detailed molecular characteristics of the FUS-CHOP and EWS-CHOP breakpoints were determined. Loss of heterozygozity analysis at twelve loci was then used to further analyze clonal relationships. In all patients, tumor sites showed identical FUS-CHOP fusion products. In six patients, identical rare fusion transcripts were found, supporting a clonal relationship. Nine patients had the common exon5-FUS/exon2-CHOP fusion transcript, and two of these were identified as clonally related by loss of heterozygozity analysis. In all other patients, loss of heterozygozity analysis was highly suggestive of a clonal relationship, and no evidence for interpretation of a second primary tumor was found. This study supports the metastatic nature of apparent multifocal myxoid/round cell liposarcoma. Multifocal presentation in soft tissue tumors, especially in myxoid/round cell liposarcoma (MRLS), has been a matter of debate for some time. This issue has not been fully resolved because of the limited patients for whom data are available.1-5 Multifocality in soft tissue sarcoma is defined as the presence of sarcoma on at least two separate sites before manifestation of disease in sites where sarcomas most commonly metastasize, in particular the lungs. The first reported case of multifocal sarcoma dates to 1934, when Siegmund described a patient with multiple fatty tumors, which was interpreted as "Lipoblastische Sarcomatose" or a systemic malignant disease of the soft tissue.6 Since then, the debate persists whether this entity represents separate primary tumors or an unusual pattern of metastasis.Differentiation between second primary and disseminated MRLS has major clinical consequences. A resectable second primary MRLS would indicate an optimal surgical approach combined with (neo) adjuvant radiotherapy with curative intent, whereas in metastatic disease, the choice of treatment, surgery, radiotherapy, or chemotherapy is made with a limited expectation of ultimate cure, predicting other metastases in the near future.A clonal relationship between two tumors proves their common origin in case of metastases. Conversely, the absence of a clonal relationship would suggest a second primary sarcoma. Several assays have been developed to evaluate clonal relationship between tumors....