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Analyses of cancer incidence data in the United States and Western Europe revealed steadily rising rates over the past decades of adenocarcinomas of the esophagus and gastric cardia. Genetic information on gastric cardia adenocarcinoma and its preneoplasias is sparse. We have used comparative genomic hybridization to obtain a genome-wide overview of 20 archival gastric cardia adenocarcinomas and 10 adjacent preneoplastic lesions (4 metaplasias, 1 low-grade dysplasia, 5 high-grade dysplasias). Multiple genetic alterations were discriminated in all adenocarcinomas. Frequent loss (≥25% of all tumors) was detected, in decreasing order of frequency, on 5q, 18q, 4q, 3p, 9p, 2q, 11q, 14q, 21q, 4p, 9q, 16q, 1p, and 8p. Frequent gain (≥25% of all tumors) was disclosed, in decreasing order of frequency, on 20q, 7p, 8q, 1q, 7q, 20p, 17q, 13q, Xp, 6q, 8p, 19q, 5p, 6p, and Xq. Loss of the Y chromosome was found in 60% of male cases. High level amplification was frequently (>10% of all tumors) detected on 7q21, 8p22, 12p11.2, 17q12-q21, and 19q13.1-q13.2. The precursor lesions showed multiple aberrations in all high-grade dysplasias, whereas few genetic changes were discerned in LGD and metaplasias. High level amplifications were also found in high-grade dysplasias, ie, on 7q21, 8p22, and 17q12-q21. Moreover, the percentage of aberrations was not significantly different for invasive carcinomas or high-grade dysplasias. Approximately 70% of the precursor aberrations were also present in the adjacent carcinoma. Minimal overlapping regions in the preneoplasias included loss on 18q12-q21 and gains on 8q23 and 17q12-q21, suggesting involvement of genes residing in these regions. In conclusion, we have (i) created a map of genetic alterations in gastric cardia adenocarcinomas and (ii) provided evidence for the presence of a metaplasia-dysplasia-carcinoma sequence in this poorly understood type of cancer.

Despite the high incidence of prostate cancer, only limited data are available on genes or chromosomes specifically involved in its initiation and progression. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded, tissues at different times in prostatic tumor progression to screen the tumor genome for gains and losses. Our panel included specimens derived from 56 different patients: 23 patients with primary, prostate-confined carcinomas; 18 patients with regional lymph node metastases; and 15 patients with distant metastases. Chromosome arms that most frequently showed losses, included 13q (55%), 8p (48%), 6q (43%), 5q (32%), 16q (25%), 18q (20%), 2q (18%), 4q (18%), 10q (18%), and Y (16%). Gains were often seen of chromosome arms 8q (36%), 17q (23%), Xq (23%), 7q (21%), 3q (18%), 9q (18%), 1q (16%), Xp (16%). Furthermore, specific high-level amplifications, eg, of 1q21, 1q25, and Xq12 to q13, were found in metastatic cancers. A significant accumulation of genetic changes in distant metastases was observed, eg, loss of 10q (p = 0.03) and gain of 7q (p = 0.03) sequences. In addition, investigation of a potential biomarker identified in previous studies by our group, ie, extra copies of #7 and/or #8, revealed a high prevalence of 7pq and/or 8q gain in the distant metastases (p = 0.02). Importantly, gains were observed more frequently in tumors derived from progressors after radical prostatectomy, than in nonprogressors (mean time of follow-up, 74 months). Specifically, gain of chromosome 7pq and/or 8q sequences appeared an accurate discriminator between the progressors and nonprogressors. Multivariate analysis showed a significant correlation between progressive disease and the number of chromosomes with gains. This correlation also held true when stage (p = 0.007) or grade (p = 0.002) were taken into account. Likewise, this applied for gain of chromosome 7pq and/or 8q sequences (p = 0.03 and p = 0.005 for stage or grade, respectively). Additionally, an increase in the number of chromosomes with gains per case was related to a decrease in biochemical progression-free survival (Ptrend <0.001). More specifically, the gain of 7pq and/or 8q sequences markedly reduced the biochemical progression-free survival (p < 0.001). In conclusion, this study has, firstly, documented the spectrum of chromosomal alterations in subsequent stages of prostate cancer, a number of which had not been described previously. It allowed us to identify chromosomal regions related to advanced tumor stage, ie, loss of 10q24 and gain of 7q11.2 and/or 7q31 sequences. Secondly, gain of 7pq and/or 8q was identified as a potential genetic discriminator between progressors and nonprogressors after radical surgery.

Gliomatosis cerebri is a rare condition in which the brain is infiltrated by an exceptionally diffusely growing glial cell population involving at least 2 lobes, though often more extensive, sometimes even affecting infratentorial regions. The neoplastic proliferation may have a monoclonal origin, or alternatively, reflect progressive neoplastic change of an entire tissue field (“field cancerization”). The presence of an identical set of genetic aberrations throughout the lesion would point to monoclonality of the proliferation. In contrast, the finding of non-identical genetic changes in widely separated regions within the neoplasm would support the concept of field cancerization.In the present study, a unique autopsy case of gliomatosis was available to verify either one of these hypotheses. Tissue samples were randomly taken from 24 locations throughout the brain and used for genetic investigation. In all samples the histology showed an identical picture of slightly elongated astrocytic cells, typical for gliomatosis. TP53 exon 5–8 mutation analysis was performed on all samples. Genome-wide screening for chromosomal aberrations was accomplished by comparative genomic hybridization (CGH). In addition, loss of heterozygosity analysis for polymorphic markers on chromosomal regions of the 2 most frequently observed DNA deletions was carried out. The most widespread genetic aberration was mutation of exon 7 of TP53, which was detected in 20 of 24 samples. Bidirectional sequencing revealed a mutation in codon 234 (TAC234TGC), resulting in an amino acid substitution Tyr-Cys. CGH analysis revealed losses on 2q11-q31 in 13 of 24 samples and losses on 19q13-qter in 10 of 24 samples from both left and right hemispheres. Allelic imbalances for markers on 2q (2q14.3 and 2q22.1) and 19q (both 19q13.2) were demonstrated in 10 of 24 and 18 of 24 samples, respectively. Other widespread chromosomal aberrations included losses on 3q13-qter and 16q22-qter and gains on 7q22-qter. The wide distribution of a particular set of genetic aberrations in this case supports the concept of monoclonal tumor proliferation. The results point to involvement of TP53 mutation in the tumorigenesis of gliomatosis cerebri.

No objective parameters have been found so far that can predict the biological behavior of early stages of prostatic cancer, which are encountered frequently nowadays due to surveillance and screening programs. We have applied comparative genomic hybridization to routinely processed, paraffin-embedded radical prostatectomy specimens derived from patients who participated in the European Randomized Study of Screening for Prostate Cancer. We defined a panel consisting of 36 early cancer specimens: 13 small (total tumor volume (Tv) < 0.5 ml) carcinomas and 23 intermediate (Tv between 0.5-1.0 ml) tumors. These samples were compared with a set of 16 locally advanced, large (Tv > 2.0 ml) tumor samples, not derived from the European Randomized Study of Screening for Prostate Cancer. Chromosome arms that frequently (ie, > or = 15%) showed loss in the small tumors included 13q (31%), 6q (23%), and Y (15%), whereas frequent (ie, > or = 15%) gain was seen of 20q (15%). In the intermediate cancers, loss was detected of 8p (35%), 16q (30%), 5q (26%), Y (22%), 6q, and 18q (both 17%). No consistent gains were found in this group. In the large tumors, loss was seen of 13q (69%), 8p (50%), 5q, 6q (both 31%), and Y (15%). Gains were observed of 8q (37%), 3q (25%), 7p, 7q, 9q, and Xq (all 19%). Comparison of these early, localized tumors with large adenocarcinomas showed a significant increase in the number of aberrant chromosomes per case (Rs = 0.36, P = 0.009). The same was true for the number of lost or gained chromosomes per case (Rs = 0.27, P: = 0.05; Rs = 0.48, respectively; P < 0.001). Interestingly, chromosomal alterations that were found in previous studies to be potential biomarkers for tumor aggressiveness, ie, gain of 7pq and/or 8q, were already distinguished in the small and intermediate cancers. In conclusion, our data show that chromosomal losses, more specifically of 6q and 13q, are early events in prostatic tumorigenesis, whereas chromosomal gains, especially of 8q, appear to be late events in prostatic tumor development. Finally, early localized tumors, as detected by screening programs, harbor cancers with aggressive genetic characteristics.

Over-representation of sequences on chromosome 7 and 8 have been reported to be associated with aggressive behavior of prostate cancer. In this study we have performed a molecular cytogenetic survey by comparative genomic hybridization of a cohort of 40 prostate cancer patients, consisting of 20 progressors and 20 nonprogressors, after radical surgery for localized adenocarcinoma. Progression was defined as a biochemical relapse, ie, an elevation in prostate-specific antigen level in the serum. The mean follow-up after prostatectomy for the progressor group was 10.6 years, for the nonprogressor group, 9.1 years. Using comparative genomic hybridization, we found that progressors harbored on average more aberrations than nonprogressors. Gains were especially more prominent among progressors (p < 0.05), whereas a statistical trend was detected for losses (p = 0.10). As a consequence we examined all chromosome arms separately. The frequencies of loss for areas known to be frequently deleted in prostate cancer, such as 6q, 8p, or 13q, were not different between the two groups. A tendency was observed for more frequent gain on 3q in the progressor group (p = 0.09). However, gain of 8q (minimal overlapping region at 8q24-qter) was significantly more frequent in the progressor group (p = 0.04). This biomarker retained its significance when adjusted for the factors age, tumor grade, tumor stage, resection margin status, and preoperative prostate-specific antigen level. In conclusion we have created a map of genetic changes in progressive and nonprogressive prostatic carcinomas. Importantly, the presence of gain of distal 8q markedly reduced the progression-free survival, suggesting a clinical role for 8q gain in assessing the malignant potential of localized prostatic adenocarcinoma.

In the present study the clinical data, histology, proliferation rate, DNA ploidy status and the results of TP53 mutation analysis and comparative genomic hybridization (CGH) of three typical cases of desmoplastic infantile astrocytoma and ganglioglioma are presented. Postoperative disease-free intervals of 11, 8 and 3 years were recorded and in none of the cases were radiological signs of tumor recurrence. No TP53 mutations (exons 5-8) were found. CGH analysis revealed loss of 8p22-pter in one case, while in another case gain of 13q21 was detected. In the case with the follow-up of 11 years an aneuploid DNA-flow cytogram along with slightly increased MIB-1 labeling index (LI) was found. The results demonstrate little genetic instability in these low-grade lesions. DNA-aneuploidy seems not to be indicative of tumor progression. It is concluded that the genetic aberrations found in desmoplastic infantile ganglioglioma differ from those encountered in common astrocytomas.

There is a need in The Netherlands to understand the future prospects of imaging techniques in cancer care to deal with current and expected capacity decisions. For this, a Delphi research was performed with a panel of 35 noted experts. The panel anticipates that the application of imaging techniques (e.g., CT, MRI, PET) will gradually change; especially, their use will also include earlier stages, i.e., cancer screening and treatment. The increasing need and investments for these techniques will be partly balanced by new developments (e.g., faster technology). There will be a substantial decrease in the use of ultrasound, CT (except for screening), and conventional radiographic diagnostics. Radical new techniques and/or developments are not expected. The panel foresees increasing partial task substitution and subspecialization. Further, a profound impact on imaging techniques is expected from developments outside the imaging field such as digitalization, changing patient demands, and commercialization.

In the present study, the distribution of genetic aberrations in a glioblastoma resection specimen of unusually large size (9x8x2 cm) was investigated using comparative genomic hybridization (CGH). CGH was performed on 20 samples taken from the specimen, and the genetic aberrations found were compared with the regional histology. The samples were histopathologically graded according to WHO criteria, and a division in high- and low-grade areas and infiltration rims was made. In high-grade areas, low-grade areas as well as infiltration rims, gains on 10p11.2-pter (14/20), 11q12-q22 (6/20) and losses on 4q13-qter (9/20), 10q22-qter (8/20), 11p14-pter (5/20), 13q12-qter (7/20) were revealed. Gains on 1q21-32 (2/4) and losses on 7p21-pter (3/4) were exclusively found in the high-grade areas. In the low-grade tumor samples and in the infiltration rim, gains on 16p11.2-pter (6/16), 17p11.2-pter (6/16), 17q11.2-qter (5/16), 20q11.2-q13 (3/16) and deletions on 5q31-qter (4/16) were detected. Gains on 7q21-qter (8/11) and 8q11.2-qter (6/11), and loss of chromosome 9 (4/11) and the Y-chromosome (4/11) were found in the high-grade and low-grade samples, not in the infiltration rims. The finding of a set of identical chromosomal aberrations throughout the resection specimen, most of which have been previously reported in gliomas, confirms a mechanism of clonal tumor proliferation operative in gliomas. The previously unreported genetic alterations which were predominantly traced in the tumor rims, might reflect either selection for properties related to infiltrating behavior, or genomic instability of subclones. The findings illustrate the importance of searching for high-grade genetic aberrations in low-grade tumor samples taken from cases in which sampling error is suspected.

Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies, especially in Asia and Africa, but also in the Western world its incidence is increasing. HCC is a complication of chronic liver disease with cirrhosis as the most important risk factor. Viral co-pathogenesis due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection seems to be an important factor in the development of HCC. Curative therapy is often not possible due to the late detection of HCC. Thus, it is attractive to find parameters which predict malignant transformation in HBV- and HCV-infected livers. In the past decade, preneoplastic lesions, i.e. dysplastic foci or nodules, have gained interest as possible markers for imminent malignancy. Noteworthy, dysplastic liver lesions are increasingly detected by imaging techniques. We describe here two cases of chronic viral liver disease, one HBV- and one HCV-related, in which dysplastic lesions were present adjacent to HCC. In the HBV case, a (smaller) satellite of HCC was present as well. The neoplastic specimens were investigated by comparative genomic hybridization (CGH) and in situ hybridization (ISH). Both methods revealed multiple genetic alterations in the HCCs. The genetic patterns of the HBV-related HCC and the satellite tumor showed many shared alterations suggesting a clonal relationship. A subset of genetic changes were already present in dysplasias illustrating their preneoplastic nature. Surrounding liver cirrhosis samples did not display chromosomal aberrations. A literature survey illustrates the relative paucity of information concerning genetic alterations in preneoplastic liver lesions. However, all the data strongly suggests a role for liver cell dysplasia as a precursor condition of liver cell cancer.

The accuracy of cytogenetic analyses of human solid cancers has improved enormously over the past decade by the introduction and refinement of DNA in situ hybridization (ISH) techniques. This methodology can be applied to cells in the interphase state, thereby making it an excellent tool for the delineation of chromosomal aberrations in solid tumors. The use of non-isotopic ISH to intact and disaggregated cancer specimens will be discussed, as well as comparative genomic hybridization (CGH) with tumor-derived DNAs. In this review we will focus on hybridocytochemical interphase approaches for the detection of chromosomal changes in frequently occurring human epithelial malignancies, e.g., breast, lung, and prostate carcinomas. We will further discuss the use of ISH procedures for the genetic analysis of precursor conditions leading to invasive carcinomas. Knowledge concerning these precancerous conditions is increasing, and its importance in cancer prevention has been recognized. Interphase cytogenetics by ISH, as well as CGH, with DNAs derived from microdissected, precancerous, dysplastic tissue areas will increase our understanding of these lesions, both at the investigative and diagnostic levels.