DNA copy number profiles of gastric cancer precursor lesions.

BACKGROUND: Chromosomal instability (CIN) is the most prevalent type of genomic instability in gastric tumours, but its role in malignant transformation of the gastric mucosa is still obscure. In the present study, we set out to study whether two morphologically distinct categories of gastric cancer precursor lesions, i.e. intestinal-type and pyloric gland adenomas, would carry different patterns of DNA copy number changes, possibly reflecting distinct genetic pathways of gastric carcinogenesis in these two adenoma types. RESULTS: Using a 5K BAC array CGH platform, we showed that the most common aberrations shared by the 11 intestinal-type and 10 pyloric gland adenomas were gains of chromosomes 9 (29%), 11q (29%) and 20 (33%), and losses of chromosomes 13q (48%), 6(48%), 5(43%) and 10 (33%). The most frequent aberrations in intestinal-type gastric adenoma were gains on 11q, 9q and 8, and losses on chromosomes 5q, 6, 10 and 13, whereas in pyloric gland gastric adenomas these were gains on chromosome 20 and losses on 5q and 6. However, no significant differences were observed between the two adenoma types. CONCLUSION: The results suggest that gains on chromosomes 8, 9q, 11q and 20, and losses on chromosomes 5q, 6, 10 and 13, likely represent early events in gastric carcinogenesis. The phenotypical entities, intestinal-type and pyloric gland adenomas, however, do not differ significantly (P = 0.8) at the level of DNA copy number changes.

Identification of the human/mouse syntenic common fragile site FRA7K/Fra12C1--relation of FRA7K and other human common fragile sites on chromosome 7 to evolutionary breakpoints.

Common fragile sites (CFSs) are expressed as chromosome gaps in cells of different species including human and mouse as a result of the inhibition of DNA replication. They may serve as hot spots for DNA breakage in processes such as tumorigenesis and chromosome evolution. Using multicolor fluorescence in situ hybridization mapping, the authors describe here human CFS FRA7K on chromosome band 7q31.1 and its murine homolog Fra12C1. Within the syntenic FRA7K/Fra12C1 region lies the IMMP2L/Immp2l gene with a size of 899/983 kb. The authors further mapped 2 amplification breakpoints of the breast cancer cell line SKBR3 to the CFSs FRA7G and FRA7H. The 5 molecularly defined CFSs on chromosome 7 do not preferentially colocalize with synteny breaks between the human and mouse genomes and with intragenomic duplications that have occurred during chromosome evolution. In addition, in contrast to all currently reported data, CFSs in chromosome band 7q31 do not show increased DNA helix flexibility in comparison with control regions without CFS expression.

Small reciprocal insertion detected by spectral karyotyping (SKY) and delimited by array-CGH analysis.

A 5.4-year-old male propositus is reported with mild dysmorphic features including hypoplasia of the radial part of both hands affecting thenar, thumb and fingers 2-3, incomplete syndactyly of fingers 3-4, single palmar creases, brachymesophalangia of toes 3-5, dissociated retardation of bone age, telecanthus, spina bifida occulta, cryptorchidism, muscular hypotonia, and borderline mental retardation. His karyotype was unbalanced, 46,XY,der(16)ins(4;16)(q26q28.1; q12.1q12.2)pat. In the propositus' father who had brachydactyly of fingers 2-5 and brachymesophalangia of toes 3-5 the insertion was reciprocal, 46,XY,rep ins(4;16)(q26q28.1;q12.1q12.2). Insertions are rare, reciprocal insertions most unusual. The characterization of the insertion in the propositus and the detection of its reciprocity in the father were achieved by the application of spectral karyotyping (SKY). Further examination of the propositus' unbalanced genome by array-CGH analysis delimited the chromosomal locations of the deletion/insertion rearrangement on a 0.5-2 Mb resolution level and allowed to design specific BAC FISH analyses that pinpointed the borders of the affected segments. The rearrangement involved a segment of 7.7 Mb between RP11-1030 g22 and RP11-52k8 at the chromosomal regions 4q26 and 4q28.1, respectively, and a segment of 2.8 Mb between RP11-242n20 at 16q12.1 and RP11-324d17 at 16q12.2. A simple molecular genetic explanation of the phenotype cannot be given. A relation to the Townes Brocks gene (SALL1) located 340 kb proximal of the 16q12 deletion/insertion is unlikely. Possibly more relevant is an overlap of the 16q12 deletion/insertion with a small deletion of the syntenic chromosomal region in the mouse that causes a developmental disorder of digits ("Fused toes").

High-resolution analysis of chromosomal imbalances using the Affymetrix 10K SNP genotyping chip.

Array-based comparative genome hybridization is a powerful tool for detecting chromosomal imbalances at high resolution. However, the design and setup of such arrays are time consuming and expensive and thus worthwhile only when large numbers of arrays will be processed. To provide a feasible solution, we have developed an algorithm that renders the publicly available Affymetrix 10K SNP genotyping chip useful for high-resolution analysis of chromosomal imbalances. We have used our newly developed algorithm to analyze data from Affymetrix 10K chips that were hybridized with DNA probes from a variety of different sources, such as primary tumors, cell lines, and blood from patients with unbalanced translocations. In summary, we were able to (i) demonstrate the capability of our method by reproduction of published and unpublished data obtained with alternative methods and (ii) identify novel imbalances that were not shown before.