Tandem duplication of chromosomal segments is common in ovarian and breast cancer genomes

Abstract

The application of paired-end next generation sequencing approaches has made it possible to systematically characterize rearrangements of the cancer genome to base-pair level. Utilizing this approach, we report the first detailed analysis of ovarian cancer rearrangements, comparing high-grade serous and clear cell cancers, and these histotypes with other solid cancers. Somatic rearrangements were systematically characterized in eight high-grade serous and five clear cell ovarian cancer genomes and we report here the identification of > 600 somatic rearrangements. Recurrent rearrangements of the transcriptional regulator gene, TSHZ3, were found in three of eight serous cases. Comparison to breast, pancreatic and prostate cancer genomes revealed that a subset of ovarian cancers share a marked tandem duplication phenotype with triple-negative breast cancers. The tandem duplication phenotype was not linked to BRCA1/2 mutation, suggesting that other common mechanisms or carcinogenic exposures are operative. High-grade serous cancers arising in women with germline BRCA1 or BRCA2 mutation showed a high frequency of small chromosomal deletions. These findings indicate that BRCA1/2 germline mutation may contribute to widespread structural change and that other undefined mechanism(s), which are potentially shared with triple-negative breast cancer, promote tandem chromosomal duplications that sculpt the ovarian cancer genome.

Figure 1

Genomic rearrangements of 13 ovarian cancer genomes. The chromosomes of the reference genome are drawn around the circumference of each circos plot . Rearrangements are represented by lines linking somatically acquired breakpoints: orange, fold back inversions; light blue, one or both end map to an amplicon; purple, translocations; green, inversions; red, tandem duplications; dark blue, deletions. BRCA1/2 mutation status or mechanism of inactivation indicated

Figure 2

(A) Wild-type TSHZ3 locus (top) and schematics of the three rearrangements identified by next-generation sequencing. (B) Tissue microarray images of four cases with varying TSHZ3 rearrangements: (1) loss of the 5′ end of TSHZ3 with example of locus without rearrangement indicated by a white arrow; (ii) balanced break; (iii) amplification; and (iv) breakage with amplification of the 3′ end of TSHZ3. Green, BAC probes RP11-280H11 and RP11-241C16 (5′ TSHZ3); red, RP11-161K19 and RP11-164O11 (3′ TSHZ3). (C) Affymetrix SNP 6.0 copy number data for tumour sample PD7231a, showing multiple focal amplifications incorporating CCNE1 and TSHZ3. (D) Scatter plot of TSHZ3 expression by gene copy number status, where amplification is > three copies. (E) Scatter plot showing TSHZ3 gene expression by qRT–PCR (left) and gene expression microarray (right) in rearranged tumours (open circles) compared to samples without gene rearrangement (closed circles)