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Belgian Team Identifies Marker Associated with Triple Negative Breast Cancers Using Array CGH

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NEW YORK (GenomeWeb) – Researchers have used microarrays to pinpoint a chromosomal gain associated with BRCA1 mutated triple negative breast cancers that could serve as a target for therapeutics in the future.

Led by investigators at the Institute of Pathology and Genetics at Grand Hôpital de Charleroi in Gosselies, Belgium, the researchers analyzed more than a hundred formalin-fixed, paraffin-embedded DNA samples with known BRCA1 mutation status using CGH arrays.

A "highly significant and recurrent gain" was tagged in the 17q25.3 genomic region, and confirmed following further analysis by fluorescence in situ hybridization. The researchers also found overexpression of more than a dozen genes in the region using custom Taqman arrays.

The findings are detailed in a recent paper in the journal Breast Cancer Research.

"Beyond the amplicon, the most significant findings in our paper are the genes present in the 17q25.3 region, especially those with a demonstrated increase in expression in BRCA1-mutated breast cancers compared to non-mutated tumors," lead author Sébastien Toffoli told GenomeWeb.

"Those genes could play an important role in tumor development, and some of them are already known to be involved in cancer cell survival," Toffoli said.

According to the paper, triple negative breast cancers represent between an eighth and a fifth of all breast cancers and have a worse outcome compared to other breast cancer subtypes. Triple negative breast cancers typically show a deficiency in DNA double-strand break repair mechanisms related to the inactivation of a repair enzymatic complex involving BRCA1, which is caused either by genetic mutations, epigenetic modifications, or by post-transcriptional regulations.

The aim of the researchers therefore was to identify new markers that could allow the quick identification of breast cancer patients presenting a BRCA1 deficiency. With such information in hand, clinicians could then select patients who could best benefit from PARP inhibitors, alkylating agents, or platinum-based chemotherapy.

As detailed in the paper, the investigators collected genomic DNA from 131 FFPE tumor samples with known BRCA1 mutation status or unscreened for BRCA1 mutation. The samples were then analyzed using Agilent Technologies SurePrint G3 Human CGH Microarrays.

Toffoli said that the project discussed in the paper began in 2011, when next-generation sequencing was still "in its infancy," and sequencing techniques were "very expensive and rather slow." Array CGH "thus appeared as a good compromise, considering the costs and the speed of this technique," he said. As the IPG at Grand Hôpital de Charleroi already had an Agilent platform and performed array CGH routinely, the platform was "a natural choice."

SNP arrays were not selected for the effort "because Agilent SNP arrays are not compatible with FFPE samples, which were used in our study," Toffoli said. Overall, he said that the researchers' experience with the Agilent chips was "quite good," as protocols for CGH array analysis from FFPE samples had already been established, and "their protocols work well." Toffoli also praised Agilent's Genomic Workbench software, which he described as "flexible," given the amount of algorithms that could be used and parameters that could be changed manually.

The gain identified in the study in the 17q25.3 genomic region was found to be present in 90 percent of the BRCA1-mutated tumors, according to the paper, whereas the same chromosomal gain was present in only 28.6 percent of BRCA1 non-mutated triple negative breast cancer samples, 26.7 percent of unscreened triple negative breast cancer samples, 13.6 percent of the luminal B samples, 19 percent of HER2+ samples, and none of the luminal A breast cancer samples used for comparison in the study.

The 17q25.3 gain was also detected in half of the triple negative breast cancer samples with BRCA1 promoter methylation, though BRCA1 promoter methylation was never detected in the BRCA1-mutated breast cancer samples.

The investigators also used Taqman arrays to profile gene expression in the 17q25.3 sub-region, which demonstrated "significant overexpression" of 17 genes in BRCA1 mutated triple negative breast cancer samples, up-regulated genes that "might represent potential therapeutic targets and warrant further investigation," the authors noted.

Such research is already being initiated, Toffoli said. "We plan to study the role of the genes of the 17q25.3 sub-region in BRCA1-mutated breast cancer cells, and  we will obviously focus our attention on cell proliferation and survival," he said.

Toffoli noted that the researchers intend to use CGH arrays as part of these follow-up studies, as well as other assays, but declined to elaborate.

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