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HER2-Positive Breast Cancer Heterogeneity Revealed in Genomic, Transcriptomic Patterns

NEW YORK (GenomeWeb) – A study appearing today in Nature Communications explored the genetic diversity present in HER2-positive breast cancers, which have enhanced expression of the human epidermal growth factor receptor 2.

Members of the International Cancer Genome Consortium's Cancer Working Group did genome sequencing on 64 sets of tumor and matched normal samples from individuals with HER2-positive breast cancers. From these sequences — together with array-based gene expression profiles for 99 more HER2-positive breast tumors — they identified four subtypes within the HER2-positive cancer group.

Even so, the team's analyses indicated that the broader features of these tumors tend to place them across a wide range of clinical subtypes for breast cancer.

Based on these results, the study's authors argued that HER2-positive breast cancers do not necessarily represent an intrinsic breast cancer subtype. Rather, they explained, these tumors seem to span subtypes as diverse as estrogen receptor-positive luminal breast cancers to estrogen receptor-negative basal breast cancers.  

Starting with frozen samples from nearly 300 women diagnosed with HER2-positive breast cancer in France, the researchers focused on 99 HER2-positive tumors for Affymetrix array-based gene expression profiling.

The team used paired-end sequencing on Illumina HiSeq 2000 or 2500 instruments to do whole-genome sequencing on a subset of the samples, including tumor-matched normal pairs from 64 HER2-positive women.

From the gene expression data, the researchers found four HER2-positive tumor subgroups: two groups of estrogen receptor-positive luminal B tumors and two groups without enhanced estrogen receptor expression, including one group housing all of the tumors from the basal subtype.

When the team included information on somatic mutations, small insertions and deletions, and copy number variants, it found that an over-representation of CCND1 and RPS6KB1 amplifications in one of the ER-positive, luminal groups, for example, but a dearth of TP53 mutations. On the other hand, mutations in TP53 were more common in the two ER-negative tumor clusters.

"Although patients with HER2+ [breast cancer] benefit from HER2-targeted therapies, the response is highly variable and a significant number of patients display primary or secondary resistance," the team noted. "Heterogeneity of these cancers may explain the extent of this variability."

The researchers also got a refined look at the stretch of sequence that's affected when ERBB2 gets amplified in HER2-positive tumors, using copy number clues from the whole-genome sequence data. In at least some of the tumors, for example, they saw evidence that such amplicons arose from a so-called breakage-fusion-bridge mutational mechanism in which double-strand breaks in chromosomes are improperly repaired through fusion with sister chromatids.