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Triple-Negative Breast Cancer Mutations, Subtypes Profiled in Chinese Patients

NEW YORK (GenomeWeb) – A team from China and the US has characterized genomic and transcriptomic features in triple-negative breast cancer (TNBC) cases from China, identifying TNBC expression subtypes and somatic alterations that appear to be particularly common in this population.

"Our findings advance the understanding of TNBC subtypes, subdivide the established transcriptome-based subtypes in search of more targeted therapeutic strategies, and offer potential insights to guide subtype-specific therapy," senior author Zhi-Ming Shao, chairman of the Fudan University Shanghai Cancer Center's surgery and breast surgery departments, and his colleagues wrote in a study published online today in Cancer Cell.

Using a combination of RNA sequencing, exome sequencing, and/or array-based copy number profiling, the researchers assessed 465 primary TNBCs from female patients enrolled at the Fudan University Shanghai Cancer Center. In the process, they found recurrent alterations as well as four expression-based TNBC subtypes, including a luminal androgen receptor subtype prone to ERBB2 mutations, loss of CDKN2A, and other alterations that appeared to be over-represented in the Chinese TNBC cases relative to results reported from the Cancer Genome Atlas.

Likewise, the team noted that mutations in PIK3CA and chromosome 22 gains appeared to turn up more frequently in the TNBC cohort from China than in groups of TNBC patients profiled previously from other populations. The PIK3CA mutations turned up in 18 percent of the newly analyzed Chinese cases, for example, compared to 5 percent of TNBCs in African American patients from TCGA and 10 percent of TCGA TNBC cases overall.

"While primary TNBC continues to be typically treated as a single disease, genomic findings suggest marked heterogeneity, and our data reinforce the distinct mutational, copy number, and transcriptional features of TNBC subtypes," the authors reported.

Although TNBCs that lack estrogen receptor, progesterone receptor, and EGFR2 expression are known for their heterogeneity, aggressiveness, and poor outcomes, the team explained, relatively few targetable genetic alterations have been identified so far and most patients are still treated with chemotherapy.

"To date, genomic studies of TNBC have mainly focused on [messenger RNA] expression and DNA copy number, which have provided limited insight into the biological underpinnings, especially the genomic signatures of this disease," the authors wrote, noting that initial findings from the TCGA did include multiple genomic analyses for more than 100 tumors, but lacked formal clinical evaluations.

In an effort to untangle genomic and transcriptomic ties to clinical outcomes in a large group of Chinese women with TNBC, the researchers started with 504 female patients treated consecutively for TNBC at the Fudan University Shanghai Cancer Center. After their initial quality control steps, they were left with 465 primary TNBC cases treated surgically at some point between 2007 and 2014.

Of those, the team assessed 401 cases with array-based CNV analyses, did RNA sequencing on 360 tumors, and profiled tumor and matched normal samples from 279 cases with exome sequencing. During the nearly 46 months of median follow-up, 65 of the TNBC patients had a relapse or developed metastatic disease.

The researchers uncovered more than 24,000 single-nucleotide variants and nearly 1,700 small insertions and deletions in the exome-sequenced tumors, including recurrent mutations affecting genes such as TP53 and PIK3CA.

From the copy number profiles, the team saw recurrent alterations affecting MYC, E2F3, IRS2, and other genes, while the available RNA sequence data pointed to four transcriptomic subtypes: a group of luminal androgen receptor tumors, an immunomodulatory subtype, a subtype known as basal-like immune-suppressed TNBCs, and a mesenchymal TNBC subtype.

Nearly one-quarter of the Chinese TNBC tumors — 23 percent — fell in the luminal androgen receptor subtype, the researchers reported. In contrast, just 9 percent of TNBC tumors from African American patients profiled for TCGA and 12 percent of Caucasian TNBCs from TCGA were placed in the luminal androgen receptor subtype.

Along with its integrated analysis of the TNBC copy number, expression, and mutation profiles and searches for prognostic signatures in the Chinese patients, the team looked at alterations with potential therapeutic implications — from recurrent ERBB2 or CDKN2 mutations that might be susceptible to targeted treatment to immune checkpoint treatment approaches that might apply to the immunomodulatory subtype.

"While representing an important validation of previous molecular profiling studies on TNBC, our study highlights some potential targets and biomarkers within specific subgroups that might have been missed by smaller studies," the authors wrote, noting that "increasing genomic precision by categorizing the TNBC population into corresponding subtypes would lead to improved targeted therapies that would benefit more TNBC patients."