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Invasive Breast Cancer Study Reveals Survival-associated Gene Set

NEW YORK (GenomeWeb News) – In a study published online last night in PLOS One, a Georgetown University-led team described a set of genes that are prone to mutation and copy number changes in breast cancers with poor outcomes.

Researchers detected the prognostic signature as part of an analysis of new and existing data on invasive breast cancers, which focused on forms of the disease marked by lower-than-usual levels of SYK — a non-receptor tyrosine kinase gene that's been implicated in creeping advance and invasiveness in past cancer studies.

In breast tumors with muted SYK expression, a set of 55 motility and invasion-associated genes showed frequent copy number changes or mutation, they reported. Moreover, the presence of such alterations appeared to be associated with reduced patient survival times.

"[R]eduction in Syk expression and contributions of genomic instability to copy number and mutations in the 55 Syk interacting genes significantly contribute to poorer overall patient survival," corresponding author Susette Mueller, an oncology researcher with Georgetown University's Lombardi Comprehensive Cancer Center, and colleagues wrote.

"A closer examination of the role of Syk interacting motility and invasion genes and their prognostic and/or causative association with metastatic disease and patient outcome is warranted," they added.

Past studies have highlighted contributions the Syk tyrosine kinase makes to immunity and cancer risk, the study's authors noted. In particular, its presence in epithelial cells appears to help staunch cellular proliferation and invasiveness, while diminished expression of SYK has been linked to cancer progression and spread in both mouse models and samples from patients with a range of cancer types.

For their new look at ties between SYK loss and cancer invasiveness, the researchers used a combination of bisulfite sequencing and fluorescent in situ hybridization to compare 19 ductal carcinoma in situ samples with a handful of normal or benign breast tissues. They also tapped genomic data from infiltrating ductal carcinoma, or IDC, samples that had been generated for more than 1,000 breast cancer cases as part of the Cancer Genome Atlas project.

The team saw signs of SYK copy number loss in just over one-quarter of the breast cancer cases considered in all and in almost one-third of IDC samples tested, though the Syk protein was sometimes found at elevated levels in immune cells intertwined with the epithelial tumor tissue.

When they focused in on genes regulated by SYK in TCGA data, the researchers identified 51 genes implicated in cellular invasion and motility-related processes that were also more apt to be mutated or affected by copy number changes in tumor samples from breast cancer patients with poor survival patterns.

By folding in alteration information on four more genes associated in some manner with the SYK network — including the well-known cancer contributor TP53 — the group got further prognostic refinement of this prognostic signature.

Within the set of TCGA tumors, genes in the signature were particularly prone to alteration in basal-like and Her2-positive breast cancers, researchers reported, with more than 90 percent of tumors from those sub-types containing changes involving the gene set.

Mutations or copy number shifts in the 55 genes were also detected in more than half of luminal A breast tumors, meanwhile, and almost 77 percent of tumors from the luminal B sub-type.

Nevertheless, the survival information that could be gleaned from the signature was specific to the luminal breast cancer cases, the study's authors noted, and did not significantly improve prognostic predictions in tumors belonging to the basal-like and Her2-positive sub-types.

In the latter sub-types, they explained, "the majority of basal-like and Her2 cases were already altered [with respect to the 55-gene set] so that a comparison of altered versus non-altered cases was not useful."

More generally, though, the researchers argued that the gene set "powerfully predicted poorer patient outcome when copy number and mutational alterations of one or more of these genes occurred."