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Breast Cancer Substitution Signatures Associated With Immune Cell Response

NEW YORK (GenomeWeb) – A new study suggests that specific types of mutations in breast cancer may be just as important as overall mutational load in prompting an immune response from tumor-infiltrating lymphocyte immune cells.

As they reported today in Nature Communications, researchers from Erasmus University Medical Center and other centers around the world turned to genome and transcriptome data for nearly 300 breast cancer samples in an effort to examine ties between subtype-specific mutation or rearrangement signatures, gene expression shifts, and immune cell response patterns. Their results highlighted two substitution signatures that were closely tied to tumor-infiltrating lymphocyte response in the estrogen receptor-positive tumors.

"[W]hile earlier reports imply that the sheer number of somatic aberrations could trigger an immune-response," the authors wrote, "our data suggests that substitutions of a particular type are more effective in doing so than others."

The team brought together new and available genome sequence, copy number, methylation, RNA sequence, and microRNA sequence data for 266 individuals with breast cancer — 191 estrogen receptor (ER)-positive/HER2-negative cases and 75 triple negative cases.

Based on patterns for some 5,000 transcripts with pronounced expression differences across the sample set, the researchers clustered the tumors into five expression-based subtypes. They noted, for example, that more than 90 percent of the ER-negative samples fell into the basal-like intrinsic expression subtype.

The basal-like tumors, marked by TP53 mutations and amplifications in MYC or other driver genes, also tended to have higher-than-usual substation rates. On the other hand, CCND1 amplifications and mutations in the PIK3CA and GATA3 genes tended to turn up in tumors from the luminal subtypes, which spanned four of the expression clusters.

Along with analyses relating river amplifications, deletions, or mutations to gene expression, the team looked at the pathways that were most pronounced in various breast cancer subtypes. While cell cycle-related processes tended to show transcriptome shifts in substitution-rich, ER-positive tumors, for example, the tumors with substitution signatures related to APOBEC family cytidine deaminase enzymes were linked to immune response pathway expression.

Across the set of ER-positive tumors, the researchers found that tumor-infiltrating cell signatures were over-represented in tumors with higher-than-usual levels of APOBEC-related substitution signatures called signature 3 and signature 13. But they did not detect clear ties between tumor-infiltrating lymphocyte-related gene expression and the overall mutation burdens in the tumors.

The team also saw hints that the cases marked by enhanced expression of tumor-infiltrating lymphocyte genes but low cell cycle gene expression tended to coincide with better clinical outcomes than tumors with the opposite patterns — results that were subsequently validated in another 625 breast cancer cases.

And it was substitution signatures rather than mutational load that seemed to correspond with actual immune cells infiltration of the ER-positive tumor set, the researchers reported, though the reason for such associations remains unclear.

"[B]y untangling the mutational load into specific signatures, our results suggest that the breast tumor cell, while gaining advantage by those mutations stimulating proliferation, may inadvertently provoke the immune system more effectively if the mutational load is molded through specific mutational process," the authors speculated.