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Breast Cancer Study Highlights Germline Genetic Influence on Tumor Subtype, Aggressiveness

NEW YORK – New research suggests breast cancer subtypes and aggressiveness are influenced by the presence or absence of accumulated germline genetic variants. These variants lead to the formation of epitopes that individually have small effects but collectively prompt immune activity that nudges tumor evolution in a certain direction, particularly when the epitopes fall in driver genes prone to amplification in breast cancer.

The team's study, published in Science on Thursday, "explores how hereditary factors and immunity constrain the path to tumor development and sculpt disease progression," senior and corresponding author Christina Curtis, an oncology, genetics, and biomedical data science researcher at Stanford University School of Medicine and the Chan Zuckerberg Biohub, said in an email.

Together, the results suggested that "inherited genetic differences in cancer-related genes influence the subtype of disease a patient develops and its aggressiveness by modulating epitope burden … via immunoediting," Curtis said, meaning "tumor evolution is not random."

For their analyses, Curtis and colleagues from Stanford and Chan Zuckerberg relied on machine learning and analytical algorithms to analyze exome or whole-genome sequences for matched tumor and normal samples from 5,870 breast cancer cases profiled for efforts such as the Cancer Genome Atlas project or International Cancer Genome Consortium. The set included 4,918 primary breast cancer cases, 611 cases of metastatic breast cancer, and 341 cases of ductal carcinoma in situ (DCIS).

When the team focused on germline variant profiles in genes such as HER2 that are recurrently amplified somatically in breast cancer, it found that weak-effect epitopes stemming from genetic variants — dubbed the "germline epitope burden" (GEB) of the genes — corresponded with distinct tumor features and evolutionary trajectories.

Such relationships appear to reflect immunoediting directed against oncogenes with an enhanced GEB that, in turn, is influenced by an individual's human leukocyte antigen (HLA) type.

"Specifically, we find that hereditary variants in specific oncogenes, combined with a patient's HLA-type, sculpts the subtype of disease a patient is likely to develop and its aggressiveness," Curtis explained. "This includes HER2-positive subgroups and ER-positive subgroups with a persistent risk of relapse for up to two decades after diagnosis, both of which are fueled by distinct genomic copy number drivers."

In particular, the somatic amplification of HER2 or of genes linked to high-risk forms of ER -positive breast cancer appeared to be dialed down by immunoediting in pre-invasive DCIS samples with higher-than-usual oncogene GEB.

On the other hand, the presence of high GEB in combination with oncogene amplification in invasive or metastatic cases tended to coincide with more aggressive disease and a lymphocyte-depleted "immune cold" microenvironment, apparently reflecting the immune suppression that occurred as tumor cells dodged selective pressure exerted by the immune system earlier in the disease process.

"This switch during disease progression reflects a potential shift towards immune tolerance," Curtis explained, "and emphasizes the intricate balance between the tumor and host immune system, which co-evolve throughout the course of disease."

Based on these and other results, the investigators suggested oncogene GEB patterns may eventually serve as blood-based markers to help in teasing out breast cancer risk, disease trajectory, relapse risk, and potential treatment strategies, particularly in subgroups of HER2-positive and ER-positive breast cancers.

"These findings reveal mechanisms of immune suppression and have implications for the timing and type of therapeutic interventions," Curtis noted, adding that the new results "also inform a potential approach to stratify disease earlier to enable cancer interception."