Germline variants associated with leukocyte genes predict tumor recurrence in breast cancer patients

Abstract

Germline variants such as BRCA1/2 play an important role in tumorigenesis and clinical outcomes of cancer patients. However, only a small fraction (i.e., 5–10%) of inherited variants has been associated with clinical outcomes (e.g., BRCA1/2, APC, TP53, PTEN and so on). The challenge remains in using these inherited germline variants to predict clinical outcomes of cancer patient population. In an attempt to solve this issue, we applied our recently developed algorithm, eTumorMetastasis, which constructs predictive models, on exome sequencing data to ER+ breast (n = 755) cancer patients. Gene signatures derived from the genes containing functionally germline variants significantly distinguished recurred and non-recurred patients in two ER+ breast cancer independent cohorts (n = 200 and 295, P = 1.4 × 10−3). Furthermore, we compared our results with the widely known Oncotype DX test (i.e., Oncotype DX breast cancer recurrence score) and outperformed prediction for both high- and low-risk groups. Finally, we found that recurred patients possessed a higher rate of germline variants. In addition, the inherited germline variants from these gene signatures were predominately enriched in T cell function, antigen presentation, and cytokine interactions, likely impairing the adaptive and innate immune response thus favoring a pro-tumorigenic environment. Hence, germline genomic information could be used for developing non-invasive genomic tests for predicting patients’ outcomes in breast cancer.

Plasma exosome-derived microRNAs expression profiling and bioinformatics analysis under cross-talk between increased low-density lipoprotein cholesterol level and ATP-sensitive potassium channels variant rs1799858

“…Germline variants influence clinic outcomes of complex disease. Recent studies found that functionally mutations of natural killer cells were positively associated with cancer risk [7,8]. Similarly, in our previous study found that the KATP SNP rs1799858 was associated with increased risk of elevated LDL-C serum concentration (≥ 1.8 mmol/L) and its related macro-/micro-vascular arteriosclerotic events.…”

<p>Construction and Analysis of a Long Non-Coding RNA-Associated Competing Endogenous RNA Network Identified Potential Prognostic Biomarkers in Luminal Breast Cancer</p>

“…21,22 Further, germline mutations can also predict tumor recurrence in breast cancer patients. 38 In the present study, we used ceRNA to detect and validate potential prognostic lncRNAs in the luminal BC.…”

A Multi-Gene Model Effectively Predicts the Overall Prognosis of Stomach Adenocarcinomas With Large Genetic Heterogeneity Using Somatic Mutation Features

“…Besides somatic mutation signatures, germline variants could also be associated with tumor prognosis. Recently, Milanese et al reported different germline variants in recurred and non-recurred patients of breast cancers ( Milanese et al, 2019 ). These signature germline variants could potentially facilitate the formation of the pro-tumorigenic environment by impairing adaptive and innate immune pathways and could be used for prediction of breast cancer outcomes ( Milanese et al, 2019 ).…”

“…Recently, Milanese et al reported different germline variants in recurred and non-recurred patients of breast cancers ( Milanese et al, 2019 ). These signature germline variants could potentially facilitate the formation of the pro-tumorigenic environment by impairing adaptive and innate immune pathways and could be used for prediction of breast cancer outcomes ( Milanese et al, 2019 ). In another study, Xu et al (2019) observed negative associations between the number of germline defective genes in natural killer cells and survival time in a variety of cancer types.…”