Genomic Profiling Comparison of Germline BRCA and Non-BRCA Carriers Reveals CCNE1 Amplification as a Risk Factor for Non-BRCA Carriers in Patients With Triple-Negative Breast Cancer.

Xin Huang,Changjun Wang,Tao Lu,Changbin Zhu,Bin Zhao,Yidong Zhou,Huanwen Wu,Dan Guo,Yan Lin,Qiang Sun,Di Shao,Chang Chen

doi:10.3389/fonc.2020.583314

Abstract

Background: Differences in genomic profiling and immunity-associated parameters between germline BRCA and non-BRCA carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets.Methods: The study cohort included 21 consecutive TNBC cases with germline BRCA1/2 mutations and 54 non-BRCA carriers with a tumor size ≥ 2 cm and/or ≥1 affected lymph nodes. Differences in clinicopathological characteristics and genomic profiles were analyzed through next-generation sequencing. Univariate Kaplan–Meier analysis and Cox regression model were applied to survival analysis. Immunohistochemistry was used to confirm the consistency between CCNE1 amplification and cyclin E1 protein overexpression.Results: The cohort included 16 and five patients with germline BRCA1 and BRCA2 mutations, respectively. Patients with germline BRCA1/2 mutations were diagnosed at a significantly younger age and were more likely to have a family history of breast and/or ovarian cancer. Six non-BRCA carriers (11.11%) carried germline mutations in other cancer susceptibility genes, including five mutations in five homologous recombination repair (HRR) pathway genes (9.26%) and one mutation in MSH3 (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-BRCA and BRCA carriers, respectively. PIK3CA missense mutation (p = 0.046) and CCNE1 amplification (p = 0.2) were found only in the non-BRCA carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). BRCA status did not affect disease-free survival (DFS, p = 0.15) or overall survival (OS, p = 0.52). CCNE1 amplification was an independent risk factor for DFS in non-BRCA carriers with TNBC (HR 13.07, 95% CI 2.47–69.24, p = 0.003). Consistency between CCNE1 amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity.Conclusions: We found differences in genetic alterations between germline BRCA and non-BRCA carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

Highlights

Triple-negative breast cancer (TNBC) has been defined as a subtype of breast cancer negatively expressing estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [1], accounting for ∼15–20% of newly diagnosed breast cancer [2]
The prevalence of BRCA1/2 mutations in the current cohort of TNBC cases reached 24.1%, which was close to the reported rate of 21.4% in unselected Chinese populations [50], indicating that BRCA1/2 mutations were not related to high tumor burden or worse prognosis, in agreement with the findings of the POSH study [16]
Except for MSH3, the rest of the germline mutant genes in non-BRCA carriers with TNBC were involved in the homologous recombination repair (HRR) pathway, including BLM, PALB2, NBN, RAD51C, and RAD51D, with the mutation rate of 9.26% (5/54), which increased the risk of other cancers, such as PLAB2 for pancreatic cancer [53]

Summary

Introduction

Triple-negative breast cancer (TNBC) has been defined as a subtype of breast cancer negatively expressing estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [1], accounting for ∼15–20% of newly diagnosed breast cancer [2]. Testing for other breast cancer predisposition genes such as TP53, PTEN, and PLAB2 is still required to determine family history or specific clinical features [9, 10] compared with other cancer predisposition genes. Not all patients with germline mutations have a known family cancer history or specific clinical features, which results in about 50–80% of at-risk individuals not being successfully identified as such [11]. These criteria alone may not provide sufficient information for testing and assessment of other genetic cancer predisposition genes [12] in non-BRCA carriers with TNBC. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets

Objectives

Methods

Results

Discussion

Conclusion