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

TITLE=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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.583314

DOI=10.3389/fonc.2020.583314

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> Differences in genomic profiling and immunity-associated parameters between germline <italic>BRCA</italic> and non-<italic>BRCA</italic> carriers in TNBC with high tumor burden remain unexplored. This study aimed to compare the differences and explore potential prognostic predictors and therapeutic targets.</p><p><bold>Methods:</bold> The study cohort included 21 consecutive TNBC cases with germline <italic>BRCA1/2</italic> mutations and 54 non-<italic>BRCA</italic> 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 <italic>CCNE1</italic> amplification and cyclin E1 protein overexpression.</p><p><bold>Results:</bold> The cohort included 16 and five patients with germline <italic>BRCA1</italic> and <italic>BRCA2</italic> mutations, respectively. Patients with germline <italic>BRCA1/2</italic> 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-<italic>BRCA</italic> 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 <italic>MSH3</italic> (1.85%). Somatic mutations in HRR pathway genes were found in 22.22 and 14.29% of the non-<italic>BRCA</italic> and <italic>BRCA</italic> carriers, respectively. <italic>PIK3CA</italic> missense mutation (<italic>p</italic> = 0.046) and <italic>CCNE1</italic> amplification (<italic>p</italic> = 0.2) were found only in the non-<italic>BRCA</italic> carriers. The median tumor mutation burden (TMB) was 4.1 Muts/Mb, whereas none of the cases had high microsatellite instability (MSI). <italic>BRCA</italic> status did not affect disease-free survival (DFS, <italic>p</italic> = 0.15) or overall survival (OS, <italic>p</italic> = 0.52). <italic>CCNE1</italic> amplification was an independent risk factor for DFS in non-<italic>BRCA</italic> carriers with TNBC (HR 13.07, 95% CI 2.47–69.24, <italic>p</italic> = 0.003). Consistency between <italic>CCNE1</italic> amplification and cyclin E1 protein overexpression was confirmed with an AUC of 0.967 for cyclin E1 signal intensity.</p><p><bold>Conclusions:</bold> We found differences in genetic alterations between germline <italic>BRCA</italic> and non-<italic>BRCA</italic> carriers with TNBC and a high tumor burden. TMB and MSI may not be suitable predictors of TNBC for immune checkpoint inhibitors. Notably, <italic>CCNE1</italic> amplification is a novel potential prognostic marker and therapeutic target for non-<italic>BRCA</italic> carriers with TNBC. Cyclin E1 may be used instead of <italic>CCNE1</italic> to improve clinical applicability.</p>