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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.

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.

SUBMITTER: Huang X

PROVIDER: S-EPMC7662137 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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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.

Huang Xin X Shao Di D Wu Huanwen H Zhu Changbin C Guo Dan D Zhou Yidong Y Chen Chang C Lin Yan Y Lu Tao T Zhao Bin B Wang Changjun C Sun Qiang Q

Frontiers in oncology 20201030

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 nod ...[more]

PMID: 33194720

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Project description:We report a deep next-generation sequencing analysis of 13 sequentially obtained tumor samples, eight sequentially obtained circulating tumor DNA (ctDNA) samples and three germline DNA samples over the life history of 3 patients with triple-negative breast cancer (TNBC), 2 of whom had germline pathogenic BRCA1 mutation, to unravel tumor evolution. Tumor tissue from all timepoints and germline DNA was subjected to whole-exome sequencing (WES), custom amplicon deep sequencing (30,000X) of a WES-derived somatic mutation panel, and SNP arrays for copy-number variation (CNV), while whole transcriptome sequencing (RNA-seq) was performed only on somatic tumor.There was enrichment of homologous recombination deficiency signature in all tumors and widespread CNV, which remained largely stable over time. Somatic tumor mutation numbers varied between patients and within each patient (range: 70-216, one outlier). There was minimal mutational overlap between patients with TP53 being the sole commonly mutated gene, but there was substantial overlap in sequential samples in each patient. Each patient's tumor contained a founding ("stem") clone at diagnosis, which persisted over time, from which all other clones ("subclone") were derived ("branching evolution"), which contained mutations in well-characterized cancer-related genes like PDGFRB, ARID2, TP53 (Patient_02), TP53, BRAF, BRIP1, CSF3R (Patient_04), and TP53, APC, EZH2 (Patient_07). Including stem and subclones, tumors from all patients were polyclonal at diagnosis and during disease progression. ctDNA recapitulated most tissue-derived stem clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.SignificanceIn germline BRCA1 mutated and BRCA wild-type patients, TNBC shows a branching evolutionary pattern of mutations with a single founding clone, are polyclonal throughout their disease course, and have widespread copy-number aberrations. This evolutionary pattern may be associated with treatment resistance or sensitivity and could be therapeutically exploited.

Project description:Objective:To compare the efficacy of platinum- and non-platinum-based regimens as first-line treatment for advanced triple-negative breast cancer (TNBC) and analyze the relationship between their efficacy and BRCA gene status. Methods:Retrospectively analyze clinical data of 220 patients diagnosed pathologically with advanced TNBC and treated at the Department of Breast Oncology, Peking University Cancer Hospital from 2013 to 2018 and evaluate the efficacy of chemotherapy. A total of 114 patients had BRCA1/2 gene tested by next generation sequencing (NGS) using peripheral blood, and we analyzed the correlation between their efficacy and BRCA1/2 gene status. Results:Non-platinum-based chemotherapy (NPCT) was administered to 129 and platinum-based chemotherapy (PBCT) to 91 study patients. The clinical benefit rate (CBR) and median progression-free survival (PFS) were not statistically different between NPCT and PBCT groups. The median overall survival (OS) was 30.0 and 22.5 months for PBCT and NPCT group, respectively [P=0.090, hazard ratios (HR)=0.703]. BRCA status was assessed in 114 patients, 14 of whom had deleterious germline BRCA1/2 (gBRCA) mutations (seven in each group). In PBCT group, the CBR was 85.7% and 35.1% for patients with and without deleterious gBRCA mutations, respectively (P=0.039). The median PFS were 14.9 and 5.3 months and median OS were 26.5 and 15.5 months for patients with and without deleterious gBRCA mutations, respectively (P=0.001, P=0.161, respectively). Patients in PBCT group had significantly greater rates of grade 3-4 anemia (5.5%vs. 0%) and thrombocytopenia (8.8% vs. 0%), whereas palmar-plantar erythrodysesthesia (12.4% vs. 0%) and peripheral neuropathy (8.6% vs. 1.1%) occurred more frequently in NPCT group. Conclusions:Platinum-based regimens are more effective in patients with deleterious gBRCA mutations, but no difference in patients without BRCA gene mutations, so non-platinum is an option in patients without BRCA gene mutations considering the toxicity and side effect. And we recommend that patients with advanced TNBC should have BRCA gene test.

Project description:BackgroundBreast cancer development and progression involve both germline and somatic mutations. High-throughput genotyping and next-generation sequencing technologies have enabled discovery of genetic risk variants and acquired somatic mutations driving the disease. However, the possible oncogenic interactions between germline genetic risk variants and somatic mutations in triple-negative breast cancer (TNBC) and non-triple-negative breast cancer (non-TNBC) have not been characterized. Here, we delineated the possible oncogenic interactions between genes containing germline and somatic mutations in TNBC and non-TNBC and investigated whether there are differences in gene expression and mutation burden between the two types of breast cancer.MethodsWe addressed this problem by integrating germline mutation information from genome-wide association studies with somatic mutation information from next-generation sequencing using gene expression data as the intermediated phenotype. We performed network and pathway analyses to discover molecular networks and signalling pathways enriched for germline and somatic mutations.ResultsThe investigation revealed signatures of differentially expressed and differentially somatic mutated genes between TNBC and non-TNBC. Network and pathway analyses revealed functionally related genes interacting in gene regulatory networks and multiple signalling pathways enriched for germline and somatic mutations for each type of breast cancer. Among the signalling pathways discovered included the DNA repair and Androgen and ATM signalling pathways for TNBC and the DNA damage response, molecular mechanisms of cancer, and ATM and GP6 signalling pathways for non-TNBC.ConclusionsThe results show that integrative genomics is a powerful approach for delineating oncogenic interactions between genes containing germline and genes containing somatic mutations in TNBC and non-TNBC and establishes putative functional bridges between genetic and somatic alterations and the pathways they control in the two types of breast cancer.

Dataset Information

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.

Publications

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

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