Abstract PS18-41: Somatic mutational landscapes of invasive ductal and lobular carcinomas in the GENIE consortium cohort: Real-world gene actionability assessment of 8,756 breast cancer patients
Authors: Leal Alessandro , Taranto Patricia , Blasi Poliana BG , Garrote Carlos Tadeu , Moura Fernando 
Published: February 2021

Abstract
Background: Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of the breast typically present distinct clinicopathological characteristics and responsiveness to systemic therapy. In addition, breast cancer data from The Cancer Genome Atlas (TCGA) have shown these two pathological subtypes also present distinct genomic features when analyzed using DNA copy number arrays and whole exome sequencing platforms. More recently, the AACR Project GENIE Consortium, which is a publicly accessible international cancer registry of real-world data assembled through data sharing among leading cancer centers in the world, have allowed in-depth analyses of clinical actionability using patient-level data from clinical next-generation sequencing (NGS) assays. In this study, we assessed the somatic mutational landscapes of a large cohort (n = 8,756) of invasive breast carcinomas from 19 institutions participating in the GENIE Consortium Cohort (v8.0) and examined clinical actionability of unique mutations identified in each breast cancer subtype. Method: We assessed the eighth data release of the GENIE Consortium Cohort encompassing targeted sequencing data from 7,647 IDC and 1,109 ILC cases. Clinical features and somatic mutations including single-nucleotide variants, small indels, fusions, and copy number alterations (CNAs) were retrieved from cBioportal and SAGE Bionetworks. Gene actionability was examined using both OncoKB and CiVIC publicly available knowledgebases. All patient samples were de-identified and encoded with GENIE sample codes. Results: Patients with IDC tumors were 5 years younger than patients with ILC tumors at the time sequencing data was reported (median 55 versus median 60 years old, Kruskal-Wallis, p &lt; 10e-10). Both IDC and ILC had on average 2 mutations per tested sample. Overall, IDC and ILC tumors had median fractions of 22% and 14% of their genomes altered, respectively (Kruskal-Wallis, p &lt; 10e-10). An initial gene enrichment analysis including 938 genes with point mutations and small indels identified CDH1 [Log-ratio (LR) 4.66, p &lt; 1e-10], RHOA (LR 2.81, p = 1.3e-10), PTK2B (LR 2.68, p = 5.2e-4), ERBB2 (LR 1.80, p &lt; 1e-10), TBX3 (LR 1.72, p &lt; 1e-10), FOXA1 (LR 1.49, p = 2.5e-10) and RUNX1 (LR 1.25, p = 3.1e-9) as genes significantly enriched in ILC tumors. On the other hand, mutations in GATA3 (LR = 1.67, p &lt; 1e-10) and TP53 (LR = 1.55, p &lt; 1e-10) were significantly enriched in IDC tumors. A further gene enrichment analysis for copy-number alterations in 1139 genes showed amplification in PARP1 (LR 1.55 p = 2.5e-3) and deep deletions in IKZF1 (LR 2.8, p = 2.2e-3) and CDH1 (LR = 1.88, p = 1.7e-4) as the most enriched genes with CNAs in ILC. In parallel, amplifications in AURKA (LR 3.2, p = 1e-8), PPM1D (LR 3.1, p &lt;1e-10), RAD51C (LR 2.85, p = 3.8e-8), BRIP1 (LR 2.66, p &lt; 1e-10), ERBB2 (LR 1.65, p = 1e-10), MYC (LR 1.64, p = 1e-10), CDK12 (LR 1.55, p = 2.6e-9), and COL22A1 (LR 1.19, p = 1.6e-5), and deep deletion in CDKN2A (LR 2.1, p = 1.9e-6) were enriched in IDC tumors. Among those enriched alterations for each histological subtype, the knowledgebase CiVIC did not present curated data available for genes TBX3, FOXA1, GATA3, COL22A1, BRIP1, PPM1D, and RAD51C. OncoKB only missed genes PTK2B and COL22A1. Conclusions: Real-world genomic data from the GENIE Consortium Cohort support that breast cancer presents distinct mutational landscapes for IDC and ILC tumors. For each histological subtype, we confirmed there are different levels of enrichments for shared mutations in actionable genes. Despite the fact that publicly available knowledgebases present comprehensive curated information about commonly mutated genes in cancer, we noticed that actionability data of important cancer driver genes were missed.
Citation Format: Alessandro Leal, Patricia Taranto, Poliana BG Blasi, Carlos Tadeu Garrote, Fernando Moura. Somatic mutational landscapes of invasive ductal and lobular carcinomas in the GENIE consortium cohort: Real-world gene actionability assessment of 8,756 breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-41.