Comprehensive characterization of distinct genetic alterations in metastatic breast cancer across various metastatic sites

Soojin Cha,Hong-Hee Won,Esak Lee

doi:10.1038/s41523-021-00303-y

Soojin Cha, Hong-Hee Won + Show 1 more

Open Access

https://doi.org/10.1038/s41523-021-00303-y

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Abstract

Metastasis is the major cause of death in breast cancer patients. Although previous large-scale analyses have identified frequently altered genes specific to metastatic breast cancer (MBC) compared with those in primary breast cancer (PBC), metastatic site-specific altered genes in MBC remain largely uncharacterized. Moreover, large-scale analyses are required owing to the low expected frequency of such alterations, likely caused by tumor heterogeneity and late dissemination of breast cancer. To clarify MBC-specific genetic alterations, we integrated publicly available clinical and mutation data of 261 genes, including MBC drivers, from 4268 MBC and 5217 PBC patients from eight different cohorts. We performed meta-analyses and logistic regression analyses to identify MBC-enriched genetic alterations relative to those in PBC across 15 different metastatic site sets. We identified 11 genes that were more frequently altered in MBC samples from pan-metastatic sites, including four genes (SMARCA4, TSC2, ATRX, and AURKA) which were not identified previously. ARID2 mutations were enriched in treatment-naïve de novo and post-treatment MBC samples, compared with that in treatment-naïve PBC samples. In metastatic site-specific analyses, associations of ESR1 with liver metastasis and RICTOR with bone metastasis were significant, regardless of intrinsic subtypes. Among the 15 metastatic site sets, ESR1 mutations were enriched in the liver and depleted in the lymph nodes, whereas TP53 mutations showed an opposite trend. Seven potential MBC driver mutations showed similar preferential enrichment in specific metastatic sites. This large-scale study identified new MBC genetic alterations according to various metastatic sites and highlights their potential role in breast cancer organotropism.

Highlights

Breast cancer is the most common type of cancer in women and the second-most common cause of death due to its metastasis or progression to advanced disease[1]
To investigate metastatic breast cancer (MBC)-specific genetic alterations related to organotropism, we performed three analyses using different datasets and methods (Fig. 1)
Ten of the most frequently altered genes in MBC samples exhibited no difference in the frequency of genetic alterations, compared to that in primary breast cancer (PBC) samples, except for estrogen receptor 1 (ESR1), ARID1A, and NF1 which were more frequently altered in MBC samples (Supplementary Fig. 10)

Summary

Introduction

Breast cancer is the most common type of cancer in women and the second-most common cause of death due to its metastasis or progression to advanced disease[1]. 31 candidate driver genes of MBC were identified through analyses of various datasets, including those based on whole-genome sequencing, whole-exome sequencing, or targeted gene sequencing with appropriate statistical methods[4,5,6]. Most of these studies attempted to identify the driver genes enriched in MBC by comparing the frequency of driver genes between unpaired MBC and PBC samples. Razavi et al.[7] identified more than 20 additional MBC-enriched altered genes that were not identified in other studies by comparing the frequency of 468 cancer-related genes between MBC and PBC unpaired samples. The identified MBCenriched altered genes may have functional impacts on MBC clones in the metastatic sites of breast cancer, which should be elucidated in detail

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