Abstract
Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Although it is a rare subtype, IBC is responsible for roughly 10% of breast cancer deaths. In order to obtain a better understanding of the genomic landscape and intratumor heterogeneity (ITH) in IBC, we conducted whole-exome sequencing of 16 tissue samples (12 tumor and four normal samples) from six hormone-receptor-positive IBC patients, analyzed somatic mutations and copy number aberrations, and inferred subclonal structures to demonstrate ITH. Our results showed that KMT2C was the most frequently mutated gene (42%, 5/12 samples), followed by HECTD1, LAMA3, FLG2, UGT2B4, STK33, BRCA2, ACP4, PIK3CA, and DNAH8 (all nine genes tied at 33% frequency, 4/12 samples). Our data indicated that PTEN and FBXW7 mutations may be considered driver gene mutations for IBC. We identified various subclonal structures and different levels of ITH between IBC patients, and mutations in the genes EIF4G3, IL12RB2, and PDE4B may potentially generate ITH in IBC.
Highlights
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer defined by the rapid onset of inflammatory signs involving more than one-third of the breast[1,2,3]
The scarcity of data from IBC patients and the poor understanding at the molecular level has hindered the development of specific therapeutic interventions
By only considering HR+ IBC tumors, our study eliminated additional confounding introduced by differences in HR subtypes seen in previous studies
Summary
Inflammatory breast cancer (IBC) is an aggressive form of breast cancer defined by the rapid onset of inflammatory signs (such as erythema, edema, warmth, and induration) involving more than one-third of the breast[1,2,3]. Frequent genomic alterations in the PI3K/AKT/mTOR pathway have been seen[15], and somatic activation of this pathway (i.e., PIK3CA activating mutation or gain[14], ERBB2 activating mutation, PTEN deletion, AKT1 activating mutation) was significantly associated with shorter progression-free survival (PFS) in trastuzumab-naïve HER2-positive IBC patients[19]. Most of these studies were based on targeted sequencing panels, and none of them provided information for intratumor subclonal structures or evaluated ITH. Based on the mutation calls and somatic copy number alterations, we characterized ITH and subclonal structures, identified primary and secondary driver genes for the tumor and subclone formation, which could shed light on potential new treatment strategies for IBC
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