Comprehensive Cohort Analysis of Mutational Spectrum in Early Onset Breast Cancer Patients.

Mohit K Midha,Yu-Feng Huang,Chen-Yang Shen,King-Jen Chang,Kuo-Ping Chiu,Wen-Hung Kuo,Yu-Tai Wang,Hsiao-Hsiang Yang,Chien-Jen Chen,Tzu-Han Chen,Nai-Chuan Chang,Tan-Chi Fan,Alice L Yu

doi:10.3390/cancers12082089

Abstract

Early onset breast cancer (EOBC), diagnosed at age ~40 or younger, is associated with a poorer prognosis and higher mortality rate compared to breast cancer diagnosed at age 50 or older. EOBC poses a serious threat to public health and requires in-depth investigation. We studied a cohort comprising 90 Taiwanese female patients, aiming to unravel the underlying mechanisms of EOBC etiopathogenesis. Sequence data generated by whole-exome sequencing (WES) and whole-genome sequencing (WGS) from white blood cell (WBC)–tumor pairs were analyzed to identify somatic missense mutations, copy number variations (CNVs) and germline missense mutations. Similar to regular breast cancer, the key somatic mutation-susceptibility genes of EOBC include TP53 (40% prevalence), PIK3CA (37%), GATA3 (17%) and KMT2C (17%), which are frequently reported in breast cancer; however, the structural protein-coding genes MUC17 (19%), FLG (16%) and NEBL (11%) show a significantly higher prevalence in EOBC. Furthermore, the top 2 genes harboring EOBC germline mutations, MUC16 (19%) and KRT18 (19%), encode structural proteins. Compared to conventional breast cancer, an unexpectedly higher number of EOBC susceptibility genes encode structural proteins. We suspect that mutations in structural proteins may increase physical permeability to environmental hormones and carcinogens and cause breast cancer to occur at a young age.

Highlights

Onset breast cancer (EOBC) diagnosed at age ~40 or younger is associated with a poorer prognosis, higher recurrence rate and higher mortality rate than breast cancer (BC) diagnosed at laterCancers 2020, 12, 2089; doi:10.3390/cancers12082089 www.mdpi.com/journal/cancersCancers 2020, 12, 2089 ages [1,2,3]
Through the comparison of missense mutations between white blood cell (WBC)–tumor pairs, we examined the association of these molecular alterations with biologic pathways and clinical subtypes
The results indicate that a significantly higher fraction of Early onset breast cancer (EOBC) susceptibility genes encode extracellular structural proteins compared to breast cancer susceptibility genes as a whole

Summary

Introduction

Onset breast cancer (EOBC) diagnosed at age ~40 or younger is associated with a poorer prognosis, higher recurrence rate and higher mortality rate than breast cancer (BC) diagnosed at laterCancers 2020, 12, 2089; doi:10.3390/cancers12082089 www.mdpi.com/journal/cancersCancers 2020, 12, 2089 ages [1,2,3]. There are over one million (e.g., 1.38 million in 2008 alone) new breast cancer cases each year worldwide [4,5]. Among these cases, approximately 4%–14% are EOBC: ~6.6% in American women [6], ~12% in Taiwanese women [7] and over 13% in Singaporean women [8]. While late-onset breast cancer (LOBC) is becoming more manageable, EOBC has continued to increase steadily in many countries over the past few decades and demands intensive investigation [3,6,9,10,11]. Based on the pattern of gene expression and histopathologic staining [12,13,14], previous studies have classified breast cancer into several clinically relevant subtypes, each of which is more or less associated with epidemiological risk factors and clinical responses [11,15,16]

Objectives

Methods

Discussion

Conclusion