Multigene clinical mutational profiling of breast carcinoma using next-generation sequencing.
OBJECTIVE
The advent of next-generation sequencing (NGS) platforms in the realm of clinical molecular diagnostics provides multigene mutational profiling through massively parallel sequencing.


METHODS
We analyzed 415 breast carcinoma samples from 354 patients using NGS in known hotspots of 46 commonly known cancer-causing genes.


RESULTS
A total of 281 somatic nonsynonymous mutations were detected in 62.1% of patients. TP53 was most frequently mutated (38.8%), followed by PIK3CA (31.7%), AKT1 (6%), and ATM (3.9%), with other mutations detected at a lower frequency. When stratified into clinically relevant therapeutic groups (estrogen receptor [ER]/progesterone receptor [PR]+ human epidermal growth factor receptor 2 [HER2]-, ER/PR+HER2+, ER/PR-HER2+, ER/PR/HER2-), each group showed distinct mutational profiles. The ER/PR+HER2- tumors (n = 132) showed the highest frequency of PIK3CA mutations (38%), while the triple-negative tumors (n = 64) had a significantly higher number of TP53 mutations (62%). Of the 61 patients tested for both primary and metastatic tumors, concordant results were seen in 47 (77%) patients, while 13 patients showed additional mutations in the metastasis.


CONCLUSIONS
Our results indicate that breast cancers may harbor potentially actionable mutations for targeted therapeutics. Therefore, NGS-based mutational profiling can provide useful information that can guide targeted cancer therapy.
From the Division of Pathology and Laboratory Medicine and sroy2@mdanderson.org.
Sinchita
S
Roy-Chowdhuri
Departments of Breast Medical Oncology.
Debora
D
de Melo Gagliato
From the Division of Pathology and Laboratory Medicine and.
Mark J
MJ
Routbort
From the Division of Pathology and Laboratory Medicine and.
Keyur P
KP
Patel
From the Division of Pathology and Laboratory Medicine and.
Rajesh R
RR
Singh
From the Division of Pathology and Laboratory Medicine and.
Russell
R
Broaddus
From the Division of Pathology and Laboratory Medicine and.
Alexander J
AJ
Lazar
From the Division of Pathology and Laboratory Medicine and.
Aysegul
A
Sahin
Departments of Breast Medical Oncology.
Ricardo H
RH
Alvarez
Departments of Breast Medical Oncology.
Stacy
S
Moulder
Investigational Cancer Therapeutics.
Jennifer J
JJ
Wheler
Investigational Cancer Therapeutics.
Filip
F
Janku
Departments of Breast Medical Oncology.
Ana M
AM
Gonzalez-Angulo
Departments of Breast Medical Oncology.
Mariana
M
Chavez-MacGregor
Departments of Breast Medical Oncology.
Vicente
V
Valero
Departments of Breast Medical Oncology.
Naoto T
NT
Ueno
Systems Biology.
Gordon
G
Mills
Experimental Therapeutics.
John
J
Mendelsohn
Bioinformatics and Computational Biology and.
Hui
H
Yao
From the Division of Pathology and Laboratory Medicine and.
Kenneth
K
Aldape
From the Division of Pathology and Laboratory Medicine and.
Rajyalakshmi
R
Luthra
Investigational Cancer Therapeutics Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
Funda
F
Meric-Bernstam
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C508053:ERBB2 protein, human
Breast carcinoma; ER positive; Mutational profiling; Next-generation sequencing; Triple negative