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Somatic Mutation of PIK3CA (H1047R) Is a Common Driver Mutation Hotspot in Canine Mammary Tumors As Well As Human Breast Cancers

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Somatic Mutation of PIK3CA (H1047R) Is a Common Driver Mutation Hotspot in Canine Mammary Tumors As Well As Human Breast Cancers cancers Article Somatic Mutation of PIK3CA (H1047R) Is a Common Driver Mutation Hotspot in Canine Mammary Tumors as Well as Human Breast Cancers 1, 1, 2 1 1, Kang-Hoon Lee y, Hyeon-Ji Hwang y, Hyun Ji Noh , Tae-Jin Shin and Je-Yoel Cho * 1 Department of Biochemistry, BK21 Plus and Research Institute for Veterinary Science, School of Veterinary Medicine, Seoul National University, Seoul 08826, Korea; [email protected] (K.-H.L.); [email protected] (H.-J.H.); [email protected] (T.-J.S.) 2 Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; [email protected] * Correspondence: [email protected]; Tel.: +82-02-880-1268 These authors contributed equally to this work. y Received: 7 November 2019; Accepted: 10 December 2019; Published: 12 December 2019 Abstract: Breast cancer is one of the most frequently diagnosed cancers in both women and female dogs. Genome-wide association studies in human breast cancer (HBC) have identified hundreds of genetic variations and somatic driver mutations. However, only a handful of variants have been studied for rare HBC and their associations remain inconclusive. Spontaneous canine mammary tumor (CMT) is a great model for HBC, with clinical similarity. We thus performed whole-exome sequencing in 20 pairs of CMT and normal tissues in dogs. We newly found that PIK3CA was the most frequently mutated gene in CMT (45%). Furthermore, canine PIK3CA A3140G (H1047R), at what is known as the mutational hotspot of HBC, is also a hotspot in CMT. Targeted sequencing confirmed that 29% of CMTs had the same PIK3CA A3140G mutation. Integration of the transcriptome suggests that the PIK3CA (H1047R) induced cell metabolism and cell cycle via an increase of PCK2 and a decrease of CDKN1B but had no effect on cell apoptosis. We identified additional significantly mutated genes, including SCRN1 and CLHC1, which have not been reported in HBC. Our study recapitulated some known HBC-associated genes and human cancer signatures in CMT, and identified novel genes that may be relevant to HBC. This study may allow us to better understand both HBC and CMT and lend new insights into the development of biomarkers. Keywords: breast cancer; WES; exome-seq; transcriptome; dog; mammary gland tumor; CMT 1. Introduction Human breast cancer (HBC) now affects one in four women worldwide [1]. It is well known that women who have a family history of HBC have an increased risk of developing HBC. Some high-penetrance mutations responsible for an increased risk of HBC have been found, such as BRCA1 and BRCA2, PTEN, RAD50, and TP53 [2]. Over the last few decades, together with the development of high-throughput sequencing technology, a huge number of genome-wide association studies (GWAS) have identified many genetic loci that are associated with HBC and have been able to explain up to 18% of heritability [3]. However, this percentage will be increased with the consideration of recent GWAS data which revealed that silent mutations (synonymous mutations without amino acid changes) frequently contribute to various cancers [4]. This may suggest that HBC is a very complex disease and non-genetic factors, as well as the heterogeneity of human populations, need to be addressed and overcome to discover missing high-risk genes. Studies comparing matched tumor/normal pairs (T/N) have revealed many probable driver genes for HBC, including TP53 and PIK3CA, that are most frequently mutated [5,6]. Cancers 2019, 11, 2006; doi:10.3390/cancers11122006 www.mdpi.com/journal/cancers Cancers 2019, 11, 2006 2 of 16 Cancers 2019, 11, 2006 2 of 16 Canine mammary tumors (CMTs) are potentially a good natural animal model for HBC due Canine mammary tumors (CMTs) are potentially a good natural animal model for HBC due to to their biological and pathophysiological similarities, as well as an increased rate of incidence and their biological and pathophysiological similarities, as well as an increased rate of incidence and malignancy in dogs. CMT’s molecular characteristics resemble HBC’s, including the expression of malignancy in dogs. CMT’s molecular characteristics resemble HBC’s, including the expression of estrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor 2 (EGFR), estrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor 2 (EGFR), basal cytokeratins 5/6, and p53 mutation [7]. Mixed type CMTs share several histopathological features basal cytokeratins 5/6, and p53 mutation [7]. Mixed type CMTs share several histopathological and risk factors with metaplastic HBC and complex subtype CMTs offer an ideal system to study features and risk factors with metaplastic HBC and complex subtype CMTs offer an ideal system to myoepithelial cells, the second major cell lineage of the mammary gland [8,9]. Genes and variations study myoepithelial cells, the second major cell lineage of the mammary gland [8,9]. Genes and known as high-risk factors in HBC, such as single nucleotide polymorphisms (SNPs) in BRCA1, BRCA2, variations known as high-risk factors in HBC, such as single nucleotide polymorphisms (SNPs) in and ER, have also been reported to be significantly associated with CMTs [10,11]. In addition, Liu BRCA1, BRCA2, and ER, have also been reported to be significantly associated with CMTs [10,11]. In D et al. reported molecular similarities such as copy number variation and epigenetic modification addition, Liu D et al. reported molecular similarities such as copy number variation and epigenetic between CMTs and HBC, but they could not show significant somatic mutations in CMTs due to the modification between CMTs and HBC, but they could not show significant somatic mutations in limitation of small sample size [9]. Interestingly, breed predispositions to various types of cancer have CMTs due to the limitation of small sample size [9]. Interestingly, breed predispositions to various been reported, including sarcomas, mast cell tumors, lymphoma/leukemia, melanoma, and mammary types of cancer have been reported, including sarcomas, mast cell tumors, lymphoma/leukemia, tumors [12]. Specifically, Yaritza Salas et al. reported breed predisposition in specific subtypes of melanoma, and mammary tumors [12]. Specifically, Yaritza Salas et al. reported breed predisposition CMTs—Poodle and Schnauzer breeds showed the strongest association with complex and tubular in specific subtypes of CMTs—Poodle and Schnauzer breeds showed the strongest association with type carcinomas, while Cocker Spaniels showed a higher correspondence with carcinosarcoma and complex and tubular type carcinomas, while Cocker Spaniels showed a higher correspondence with mesenchymal origin tumors [13]. The Maltese breed was mainly associated with epithelial tumors, carcinosarcoma and mesenchymal origin tumors [13]. The Maltese breed was mainly associated with which are the most common type in HBC [13]. These possibly indicates that specific dog breeds are epithelial tumors, which are the most common type in HBC [13]. These possibly indicates that specific enriched with risk alleles for specific subtypes of CMT. dog breeds are enriched with risk alleles for specific subtypes of CMT. The goal of this study is to determine mutation profile in CMTs that may help us to understand The goal of this study is to determine mutation profile in CMTs that may help us to understand better the mutations rare in HBC. In this study, we performed exome sequencing in T/N tissue pairs of better the mutations rare in HBC. In this study, we performed exome sequencing in T/N tissue pairs CMTs from two canine breeds to explore germline and somatic variations relevant to CMTs. of CMTs from two canine breeds to explore germline and somatic variations relevant to CMTs. 2. Results 2. Results 2.1. Whole Exome Sequencing in CMT Was Performed 2.1. Whole Exome Sequencing in CMT Was Performed A total of 20 paired CMTs and adjacent normal tissues from small sized dog breeds were subjected to genomicA total DNAof 20 isolation,paired CMTs followed and byadjacent high-throughput normal tissues whole from exome small sequencing sized dog (Materials breeds were and subjectedMethods; Figureto genomic1). The DNA average isolation, age was 11.5followed years andby halfhigh-throughput were spayed (Tablewhole S1). exome It was sequencing unexpected (Materialsbecause it and is well-known Methods; Figure thatthe 1). The risk average of a dog age developing was 11.5 years a mammary and half tumor were isspayed less than (Table 0.5% S1). if Itthey was are unexpected spayed before because the it first is well-known estrus, while that the the risk risk increases of a dog to 26%developing after the a secondmammary or any tumor estrus. is lessThe than high 0.5% frequency if they are ofspayed spayed dogsbefore in the this first study estrus, can while be explained the risk increases by the fact to 26% that after only the 2.7% second of dogs or anyunderwent estrus. The spaying high frequency surgery before of spayed 1 year dogs of age, in this and study more can than be 60% explained of dogs by get the spayed fact that after only 2 2.7% years of of dogsage inunderwent Korea (Report spaying for surgery Survey before on the 1 Recognitionyear of age, and and more Parenting than 60% Status of dogs of Pets get inspayed 2018) after [14,15 2 ].years of age in Korea (Report for Survey on the Recognition and Parenting Status of Pets in 2018) [14,15]. FigureFigure 1. 1. ExperimentalExperimental scheme. scheme. The The overall overall procedure procedure of of exome exome sequencing sequencing was was depicted depicted with with major major information,information, such such as as numbers numbers of of specimens, specimens, tools, tools, and and parameters. parameters. SequenceSequence reads werewere mappedmapped to to the the CanFam3.1 CanFam3.1 dog dog reference reference genome, genome, revealing revealing a median a median depth of coverage of ~102 in both normal and CMT, and a read depth of at least 30 in ~95% of the targeted depth of coverage of× ~102 × in both normal and CMT, and a read depth of at ×least 30 × in ~95% of the targeted exome region (Table S2).
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