title: Molecular Differences between Screen-Detected and Interval Breast Cancers Are Largely Explained by PAM50 Subtypes.
abstract: Purpose:Interval breast cancer is of clinical interest, as it exhibits an aggressive phenotype and evades detection by screening mammography. A comprehensive picture of somatic changes that drive tumors to become symptomatic in the screening interval can improve understanding of the biology underlying these aggressive tumors.Experimental Design:Initiated in April 2013, Clinical Sequencing of Cancer in Sweden (Clinseq) is a scientific and clinical platform for the genomic profiling of cancer. The breast cancer pilot study consisted of women diagnosed with breast cancer between 2001 and 2012 in the Stockholm/Gotland regions. A subset of 307 breast tumors was successfully sequenced, of which 113 were screen-detected and 60 were interval cancers. We applied targeted deep sequencing of cancer-related genes; low-pass, whole-genome sequencing; and RNA sequencing technology to characterize somatic differences in the genomic and transcriptomic architecture by interval cancer status. Mammographic density and PAM50 molecular subtypes were considered.Results:In the univariate analyses,TP53, PPP1R3A, andKMT2Bwere significantly more frequently mutated in interval cancers than in screen-detected cancers. Acquired somatic copy number aberrations with a frequency difference of at least 15% between the two groups included gains in 17q23-q25.3 and losses in 16q24.2. Gene expression analysis identified 447 significantly differentially expressed genes, of which 120 were replicated in an independent microarray dataset. After adjusting for PAM50, most differences were no longer significant.Conclusions:Molecular differences by interval cancer status were observed, but they were largely explained by PAM50 subtypes. This work offers new insights into the biological differences between the two tumor groups.Clin Cancer Res; 23(10); 2584-92. ©2016 AACR.
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. jingmei.li@ki.se.
authors: Jingmei
authors: J
authors: Li
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Swedish eScience Research Centre (SeRC), Karolinska Institutet, Stockholm, Sweden.
authors: Emma
authors: E
authors: Ivansson
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Daniel
authors: D
authors: Klevebring
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Nicholas P
authors: NP
authors: Tobin
authors: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors: Linda Sofie
authors: LS
authors: Lindström
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Johanna
authors: J
authors: Holm
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Gabriela
authors: G
authors: Prochazka
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Camilla
authors: C
authors: Cristando
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Swedish eScience Research Centre (SeRC), Karolinska Institutet, Stockholm, Sweden.
authors: Juni
authors: J
authors: Palmgren
authors: Stockholm-Gotland Regional Cancer Centre, Stockholm, Sweden.
authors: Sven
authors: S
authors: Törnberg
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Swedish eScience Research Centre (SeRC), Karolinska Institutet, Stockholm, Sweden.
authors: Keith
authors: K
authors: Humphreys
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Johan
authors: J
authors: Hartman
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
authors: Jan
authors: J
authors: Frisell
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Mattias
authors: M
authors: Rantalainen
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Johan
authors: J
authors: Lindberg
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Per
authors: P
authors: Hall
authors: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.
authors: Jonas
authors: J
authors: Bergh
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Swedish eScience Research Centre (SeRC), Karolinska Institutet, Stockholm, Sweden.
authors: Henrik
authors: H
authors: Grönberg
authors: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors: Kamila
authors: K
authors: Czene
mesh_terms: D000368:Aged; D001940:Breast / Q000000981:diagnostic imaging / Q000473:pathology; D000071060:Breast Density / Q000235:genetics; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006801:Humans; D008327:Mammography; D008403:Mass Screening; D008875:Middle Aged; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D010865:Pilot Projects; D013548:Sweden; D059467:Transcriptome / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D011495:Histone-Lysine N-Methyltransferase; C000619080:KMT2B protein, human; C114205:PPP1R3A protein, human; D010749:Phosphoprotein Phosphatases