Targeted sequencing reveals the somatic mutation landscape in a Swedish breast cancer cohort

Sci Rep. 2020 Nov 9;10(1):19304. doi: 10.1038/s41598-020-74580-1.


Breast cancer (BC) is a genetically heterogeneous disease with high prevalence in Northern Europe. However, there has been no detailed investigation into the Scandinavian somatic landscape. Here, in a homogeneous Swedish cohort, we describe the somatic events underlying BC, leveraging a targeted next-generation sequencing approach. We designed a 20.5 Mb array targeting coding and regulatory regions of genes with a known role in BC (n = 765). The selected genes were either from human BC studies (n = 294) or from within canine mammary tumor associated regions (n = 471). A set of predominantly estrogen receptor positive tumors (ER + 85%) and their normal tissue counterparts (n = 61) were sequenced to ~ 140 × and 85 × mean target coverage, respectively. MuTect2 and VarScan2 were employed to detect single nucleotide variants (SNVs) and copy number aberrations (CNAs), while MutSigCV (SNVs) and GISTIC (CNAs) algorithms estimated the significance of recurrent somatic events. The significantly mutated genes (q ≤ 0.01) were PIK3CA (28% of patients), TP53 (21%) and CDH1 (11%). However, histone modifying genes contained the largest number of variants (KMT2C and ARID1A, together 28%). Mutations in KMT2C were mutually exclusive with PI3KCA mutations (p ≤ 0. 001) and half of these affect the formation of a functional PHD domain. The tumor suppressor CDK10 was deleted in 80% of the cohort while the oncogene MDM4 was amplified. Mutational signature analyses pointed towards APOBEC deaminase activity (COSMIC signature 2) and DNA mismatch repair (COSMIC signature 6). We noticed two significantly distinct patterns related to patient age; TP53 being more mutated in the younger group (29% vs 9% of patients) and CDH23 mutations were absent from the older group. The increased somatic mutation prevalence in the histone modifying genes KMT2C and ARID1A distinguishes the Swedish cohort from previous studies. KMT2C regulates enhancer activation and assists tumor proliferation in a hormone-rich environment, possibly pointing to a role in ER + BC, especially in older cases. Finally, age of onset appears to affect the mutational landscape suggesting that a larger age-diverse population incorporating more molecular subtypes should be studied to elucidate the underlying mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC-1 Deaminase / genetics
  • Adult
  • Aged
  • Aged, 80 and over
  • Algorithms
  • Animals
  • Antigens, CD / genetics
  • Biomarkers, Tumor / genetics*
  • Breast Neoplasms / genetics*
  • Cadherin Related Proteins
  • Cadherins / genetics
  • Cell Cycle Proteins / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Cyclin-Dependent Kinases / genetics
  • DNA Mutational Analysis
  • DNA-Binding Proteins / genetics
  • Dogs
  • Female
  • Gene Dosage
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Middle Aged
  • Mutation*
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins / genetics
  • Sequence Analysis, DNA
  • Sweden / epidemiology
  • Transcription Factors / genetics
  • Tumor Suppressor Protein p53 / genetics


  • ARID1A protein, human
  • Antigens, CD
  • Biomarkers, Tumor
  • CDH1 protein, human
  • CDH23 protein, human
  • Cadherin Related Proteins
  • Cadherins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • KMT2C protein, human
  • MDM4 protein, human
  • Proto-Oncogene Proteins
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • CDK10 protein, human
  • Cyclin-Dependent Kinases
  • APOBEC-1 Deaminase