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

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

Mathioudaki, Argyri, Ph.D student, 1986- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinska vetenskaper

Ljungström, Viktor, 1986- (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi

Melin, Malin (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för immunologi, genetik och patologi

Arendt, Maja Louise (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Nordin, Jessika (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab

Karlsson, Åsa (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab

Murén, Eva (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab

Saksena, Pushpa (author)

Meadows, Jennifer R. S. (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab

Marinescu, Voichita D. (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinsk biokemi och mikrobiologi

Sjöblom, Tobias (author): Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi

Lindblad-Toh, Kerstin (author): Uppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab,Broad Institute of MIT and Harvard

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(creator_code:org_t)

2020-11-09
2020
English.
In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1

Related links:: https://doi.org/10.1...; show more...; https://uu.diva-port... (primary) (Raw object); https://www.nature.c...; https://urn.kb.se/re...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Keyword

Breast cancer
PIK3CA
KMT2C
TP53
Sweden
targeted sequencing
NGS
Molekylär genetik
Molecular Genetics

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