A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Camilla Wendt; Taru A. Muranen; Lotta Mielikäinen; Jessada Thutkawkorapin; Carl Blomqvist; Xiang Jiao; Hans Ehrencrona; Emma Tham; Brita Arver; Beatrice Melin; Ekaterina Kuchinskaya; Marie Stenmark Askmalm; Ylva Paulsson-Karlsson; Zakaria Einbeigi; Anna von Wachenfeldt Väppling; Eija Kalso; Tiina Tasmuth; Anne Kallioniemi; Kristiina Aittomäki; Heli Nevanlinna; Åke Borg; Annika Lindblom

doi:10.1038/s41598-021-93926-x

A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Camilla Wendt, Taru A. Muranen, Lotta Mielikäinen, Jessada Thutkawkorapin, Carl Blomqvist, Xiang Jiao, Hans Ehrencrona, Emma Tham, Brita Arver, Beatrice Melin, Ekaterina Kuchinskaya, Marie Stenmark Askmalm, Ylva Paulsson-Karlsson, Zakaria Einbeigi, Anna von Wachenfeldt Väppling, Eija Kalso, Tiina Tasmuth, Anne Kallioniemi, Kristiina Aittomäki, Heli NevanlinnaÅke Borg, Annika Lindblom

Department of Clinical Microbiology

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Abstract

The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

Original language	English
Article number	14763
Journal	Scientific Reports
Volume	11
DOIs	https://doi.org/10.1038/s41598-021-93926-x
Publication status	Published - Jul 2021
Publication type	A1 Journal article-refereed

Funding

Financial support was provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet. The Helsinki study was supported by The Cancer Foundation Finland, The Sigrid Jusélius Foundation and The Helsinki University Hospital Research Fund.

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Publication forum level 1

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Wendt, C., Muranen, T. A., Mielikäinen, L., Thutkawkorapin, J., Blomqvist, C., Jiao, X., Ehrencrona, H., Tham, E., Arver, B., Melin, B., Kuchinskaya, E., Stenmark Askmalm, M., Paulsson-Karlsson, Y., Einbeigi, Z., von Wachenfeldt Väppling, A., Kalso, E., Tasmuth, T., Kallioniemi, A., Aittomäki, K., ... Lindblom, A. (2021). A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients. Scientific Reports, 11, Article 14763. https://doi.org/10.1038/s41598-021-93926-x

@article{a44628160e394fac8e3af84aa373ff45,

title = "A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients",

abstract = "The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.",

author = "Camilla Wendt and Muranen, {Taru A.} and Lotta Mielik{\"a}inen and Jessada Thutkawkorapin and Carl Blomqvist and Xiang Jiao and Hans Ehrencrona and Emma Tham and Brita Arver and Beatrice Melin and Ekaterina Kuchinskaya and {Stenmark Askmalm}, Marie and Ylva Paulsson-Karlsson and Zakaria Einbeigi and {von Wachenfeldt V{\"a}ppling}, Anna and Eija Kalso and Tiina Tasmuth and Anne Kallioniemi and Kristiina Aittom{\"a}ki and Heli Nevanlinna and {\AA}ke Borg and Annika Lindblom",

note = "Funding Information: Financial support was provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet. The Helsinki study was supported by The Cancer Foundation Finland, The Sigrid Jus{\'e}lius Foundation and The Helsinki University Hospital Research Fund. ",

year = "2021",

month = jul,

doi = "10.1038/s41598-021-93926-x",

language = "English",

volume = "11",

journal = "Scientific Reports",

issn = "2045-2322",

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Wendt, C, Muranen, TA, Mielikäinen, L, Thutkawkorapin, J, Blomqvist, C, Jiao, X, Ehrencrona, H, Tham, E, Arver, B, Melin, B, Kuchinskaya, E, Stenmark Askmalm, M, Paulsson-Karlsson, Y, Einbeigi, Z, von Wachenfeldt Väppling, A, Kalso, E, Tasmuth, T, Kallioniemi, A, Aittomäki, K, Nevanlinna, H, Borg, Å & Lindblom, A 2021, 'A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients', Scientific Reports, vol. 11, 14763. https://doi.org/10.1038/s41598-021-93926-x

TY - JOUR

T1 - A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

AU - Wendt, Camilla

AU - Muranen, Taru A.

AU - Mielikäinen, Lotta

AU - Thutkawkorapin, Jessada

AU - Blomqvist, Carl

AU - Jiao, Xiang

AU - Ehrencrona, Hans

AU - Tham, Emma

AU - Arver, Brita

AU - Melin, Beatrice

AU - Kuchinskaya, Ekaterina

AU - Stenmark Askmalm, Marie

AU - Paulsson-Karlsson, Ylva

AU - Einbeigi, Zakaria

AU - von Wachenfeldt Väppling, Anna

AU - Kalso, Eija

AU - Tasmuth, Tiina

AU - Kallioniemi, Anne

AU - Aittomäki, Kristiina

AU - Nevanlinna, Heli

AU - Borg, Åke

AU - Lindblom, Annika

N1 - Funding Information: Financial support was provided through the regional agreement on medical training and clinical research (ALF) between the Stockholm County Council and Karolinska Institutet. The Helsinki study was supported by The Cancer Foundation Finland, The Sigrid Jusélius Foundation and The Helsinki University Hospital Research Fund.

PY - 2021/7

Y1 - 2021/7

N2 - The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

AB - The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

U2 - 10.1038/s41598-021-93926-x

DO - 10.1038/s41598-021-93926-x

M3 - Article

AN - SCOPUS:85111079800

SN - 2045-2322

VL - 11

JO - Scientific Reports

JF - Scientific Reports

M1 - 14763

ER -

A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Abstract

Funding

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ASJC Scopus subject areas

UN SDGs

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