Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

Clara Bodelon; Hannah Oh; Andriy Derkach; Joshua N. Sampson; Brian L. Sprague; Pamela Vacek; Donald L. Weaver; Shaoqi Fan; Maya Palakal; Daphne Papathomas; Jackie Xiang; Deesha A. Patel; Laura Linville; Susan E. Clare; Daniel W. Visscher; Carolyn Mies; Stephen M. Hewitt; Louise A. Brinton; Anna Maria V. Storniolo; Chunyan He; Stephen J. Chanock; Montserrat Garcia-Closas; Gretchen L. Gierach; Jonine D. Figueroa

doi:10.1038/s41523-020-00184-7

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

Clara Bodelon, Hannah Oh, Andriy Derkach, Joshua N. Sampson, Brian L. Sprague, Pamela Vacek, Donald L. Weaver, Shaoqi Fan, Maya Palakal, Daphne Papathomas, Jackie Xiang, Deesha A. Patel, Laura Linville, Susan E. Clare, Daniel W. Visscher, Carolyn Mies, Stephen M. Hewitt, Louise A. Brinton, Anna Maria V. Storniolo, Chunyan HeStephen J. Chanock, Montserrat Garcia-Closas, Gretchen L. Gierach, Jonine D. Figueroa

Internal Medicine

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

Abstract

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

Original language	English
Article number	41
Journal	npj Breast Cancer
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s41523-020-00184-7
State	Published - Dec 1 2020

Bibliographical note

Publisher Copyright:
© 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Funding

This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the US National Cancer Institute. Breast Cancer Research Stamp Funds (awarded to M.E. Sherman and L.A. Brinton) and cooperative agreement U01CA70013 (P.M. Vacek, D.L. Weaver) from the National Cancer Institute funded some of the data collection for this study. The efforts of Drs. Sprague, Vacek, and Weaver were supported in part by cooperative agreement U01 CA196383 from the National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. Data from the Susan G. Komen Tissue Bank at the IU Simon Cancer Center were used in this study. We thank contributors, including Indiana University who collected data used in this study, as well as donors and their families, whose help and participation made this work possible.

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute	U01 CA196383
National Childhood Cancer Registry – National Cancer Institute
National Cancer Institute Division of Cancer Epidemiology and Genetics	1ZIACP010126-23, U01CA70013
National Cancer Institute Division of Cancer Epidemiology and Genetics

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging
Pharmacology (medical)

UN SDGs

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

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Cite this

Bodelon, C., Oh, H., Derkach, A., Sampson, J. N., Sprague, B. L., Vacek, P., Weaver, D. L., Fan, S., Palakal, M., Papathomas, D., Xiang, J., Patel, D. A., Linville, L., Clare, S. E., Visscher, D. W., Mies, C., Hewitt, S. M., Brinton, L. A., Storniolo, A. M. V., ... Figueroa, J. D. (2020). Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast. npj Breast Cancer, 6(1), Article 41. https://doi.org/10.1038/s41523-020-00184-7

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title = "Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast",

abstract = "Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.",

author = "Clara Bodelon and Hannah Oh and Andriy Derkach and Sampson, {Joshua N.} and Sprague, {Brian L.} and Pamela Vacek and Weaver, {Donald L.} and Shaoqi Fan and Maya Palakal and Daphne Papathomas and Jackie Xiang and Patel, {Deesha A.} and Laura Linville and Clare, {Susan E.} and Visscher, {Daniel W.} and Carolyn Mies and Hewitt, {Stephen M.} and Brinton, {Louise A.} and Storniolo, {Anna Maria V.} and Chunyan He and Chanock, {Stephen J.} and Montserrat Garcia-Closas and Gierach, {Gretchen L.} and Figueroa, {Jonine D.}",

note = "Publisher Copyright: {\textcopyright} 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

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Bodelon, C, Oh, H, Derkach, A, Sampson, JN, Sprague, BL, Vacek, P, Weaver, DL, Fan, S, Palakal, M, Papathomas, D, Xiang, J, Patel, DA, Linville, L, Clare, SE, Visscher, DW, Mies, C, Hewitt, SM, Brinton, LA, Storniolo, AMV, He, C, Chanock, SJ, Garcia-Closas, M, Gierach, GL & Figueroa, JD 2020, 'Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast', npj Breast Cancer, vol. 6, no. 1, 41. https://doi.org/10.1038/s41523-020-00184-7

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T1 - Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

AU - Bodelon, Clara

AU - Oh, Hannah

AU - Derkach, Andriy

AU - Sampson, Joshua N.

AU - Sprague, Brian L.

AU - Vacek, Pamela

AU - Weaver, Donald L.

AU - Fan, Shaoqi

AU - Palakal, Maya

AU - Papathomas, Daphne

AU - Xiang, Jackie

AU - Patel, Deesha A.

AU - Linville, Laura

AU - Clare, Susan E.

AU - Visscher, Daniel W.

AU - Mies, Carolyn

AU - Hewitt, Stephen M.

AU - Brinton, Louise A.

AU - Storniolo, Anna Maria V.

AU - He, Chunyan

AU - Chanock, Stephen J.

AU - Garcia-Closas, Montserrat

AU - Gierach, Gretchen L.

AU - Figueroa, Jonine D.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

AB - Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

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ER -

Polygenic risk score for the prediction of breast cancer is related to lesser terminal duct lobular unit involution of the breast

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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