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[Preprint]. 2023 Dec 6:2023.12.06.23299442.
doi: 10.1101/2023.12.06.23299442.

Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study

Nijole P Tjader  1 , Abigail J Beer  1 , Johnny Ramroop  2 , Mei-Chee Tai  3 , Jie Ping  4 , Tanish Gandhi  5   6 , Cara Dauch  1   7 , Susan L Neuhausen  8 , Elad Ziv  9   10   11 , Nereida Sotelo  1 , Shreya Ghanekar  1 , Owen Meadows  5 , Monica Paredes  5 , Jessica Gillespie  12 , Amber Aeilts  13 , Heather Hampel  14 , Wei Zheng  4 , Guochong Jia  4 , Qiang Hu  15 , Lei Wei  15 , Song Liu  15 , Christine B Ambrosone  16 , Julie R Palmer  17 , John D Carpten  18   19 , Song Yao  16 , Patrick Stevens  20 , Weang-Kee Ho  3   21 , Jia Wern Pan  3 , Paolo Fadda  22 , Dezheng Huo  23 , Soo-Hwang Teo  3   24 , Joseph Paul McElroy  25 , Amanda Ewart Toland  1   12   13
Affiliations

Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study

Nijole P Tjader et al. medRxiv. .

Update in

  • Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study.
    Tjader NP, Beer AJ, Ramroop J, Tai MC, Ping J, Gandhi T, Dauch C, Neuhausen SL, Ziv E, Sotelo N, Ghanekar S, Meadows O, Paredes M, Gillespie JL, Aeilts AM, Hampel H, Zheng W, Jia G, Hu Q, Wei L, Liu S, Ambrosone CB, Palmer JR, Carpten JD, Yao S, Stevens P, Ho WK, Pan JW, Fadda P, Huo D, Teo SH, McElroy JP, Toland AE. Tjader NP, et al. Cancer Res Commun. 2024 Jun 27;4(6):1597-1608. doi: 10.1158/2767-9764.CRC-24-0026. Cancer Res Commun. 2024. PMID: 38836758 Free PMC article.

Abstract

Background: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors.

Methods: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.

Results: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons.

Conclusions: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.

Keywords: ESR1; GWAS; PIK3CA; TP53; breast cancer; germline; germline by somatic interaction; somatic.

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Conflict of interest statement

CONFLICTS OF INTEREST HH is on the scientific advisory board for Invitae Genetics, Promega, and Genome Medical and has stock/stock options in Genome Medical and GI OnDemand. None of these are direct conflicts with this study.

Figures

Figure 1:
Figure 1:. Manhattan Plots for TP53 Discovery GxM Analyses
Discovery GWAS data for (A) 879 TP53 mutation carriers and 1965 breast cancer cases without TP53 mutations, (B) 237 cases with TP53 GOF mutations and 1965 breast cancer cases without TP53 mutations, and (C) 536 cases with TP53 LOF mutations and 1965 controls are plotted by −log10(P values). Blue lines represent P values of less than 1×10−5. Chromosome numbers are indicated. GXM, Germline Variant by Mutation; GWAS, genome-wide association study; GOF, gain of function; LOF, loss of function.
Figure 2:
Figure 2:. Manhattan Plots for PIK3CA Discovery GxM Analyses
Discovery GWAS data for (A) 1095 PIK3CA mutation carriers and 1642 breast cancer cases without PIK3CA mutations, (B) 858 cases with PIK3CA activating/hotspot mutations and 1642 breast cancer cases without PIK3CA mutations, (C) 112 cases with PIK3CA p.E542K mutations and 1642 breast cancer cases without PIK3CA mutations, (D) 193 cases with PIK3CA p.E545K mutations and 1642 breast cancer cases without PIK3CA mutations, and (E) 387 cases with PIK3CA p.H1047R mutations and 1642 breast cancer cases without PIK3CA mutations are plotted by −log10(P value). Blue lines represent P values of less than 1×10−5. Chromosome numbers are indicated. GXM, Germline Variant by Mutation; GWAS, genome-wide association study.
See this image and copyright information in PMC

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