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Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes

  • Preclinical study
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Abstract

To understand the biology of low-risk breast cancer alleles, and to investigate whether these loci also contribute to disease progression that was once established, we examined the association of SNPs tagging the low-risk breast cancer loci in or near FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, MYC, and 2q35, with clinical, pathological characteristics, prognosis, and mRNA expression of the nearest genes. Tumor DNA samples of 2,480 breast cancer patients were available. Out of this cohort, 1,290 patients with lymph-node negative disease who did not receive adjuvant systemic therapy, the SNP status was associated with metastasis-free survival (MFS). In 1,401 patients, the mRNA expression levels of FGFR2, LSP1, MAP3K1, H19, TOX3, POU5F1P1, and MYC were determined and correlated with SNP genotypes. The SNP rs2981582 in FGFR2 was significantly associated with positive ER and PgR status (P < 0.001 and P = 0.003, respectively). No other significant associations with patient or tumor characteristics were observed. Only rs2107425 near H19 was significantly associated with shorter MFS in uni- and multi-variate analysis (HR: 1.53, CI: 1.12–2.08, P = 0.006 and HR: 1.59, CI: 1.16–2.20, P = 0.004, respectively), with the more aggressive minor allele displaying a recessive trait. The minor allele of SNP rs3803662 located near the TOX3 gene was associated with lower mRNA expression of this gene. In conclusion, except for the association of rs13283662 with TOX3 gene expression indicating a tumor suppressor role of TOX3, our findings suggest that breast cancer low-risk loci generally do not affect expression of the nearest gene in breast tumor tissue. Also the prognosis of patients is largely not affected by low-risk breast cancer loci except for the SNP near H19. How, this SNP affects prognosis warrants further study as it does not operate through altering H19 mRNA expression.

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Abbreviations

MFS:

Metastasis-free survival

GWAS:

Genome-wide association studies

SNPs:

Single nucleotide polymorphisms

ER:

Estrogen receptor

PgR:

Progesterone receptor

Ct:

Cycle of threshold

HWE:

Hardy–Weinberg equilibrium

LD:

Linkage disequilibrium

MAF:

Minor allele frequency

HR:

Hazard ratio

CI:

Confidence interval

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Acknowledgments

The authors are especially grateful to Pascal Arp, Iris van Staveren, Marion Meijer-van Gelder, and Mieke Timmermans for their contribution and technical support. The authors thank also the surgeons, pathologists, and internists of St. Clara Hospital, Ikazia Hospital, St. Franciscus Gasthuis at Rotterdam, and Ruwaard van Putten Hospital at Spijkenisse for the supply of tumor tissues and/or their assistance in the collection of clinical follow-up data. This study was in part financed by the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research. MR was funded by the Higher Education Commission government of Pakistan.

Conflict of interest

All authors declared that they have no competing interests.

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Authors and Affiliations

  1. Department of Medical Oncology, Josephine Nefkens Institute and Daniel den Hoed Cancer Center, Erasmus MC, Building BE, Room 400, Dr. Molewaterplein 50, 3015 GE, Rotterdam, The Netherlands

    Muhammad Riaz, Els M. J. J. Berns, Anieta M. Sieuwerts, Kirsten Ruigrok-Ritstier, Vanja de Weerd, Arwin Groenewoud, Maxime P. Look, Jan G. M. Klijn, Stefan Sleijfer, John A. Foekens & John W. M. Martens

  2. Cancer Genomic Center, Erasmus MC, Rotterdam, The Netherlands

    John A. Foekens & John W. M. Martens

  3. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands

    Andrè G. Uitterlinden

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  1. Muhammad Riaz
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  2. Els M. J. J. Berns
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  3. Anieta M. Sieuwerts
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Correspondence to John W. M. Martens.

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Riaz, M., Berns, E.M.J.J., Sieuwerts, A.M. et al. Correlation of breast cancer susceptibility loci with patient characteristics, metastasis-free survival, and mRNA expression of the nearest genes. Breast Cancer Res Treat 133, 843–851 (2012). https://doi.org/10.1007/s10549-011-1663-3

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  • DOI: https://doi.org/10.1007/s10549-011-1663-3

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