Multiple Endocrine Neoplasia Type 1 Increases Risk of Breast Cancer
In a study reported in a letter to The New England Journal of Medicine, Dreijerink et al in the International Breast Cancer in MEN1 Study Group identified a high risk of breast cancer in women with multiple endocrine neoplasia type 1 (MEN1).
MEN1 is caused by germline mutations in the MEN1 tumor-suppressor gene and is associated with parathyroid adenomas, duodenopancreatic neuroendocrine tumors, and pituitary adenomas. Recent data suggest a role of MEN1 in initiation of breast cancer and a role in progression of disease via encoding of menin (a coregulator of estrogen receptor alpha).
Increased Risk in Dutch Population
In the study, the incidence of breast cancer was assessed in the Dutch longitudinal MEN1 database, which includes more than 90% of Dutch patients with MEN1. In 190 female patients with MEN1, the relative risk of invasive breast cancer was 2.83 (P < .001) and the standardized incidence ratio was 2.14 (95% confidence interval [CI] = 1.18–3.86) compared with the general population. Mean age at diagnosis of mostly luminal-type breast cancer was 48 years vs 60 to 65 years in the general population. No elevation of risk ratios for other major cancers was observed.
Risk in Validation Cohorts
Analysis of data from a total 675 female patients from independent cohorts in the United States, Tasmania, and France yielded risk ratios of 2.40 (P = .11), 2.31 (P = .22), and 2.33 (P = .03), respectively. It was noted that the comparisons in the United States and Tasmania failed to reach statistical significance due to small patient numbers. In the pooled cohorts, the standardized incidence ratio of 1.96 was significant (95% CI = 1.33–2.88). The average age at diagnosis was 51 years.
Potential Mechanism
In a study in 10 Dutch patients, nuclear localization of menin was reduced by > 50% in eight, and analysis with DNA sequencing or multiplex ligation-dependent probe amplification showed loss of heterozygosity at the MEN1 locus in three of nine tumors. In contrast, reduced menin staining was observed in only 4 of 88 control breast tumors on tissue microarray.
The investigators concluded, “[F]emale patients with MEN1 are at increased risk for breast cancer. Loss of menin expression and loss of heterozygosity at the MEN1 locus in a subgroup of patients suggest a mammary-cell autonomous effect in MEN1-related breast cancer. Our observations indicate that MEN1 mutations are involved in human breast carcinogenesis…. Intensified breast cancer screening at a relatively young age should be considered in female patients with MEN1.”
Koen M.A. Dreijerink, MD, PhD, of Dana-Farber Cancer Institute, is the corresponding author for The New England Journal of Medicine letter.
The study was supported by the Dutch Cancer Society, Ipsen Pharmaceuticals, and Comprehensive Cancer Center of the Netherlands.
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