Abstract
Type II transmembrane serine proteases (TTSPs) are related to tumor growth, invasion, and metastasis in cancer. Genetic variants in these genes may alter their function, leading to cancer onset and progression, and affect patient outcome. Here, 464 breast cancer cases and 370 controls were genotyped for 82 single-nucleotide polymorphisms covering eight genes. Association of the genotypes was estimated against breast cancer risk, breast cancer–specific survival, and survival in different treatment groups, and clinicopathological variables. SNPs in TMPRSS3 (rs3814903 and rs11203200), TMPRSS7 (rs1844925), and HGF (rs5745752) associated significantly with breast cancer risk (P trend = 0.008–0.042). SNPs in TMPRSS1 (rs12151195 and rs12461158), TMPRSS2 (rs2276205), TMPRSS3 (rs3814903), and TMPRSS7 (rs2399403) associated with prognosis (P = 0.004–0.046). When estimating the combined effect of the variants, the risk of breast cancer was higher with 4–5 alleles present compared to 0–2 alleles (P = 0.0001; OR, 2.34; 95% CI, 1.39–3.94). Women with 6–8 survival-associating alleles had a 3.3 times higher risk of dying of breast cancer compared to women with 1–3 alleles (P = 0.001; HR, 3.30; 95% CI, 1.58–6.88). The results demonstrate the combined effect of variants in TTSPs and their related genes in breast cancer risk and patient outcome. Functional analysis of these variants will lead to further understanding of this gene family, which may improve individualized risk estimation and development of new strategies for treatment of breast cancer.
Highlights
Breast cancer is the most common cancer among women in western countries
According to the power calculations our sample set with 464 cases and 370 controls has 83% power to detect a risk allele that is in perfect linkage disequilibrium (LD) with the marker allele and has a relative risk of 1.5
TMPRSS1 single nucleotide polymorphisms (SNPs) rs12151195 and rs12461158, TMPRSS2 SNPs rs2276205, TMPRSS3 SNP rs3814903, and TMPRSS7 SNP rs2399403 remained significant in the multivariate analysis including age, tumor grade, histological type, tumor size, nodal status, estrogen receptor (ER) status, and HER2 status (P = 0.008, 0.025, 0.040, 0.046, and 0.047, respectively) (Table 2, Fig. 1)
Summary
Breast cancer is the most common cancer among women in western countries. The known high risk susceptibility genes for breast cancer, e.g. BRCA1, BRCA2, ATM, and PALB2, are responsible for approximately 20% of the hereditary cases [1], but several unknown breast cancer–predisposing genetic factors still exist. Genetic risk factors with a low or moderate penetrance affect the risk of sporadic breast cancers and may act together with environmental and lifestyle factors and with each other to enhance cancer predisposition and progression [2,3]. Type II transmembrane serine proteases (TTSPs) degrade components of the extracellular matrix (ECM) [4,5]. The TTSPs are related especially to tumor growth, invasion, and metastasis [7]
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