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Abstract：
BACKGROUND: Early menarche is an established risk factor for breast cancer but its molecular contribution to tumor biology and prognosis remains unclear.
METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses\' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952).
RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (β = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (β = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]).
CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.
METHODS: We profiled transcriptome-wide gene expression in breast tumors (N = 846) and tumor-adjacent normal tissues (N = 666) from women in the Nurses\' Health Studies (NHS) to investigate whether early menarche (age < 12) is associated with tumor molecular and prognostic features in women with breast cancer. Multivariable linear regression and pathway analyses using competitive gene set enrichment analysis were conducted in both tumor and adjacent-normal tissue and externally validated in TCGA (N = 116). Subgroup analyses stratified on ER-status based on the tumor were also performed. PAM50 signatures were used for tumor molecular subtyping and to generate proliferation and risk of recurrence scores. We created a gene expression score using LASSO regression to capture early menarche based on 28 genes from FDR-significant pathways in breast tumor tissue in NHS and tested its association with 10-year disease-free survival in both NHS (N = 836) and METABRIC (N = 952).
RESULTS: Early menarche was significantly associated with 369 individual genes in adjacent-normal tissues implicated in extracellular matrix, cell adhesion, and invasion (FDR ≤ 0.1). Early menarche was associated with upregulation of cancer hallmark pathways (18 significant pathways in tumor, 23 in tumor-adjacent normal, FDR ≤ 0.1) related to proliferation (e.g. Myc, PI3K/AKT/mTOR, cell cycle), oxidative stress (e.g. oxidative phosphorylation, unfolded protein response), and inflammation (e.g. pro-inflammatory cytokines IFN α and IFN γ ). Replication in TCGA confirmed these trends. Early menarche was associated with significantly higher PAM50 proliferation scores (β = 0.082 [0.02-0.14]), odds of aggressive molecular tumor subtypes (basal-like, OR = 1.84 [1.18-2.85] and HER2-enriched, OR = 2.32 [1.46-3.69]), and PAM50 risk of recurrence score (β = 4.81 [1.71-7.92]). Our NHS-derived early menarche gene expression signature was significantly associated with worse 10-year disease-free survival in METABRIC (N = 952, HR = 1.58 [1.10-2.25]).
CONCLUSIONS: Early menarche is associated with more aggressive molecular tumor characteristics and its gene expression signature within tumors is associated with worse 10-year disease-free survival among women with breast cancer. As the age of onset of menarche continues to decline, understanding its relationship to breast tumor characteristics and prognosis may lead to novel secondary prevention strategies.
摘要：
背景：初潮早期是乳腺癌的既定危险因素，但其对肿瘤生物学和预后的分子贡献尚不清楚。
方法：我们在护士健康研究（NHS）中分析了女性乳腺肿瘤（N=846）和肿瘤旁正常组织（N=666）的全转录组基因表达，以调查初潮早期（年龄<12岁）是否与乳腺癌女性的肿瘤分子和预后特征相关。在肿瘤和邻近正常组织中进行了使用竞争性基因集富集分析的多变量线性回归和途径分析，并在TCGA中进行了外部验证（N=116）。还进行了基于肿瘤的ER状态分层的亚组分析。PAM50标记用于肿瘤分子分型并产生增殖和复发风险评分。我们使用LASSO回归创建了一个基因表达评分，以基于NHS中乳腺肿瘤组织中FDR显著通路的28个基因捕获初潮早期，并测试了其与NHS(N=836)和METABRIC(N=952)中10年无病生存期的关联。
结果：初潮早期与与细胞外基质有关的邻近正常组织中的369个个体基因显着相关，细胞粘附，和侵入(FDR≤0.1)。初潮早期与癌症标志通路的上调有关（肿瘤中18个重要通路，23在肿瘤附近的正常，FDR≤0.1)与增殖相关(如Myc、PI3K/AKT/mTOR,细胞周期)，氧化应激(例如氧化磷酸化，未折叠的蛋白质反应)，和炎症(例如促炎细胞因子IFNα和IFNγ)。TCGA中的复制证实了这些趋势。初潮早期与PAM50增殖评分显著增高相关(β=0.082[0.02-0.14]),侵袭性分子肿瘤亚型的几率(基底样，OR=1.84[1.18-2.85]和HER2富集，OR=2.32[1.46-3.69])，和PAM50复发风险评分（β=4.81[1.71-7.92]）。我们的NHS衍生的初潮早期基因表达特征与METABRIC较差的10年无病生存率显着相关（N=952，HR=1.58[1.10-2.25]）。
结论：初潮早期与更具侵袭性的分子肿瘤特征相关，其在肿瘤中的基因表达特征与乳腺癌女性患者10年无病生存率较差相关。随着初潮开始的年龄持续下降,了解其与乳腺肿瘤特征和预后的关系可能会导致新的二级预防策略。
方法：我们在护士健康研究（NHS）中分析了女性乳腺肿瘤（N=846）和肿瘤旁正常组织（N=666）的全转录组基因表达，以调查初潮早期（年龄<12岁）是否与乳腺癌女性的肿瘤分子和预后特征相关。在肿瘤和邻近正常组织中进行了使用竞争性基因集富集分析的多变量线性回归和途径分析，并在TCGA中进行了外部验证（N=116）。还进行了基于肿瘤的ER状态分层的亚组分析。PAM50标记用于肿瘤分子分型并产生增殖和复发风险评分。我们使用LASSO回归创建了一个基因表达评分，以基于NHS中乳腺肿瘤组织中FDR显著通路的28个基因捕获初潮早期，并测试了其与NHS(N=836)和METABRIC(N=952)中10年无病生存期的关联。
结果：初潮早期与与细胞外基质有关的邻近正常组织中的369个个体基因显着相关，细胞粘附，和侵入(FDR≤0.1)。初潮早期与癌症标志通路的上调有关（肿瘤中18个重要通路，23在肿瘤附近的正常，FDR≤0.1)与增殖相关(如Myc、PI3K/AKT/mTOR,细胞周期)，氧化应激(例如氧化磷酸化，未折叠的蛋白质反应)，和炎症(例如促炎细胞因子IFNα和IFNγ)。TCGA中的复制证实了这些趋势。初潮早期与PAM50增殖评分显著增高相关(β=0.082[0.02-0.14]),侵袭性分子肿瘤亚型的几率(基底样，OR=1.84[1.18-2.85]和HER2富集，OR=2.32[1.46-3.69])，和PAM50复发风险评分（β=4.81[1.71-7.92]）。我们的NHS衍生的初潮早期基因表达特征与METABRIC较差的10年无病生存率显着相关（N=952，HR=1.58[1.10-2.25]）。
结论：初潮早期与更具侵袭性的分子肿瘤特征相关，其在肿瘤中的基因表达特征与乳腺癌女性患者10年无病生存率较差相关。随着初潮开始的年龄持续下降,了解其与乳腺肿瘤特征和预后的关系可能会导致新的二级预防策略。
