Puzone Roberto, Pfeffer Ulrich
Integrated Oncology Therapies Department, Clinical Epidemiology, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Integrated Oncology Therapies Department, Molecular Pathology, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Eur J Hum Genet. 2017 Feb;25(3):384-387. doi: 10.1038/ejhg.2016.179. Epub 2016 Dec 28.
Genome-wide association studies have revealed many breast cancer (BC) risk-associated genetic variants that might functionally interact with other molecular determinants of BC. We analysed the association of 21 known risk-associated single-nucleotide variants (SNVs) with recurrent somatic variants in two cohorts of 77 and 754 oestrogen receptor α-positive BCs. Four SNVs located at 5q11.2 were found to be associated with the somatic PIK3CA variant status in the pilot cohort of 77 cases with odds ratio (OR) up to 6.5 indicating strong effects, and were selected for the validation phase. Two of these SNVs, rs252913 and rs331499, located in the MAP3K1/SETD9 gene boundary, were confirmed to be associated with somatic PIK3CA variants in the large cohort with OR 2.97 (1.17-7.75) and 1.76 (1.11-2.77), respectively, notably higher than their BC risk-associated values, both around 1.1. In the presence of the SNV or of somatic PIK3CA variants, cancers express significantly elevated levels of MAP3K1 and SETD9, with synergy of SNV and PIK3CA variants in MAP3K1 gene overexpression, consistent with a preferential PIK3CA-dependent regulation of the variant alleles.
全基因组关联研究已经揭示了许多与乳腺癌（BC）风险相关的基因变异，这些变异可能在功能上与BC的其他分子决定因素相互作用。我们在两个分别包含77例和754例雌激素受体α阳性BC的队列中，分析了21个已知的风险相关单核苷酸变异（SNV）与复发性体细胞变异之间的关联。在77例病例的试点队列中，发现位于5q11.2的4个SNV与体细胞PIK3CA变异状态相关，优势比（OR）高达6.5，表明有强烈影响，并被选入验证阶段。其中两个SNV，rs252913和rs331499，位于MAP3K1/SETD9基因边界，在大队列中被证实与体细胞PIK3CA变异相关，OR分别为2.97（1.17 - 7.75）和1.76（1.11 - 2.77），显著高于它们与BC风险相关的值，两者都约为1.1。在存在SNV或体细胞PIK3CA变异的情况下，癌症中MAP3K1和SETD9的表达水平显著升高，SNV和PIK3CA变异在MAP3K1基因过表达中具有协同作用，这与变异等位基因的优先PIK3CA依赖性调控一致。
