Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Endocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, BrazilEndocrine Genetics Unit (Laboratorio de Investigacao Medica/LIM-25)Neuroendocrinology UnitNeuroendocrinology-Neurosurgery UnitAdrenal Unit (LIM-42)General Endocrinology UnitExperimental Oncology Laboratory (LIM-24)Department of PathologyNursing SchoolSchool of Public Health of Hospital das ClínicasUniversity of Sao Paulo School of Medicine, Sao Paulo, BrazilBrigadeiro HospitalSao Paulo, BrazilHuman Genome Research CenterUniversity of Sao Paulo, Sao Paulo, BrazilInstituto do CérebroInstituto Israelita de Ensino e Pesquisa Albert Einstein, Sao Paulo, BrazilNational Institute of AgingNational Institutes of Health (NIH), Bethesda, Maryland, USAInstitute of PathologyHelmholtz Zentrum München, Neuherberg, GermanyInstitute of Biomedical SciencesUniversity of Sao Paulo, Sao Paulo, BrazilDivision of EndocrinologyFederal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Eur J Endocrinol. 2014 Sep;171(3):335-42. doi: 10.1530/EJE-14-0130. Epub 2014 Jun 11.
To date, no evidence of robust genotype-phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for.
As the CDKN1B (p27) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1-mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals.
Genotyping of the coding p27 c.326T>G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression.
There were significant differences in p27 V109G allele frequencies between controls and MEN1-mutated patients (OR=2.55, P=0.019, CI=1.013-5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P=0.002, CI=2.88-16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors.
Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.
迄今为止，尚未发现多种内分泌肿瘤 1 型（MEN1）综合征存在强有力的基因型-表型相关性或疾病修饰因子，这使得患者临床表现的高度变异性无法得到解释。
由于 CDKN1B（p27）基因导致 MEN4 综合征，并且其转录受到 MEN1 基因产物（menin）的调控，我们试图分析 p27 是否会影响 MEN1 突变患者的表型。该队列包括 100 名携带种系 MEN1 基因突变的患者和 855 名匹配的人群对照个体。
通过测序和限制酶切分析，对编码 p27 c.326T>G（V109G）变异的基因进行基因分型，并通过计算优势比（OR）及其 95%置信区间（CI），使用逻辑回归将基因型与临床参数相关联。
在对照个体和 MEN1 突变患者之间，p27 V109G 等位基因频率存在显著差异（OR=2.55，P=0.019，CI=1.013-5.76）。在≥30 岁携带截断性 MEN1 突变的患者中，T 等位基因与多腺体肿瘤易感性密切相关（受影响的腺体数量为三到四个与受影响的腺体数量为一到两个相比；OR=18.33；P=0.002，CI=2.88-16.41）。在经过 Bonferroni 多重检验校正后，这一发现仍然具有统计学意义，表明存在稳健的关联。与 MEN1 相关肿瘤的发生如甲状旁腺功能亢进、垂体腺瘤、肠胰和肾上腺皮质肿瘤无相关性。
我们的研究表明，p27 肿瘤抑制基因作为与 MEN1 种系突变相关的 MEN1 综合征的疾病修饰因子。如果在独立的患者队列中得到证实，这一发现可能有助于管理这种临床表现复杂的疾病。
