一名疑似多發性內分泌腫瘤第一型病人CDKN1B基因之研究

CDKN1B Gene (MEN-4) in a Multiple Endocrine Neoplasia Type 1-Like Patient

李燕芬(Yen-Fen Lee)

指導教授 ： 楊偉勛

共同指導教授 ： 余家利(Chia-Li Yu)

國立臺灣大學/醫學院/分子醫學研究所/碩士(2009年)

https://doi.org/10.6342/NTU.2009.00958

摘要

所謂的MEN1定義為在一個病人身上同時出現兩個或以上的內分泌腫瘤稱之，屬於一種自體顯性遺傳疾病，具有高度的遺傳外顯機率90%以上；病人的特徵會有副甲狀腺腫瘤（100％）而導致高鈣血症，胰島細胞瘤（40％），腦垂體前葉腫瘤（30％）， 1997年的時候MEN1基因被定義出和其疾病相關，臨床上發現病人有MEN1症狀，但仍有高達20~25%的患者，其MEN1 基因檢測呈陰性反應。2006、2007年的相關文獻發現p27Kip1基因的突變也會造成腦下垂體及副甲狀腺腫瘤，p27Kip1基因轉譯出的p27Kip1蛋白，對細胞週期的調控有所影響，其表現量會影響到腫瘤細胞的生長上。

搜尋HGMD(Human Mutation Database at the Institute of Medical Genetics in Cardiff)資料庫，至今共有5篇關於CDKN1B基因突變(mutation)的文章，其中只有一篇病人的臨床症狀為腦下垂體(pituitary)和副甲狀腺(parathyroid)腫瘤。2009年美國糖尿病、消化及腎臟疾病國家研究院﹙National Institute of Diabetes and Digestive and Kidney Diseases﹚發表了一篇germline mutation 在cyclin-dependent kinase inhibitor家族(p15、p16、p18、p19、p21、p27)基因的研究，總共196個病人，臨床症狀為MEN 1，基因篩檢並沒有MEN1基因的突變，研究結果總共找到9個突變點，各佔的比例為：p15(1%)、p18 (0.5%)、p21(0.5%)、p27(1.5%)。台灣現在並無CDKN1B基因突變病例報告。

先前陳輔仁醫師曾在一位疑似MEN1的病人先做過MEN1基因可能突變的研究，結果成陰性，但並不能因此排除病人沒有基因上的缺陷，在我們所分析的p27 kip1 exon上沒有找到任何有意義的突變，但是臨床是有明顯的症狀表現，副甲狀腺亢進(Primary hyperparathyroidism, PHPT)、腦下垂體前葉腫瘤(Anterior pituitary tumours)；家族中沒有其他人發生相同的疾病，從文獻得知MEN-1的發病年齡為22-73歲，而且germ-line mutation 發病年齡通常比較年輕，第一次發病大約在40歲，病人發病的年齡為81歲，而且家族的其他成員都是正常，推測病人為sporadic MEN-1，可能是環境及其生命過程中影響所發展而來。

關鍵字

多發性內分泌腫瘤第一型

並列摘要

The definition of MEN1 is two or more multiple endocrine neoplasia tumors have occurred on same patient, this is also one type of autosomal dominant genetic diseases with over 90% of prevalence. The symptoms including hypercalcemia resulting from parathyroid tumor (100%), pancreatic islet cell tumors（40％）and anterior pituitary tumours（30％). In the year of 1997, MEN1 gene was generally known as correlation with other diseases as patients were found with MEN1 symptom during clinical observation. However, there are 20%~25% of patients with negative MEN1 gene screening test result. 2006 and 2007 also confirmed that p27Kip1 gene mutation will also resulting in anterior pituitary and parathyroid tumors. The p27Kip1 protein translational by p27Kip1 gene will influence the regulator of cell cycle and further more to the growth of tumor cells.

There are five articles related to CDKN1B gene mutation from HGMD (Human Mutation Database at the Institute of Medical Genetics in Cardiff). Only one article among the five is about patient’s clinical symptoms are pituitary and parathyroid tumors. In the year of 2009, NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases) published a study report on “germline mutation within the cyclin-dependent kinase inhibitor family (p15, p16, p18, p19, p21, p27) genes. Total 196 patients participated in the study; they had MEN1 clinical symptom but no MEN1 gene mutation result from gene screening test. The report showed that total 9 mutation points have been found and the ratios are, p15(1%), p18 (0.5%), p21(0.5%) and p27(1.5%). Currently, not CDKN1B gene mutation case being reported in Taiwan.

A case study was done by Dr. Fu-Jen Chen regarding a suspicious MEN1 patient who has been given the process of MEN1 gene mutation possibility testing. The result came back was negative, however, this could not complete rule out the possibility of patient’s self genetic defects. There is no significant genetic mutation found from the analysis of p27 kip1 exon, on the other hand, there do have clearly clinical symptoms, primary hyperparathyroidism (PHPT) and anterior pituitary tumors, whereas there is no same medical history shared with other family member. We can conclude that the age to be fall to ill is between age 22 to 73, and in the case of “germ-line mutation”, the age fall to ill will usually be younger. First time usually will onset in one’s 40s. This patient was age 81 when fall to ill, and his family members were all normal and healthy. Hence, we can presume this patient is sporadic MEN-1. This may be developed along by all the factors from outside environment or patient’s past living condition.

並列關鍵字

CDKN1B gene ； Multiple Endocrine Neoplasia Type 1

參考文獻

陳甫仁，2008，《多發性內分泌腫瘤第一型基因診斷》，國立台灣大學分子醫學研究所碩士論文。

Atsushi Ozawa, Sunita K. Agarwal, Carmen M. Mateo, A. Lee Burns, Terri S. Rice, Patricia A. Kennedy, Caitlin M. Quigley, William F. Simonds, Lee S. Weinstein, Settara C. Chandrasekharappa, Francis S. Collins, Allen M. Spiegel, and Stephen J. Marx (2007) BRIEF REPORT The Parathyroid/Pituitary Variant of Multiple Endocrine Neoplasia Type 1 Usually Has Causes Other than p27Kip1 Mutations. The Journal of Clinical Endocrinology & Metabolism 92(5):1948–1951.

A. W. K. Tso, R. Rong, C. Y. Lo, K. C. B. Tan, S. C. Tiu, N. M. S. Wat, J. Y. Xu, A. Villablanca, C. Larsson, B. T. Teh and K. S. L. Lam (2003) Multiple endocrine neoplasia type 1 (MEN1): genetic and clinical analysis in the Southern Chinese. Clinical Endocrinology 59(1) :129 – 135.

Bilezikian JP, Potts JT,Jr, Fuleihan G, Kleerekoper M, Neer R, Peacock M, Rastad J, Silverberg SJ, Udelsman R & Wells SA (2002) Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century. The Journal of Clinical Endocrinology & Metabolism 87: 5353–5361.

Burgess JR, Greenaway TM & Shepherd JJ (1998) Expression of the MEN-1 gene in a large kindred with multiple endocrine neoplasia type 1. Journal of Internal Medicine 243: 465–470.