SLC2A2基因变异与糖代谢异常疾病

SLC2A2基因是溶质转运家族2的成员之一，其编码蛋白分布于肝脏、胰腺、肾脏、下丘脑等组织，调节细胞对葡萄糖的摄取，具有重要的生理功能。研究表明SLC2A2基因的变异与糖尿病、Fanconi—Bickel综合征等糖代谢异常的疾病的发生息息相关。     

凝血酶原基因G20210A变异与血栓性疾病

凝血酶原基因 3’端非编码区 2 0 2 1 0G→A变异是新发现的一个血栓性疾病的遗传性危险因素 ,导致血液凝血酶原浓度升高。该基因变异多见于静脉血栓形成病人 ,也与年青人的心肌梗塞和脑血栓形成发病有关。这是继发现因子ⅤLeiden突变后又一重大进展 ,对血栓性疾病的预防与诊治有重要意义。     

CDKN2A/B在原发性中枢神经系统肿瘤中的研究进展

原发性中枢神经系统肿瘤具有较高的致残率和病死率。WHO(2021)中枢神经系统肿瘤分类将CDKN2A/B纳入分级诊断依据。为进一步准确理解CDKN2A/B在WHO(2021)肿瘤分类中的作用,该文就CDKN2A/B的结构特征、生物学作用、在胶质瘤和脑膜瘤中的研究进展等方面进行综述。     

乙型肝炎病毒X基因变异与临床

乙型肝炎病毒（ＨＢＶ）Ｘ基因是病毒基因组内功能重叠最明显的区域。近来的研究表明，ＨＢＶＸ基因变异类型主要为Ｃ基因启动子区内的聚集米异，尤其是第Ｔ１７６２、Ａ１７６４联合点突变，是在转录水平上造成ＨＢｅＡｇ（－）ＨＢＶ感染的原因；以及ＤＲ２变异合并Ｃ基因启动子合段或部分缺失，此类变异毒株感染是造成部分非甲－戊型肝炎的原因；ＨＢＶＸ基因变异与重型肝炎的关系仍不明确。     

乙型肝炎病毒X基因变异与临床

乙型肝炎病毒（ＨＢＶ）Ｘ基因是病毒基因组内功能重叠最明显的区域。近来的研究表明，ＨＢＶＸ基因变异类型主要为Ｃ基因启动子区内的聚集变异，尤其是第Ｔ１７６２、Ａ１７６４联合点突变，是在转录水平上造成ＨＢｅＡｇ（一）ＨＢＶ感染的原因；以及ＤＲ２变异合并Ｃ基因启动子全段或部分缺失，此类变异毒株感染是造成部分非甲－戊型肝炎的原因；ＨＢＶＸ基因变异与重型肝炎的关系仍不明确。     

ATM基因变异与淋巴系肿瘤

ATM为肿瘤抑制基因 ,编码的蛋白属于磷脂酰肌醇 3激酶家族成员 ,在DNA双链断裂诱导的信号级联转导通路中起关键性作用 ,可激活细胞周期的多个检查点 ,促进高保真的DNA同源重组修复。ATM蛋白对维持基因组及端粒的稳定也起重要作用。散发性淋巴系肿瘤如T幼淋巴细胞白血病 (T PLL)、外套细胞淋巴瘤 (MCL)和B慢性淋巴细胞白血病 (B CLL)可出现高频率的ATM基因杂合性缺失和核苷酸突变。ATM基因的功能失活与散发性淋巴系肿瘤的发病有关     

载脂蛋白E基因变异与Ⅲ型高脂血症

ａｐｏＥ作为ａｐｏＥ受体和ａｐｏＢＥ受体的配基，在脂蛋白代谢中起重要作用。ａｐｏＥ具有明显的多态性，其异构体中部分来源于结构基因变异，部分来源于翻译后修饰。常见的ａｐｏＥ２和其它一些稀有变异与Ⅲ型ＨＬＰ有关。绝大多数变异受体结合力下降。其遗传方式包括显性和隐性。     

CDKN2A/2B基因多态性与妊娠糖尿病相关

目的研究CDKN2A/2B基因rs10811661的单核苷酸多态性(SNP),探讨其与妊娠糖尿病(GDM)的相关性。方法选取鲁西南地区正常糖耐量孕妇(NGT)100例、GDM患者120例、2型糖尿病(T2DM)患者100例作为研究对象,提取基因组DNA,采用PCR-RFLP方法检测CDKN2A/2B基因rs10811661多态性。结果 CDKN2A/2B基因rs10811661的TT、TC、CC 3种基因型分布在NGT组与GDM组间有显著差别(P<0.01),GDM组危险等位基因T分布频率显著高于NGT组(P<0.05)。3种基因型及等位基因分布在NGT组与T2DM组之间亦有显著差别(P<0.05)。结论在鲁西南地区女性人群中,CDKN2A/2B基因rs10811661 T/C多态性可能与妊娠糖尿病有明显相关性。     

胃癌组织CDKN2A基因座p14ARF基因变异及意义

目的:探讨胃癌组织p14^ARF基因变异及其意义。方法: 应用PCR、PCR-SSCP、PCR甲基化分析法和RT-PCR分别检测48例胃癌及癌旁组织中p14^ARF基因纯合性缺失、突变、CpG岛甲基化及其mRNA表达状况。结果:①胃癌组织p14^ARF基因纯合性缺失率为31.3%(15/48), 癌旁组织均未见纯合性缺失。②33例无纯合性缺失的胃癌及癌旁组织均未见p14^ARF基因点突变。③胃癌组织p14^ARF基因甲基化率为47.9%(23/48), 癌旁组织仅2例甲基化, 两者差异有显著(P＜0.01)。④45.8%(22/48)的胃癌组织p14^ARFmRNA无表达。3例外显子E1β和E2共甲基化者p14^ARFmRNA均无表达(100%), 20例单纯E2甲基化者仅3例无表达(15%), 两者差异有显著(P＜0.05)。ARF基因失活多由纯合性缺失和5’CpG岛甲基化所致, 其表达缺失与胃癌的发生密切相关。     

CDKN2A (p16INK4A) somatic and germline mutations

The cell cycle is composed of a series of steps that can be negatively or positively regulated by various factors. A group of low-molecular-weight proteins have recently been identified that specifically inhibit the function of cyclin-dependent kinases in mammalian cells. Inactivation of the CDKN2A gene (also known as p16^INK4A and MTS1) attracted considerable interest after it was mapped to 9p21, a locus for familial melanoma. In an effort to standardize the information regarding human CDKN2A mutations detected in cancers, a database with information of 146 point mutations has been created. Cancer type, origin of cells, specific mutation, amino acid change, literature citation, and other data are provided for each mutation entry. Studies of biochemical and biological functions of both wild-type and mutant proteins are central to our understanding of the role of p16^INK4a mutations in tumorigenesis, a summary of these studies is also included in the present update. © 1996 Wiley-Liss, Inc.     

肺癌CDKN2/p16基因纯合缺失的研究

目的　研究 Ｃ Ｄ Ｋ Ｎ２／ｐ１６ 基因的缺失与肺癌发生、发展的关系。方法　采用多重聚合酶链反应技术,对８９ 例肺癌进行了 Ｃ Ｄ Ｋ Ｎ２／ｐ１６ 基因第１ 、２ 外显子纯合缺失的分析研究。结果　标本取材方法的改良提高了聚合酶链反应技术对基因缺失的检出率,８９ 例肺癌中检出第１ 外显子缺失率１９ ．１ ％ （１７／８９） ,第２ 外显子缺失率２２ ．５ ％ （２０／８９） ,有１４ 例第１ 、２ 外显子共同缺失,第１ 或（ 和） 第２ 外显子总缺失率为２５８ ％ （２３／８９） 。 Ｃ Ｄ Ｋ Ｎ２／ｐ１６ 基因的缺失集中发生于非小细胞肺癌, 并与转移和分期有关。结论 Ｃ Ｄ Ｋ Ｎ２／ｐ１６ 基因的缺失是非小细胞肺癌的遗传易感因素,并在其恶性进展中起一定作用。     

CDKN2A mutations in Spanish cutaneous malignant melanoma families and patients with multiple melanomas and other neoplasia

The CDKN2A gene has been implicated in cutaneous malignant melanoma (CMM) in about 40% of families with linkage to chromosome 9p21, while a small proportion of families have mutations in the CDK4 gene. In order to estimate the importance of these genes in the predisposition to CMM in Spanish families and patients we have analysed, by SSCA, a total of 56 subjects belonging to 34 CMM families, and nine patients with multiple CMM and other neoplasia. We have detected germline CDKN2A mutations in six out of the 34 families (17%). A frameshift mutation (358delG) and four missense mutations (G59V, G101W (two cases), D84Y, and R87W) were identified. Five CMM patients from different families (14%) carried the A148T variant, which is known not to affect p16 activity. No mutations were detected in the patients with multiple CMM or other neoplasms. We have not found mutations either in exon 1 beta of the CDKN2A gene or in exon 2A of CDK4. Linkage analysis of the 9p21 region showed exclusion for one of the families for CMM and for four families for CMM/dysplastic naevi. This study indicates a small role for CDKN2A in Spanish CMM families and suggests that other genes are also responsible for CMM predisposition.     

Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families: Evidence for common founders and independent mutations

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5′ region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents. Hum Mutat 11:424–431, 1998. © 1998 Wiley-Liss, Inc.     

IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A,CDK4 and PDGFRA copy number alterations

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH‐mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high‐risk group also demonstrated a shorter PFS compared to intermediate‐ (P = 0.036) and low‐risk (P < 0.0001) groups. One limitation of this study is the relatively short follow‐up period, a common confounding factor for studies on low‐grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.     

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

Background

The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.

Methods

These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.

Results

Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.

Conclusions

The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.     

CDKN2A loss and PIK3CA mutation in myoepithelial‐like metaplastic breast cancer

Metaplastic breast carcinoma comprises a heterogeneous group of tumours with poorly understood pathogenesis. A subset of metaplastic breast cancers show myoepithelial differentiation and constitute a morphological spectrum with ill‐defined borders from fibromatosis‐like spindle cell carcinoma to myoepithelial carcinoma. In a series of 34 metaplastic breast cancers with spindle cell and myoepithelial differentiation, we found recurrent genetic aberrations, which set them apart from other metaplastic breast cancers and suggest a unique pathogenesis. The majority of cases (28 of 34 patients; 82.4%) showed distinct chromosomal loss in the 9p21.3 region, including CDKN2A and CDKN2B. Biallelic loss of the CDKN2A/B region was found in 50% of deleted cases. Expression of the cyclin‐dependent kinase inhibitor CDKN2A (p16) was missing in all samples affected by 9p21.3 loss. Other genomic alterations frequently occurring in triple‐negative and metaplastic breast cancer were absent or found in only a minority of cases. Gains of whole chromosome 5 and chromosomal region 5p were observed in nine cases, and were associated with recurrences (p < 0.001). In 64.3% of cases, 9p21.3 loss was accompanied by concurrent PIK3CA mutation. Both genomic abnormalities were also detectable in adenomyoepitheliomas (4/12), which are considered to represent the precursor lesion of myoepithelial metaplastic breast cancer. In adenomyoepithelioma, PIK3CA mutation was present in both luminal epithelial and myoepithelial cells, whereas p16 loss was found only in the latter. We conclude that 9p21.3 (CDKN2A) loss and PIK3CA mutation characterize a subgroup of metaplastic breast cancers with myoepithelial and spindle cell differentiation. Myoepithelial cells in adenomyoepithelioma may show identical aberrations. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.