诊断横纹肌肉瘤的一个Li-Fraumeni综合征家系报道并文献复习

Li-Fraumeni综合征(LFS)为一种遗传易感肿瘤综合征,肿瘤发病年龄早,个体肿瘤发生率高。先证者为2岁6个月男童,病理诊断为左颌下胚胎型横纹肌肉瘤;其哥哥因横纹肌肉瘤去世,外祖母患乳腺癌。对患儿及部分家庭成员进行TP53基因突变检测,发现患儿存在EXON 8的错义突变:c.844CT(p.Arg282Trp)(杂合),患儿母亲、姐姐均检测出该突变。符合LFS诊断标准。TP53基因是比较明确的LFS致病基因。儿童患者LFS疾病谱系中最常见的依次为骨肉瘤、肾上腺皮质癌、中枢神经系统肿瘤及软组织肿瘤,其它可能相关的包括白血病、淋巴瘤等。LFS患者有较大的几率患二次甚至多次肿瘤。因此对于儿童肿瘤患者,尤其是某些具有遗传易感性的肿瘤,有必要进行遗传学评估,如果存在TP53基因突变,治疗上则应当更为积极,并对LFS家系进行系统监测管理。     

p53和淋巴系统恶性肿瘤

抑癌基因p53通过控制细胞增殖，诱导细胞调亡来维持细胞遗传物质的稳定性，其功能失活与否成为影响肿瘤发生、发展及对放疗、化疗敏感性的关键因素。淋巴系统恶性肿瘤中存在频繁的p53基因突变，本文拟综述p53与淋巴系统恶性肿瘤的发生、发展、治疗以及预后的关系。     

中国儿童白血病中P^53基因失活突变的研究

目的通过对中国儿童白血病患儿外周静脉血及骨髓标本的Ｐ５３基因失活突变的分析，探讨Ｐ５３基因突变在儿童白血病中的作用机制，及其突变类型在中国人群中的分布频率。方法用聚合酶链反应分别扩增Ｐ５３基因的外显子４，５，６，７，８；用单链构象多态性对扩增片段进行点突变检测。结果２２例儿童白血病人中９例在不同的外显子内发现了点突变，其中外显子７内的点突变发生频率最高。１例在血液系统外的体细胞中亦存在点突变，被证明是遗传性的突变，其他８例则是获得性突变。结论儿童白血病与其他实体肿瘤一样，普遍存在Ｐ５３基因的失活，因此对疾病的发生有重要意义。突变发生的频率与国外报道相同，因此是人类不同类型肿瘤的一个基本致变因素。     

原发性肠淋巴瘤p53基因与13q14染色体变异与预后的关系

目的：临床发现尽管原发性肠淋巴瘤的免疫表型相同,但预后也可以截然不同,提示其预后不是单一因素所决定的,可能还与其基因或染色体的变异有关。p53基因是一种重要的抑癌基因,13q14缺失是多种淋巴细胞增殖性疾病常见的染色体异常,该研究拟探讨p53基因与13q14染色体变异在原发性肠淋巴瘤的预后判断、指导治疗中的作用,为临床治疗方案的制定提供依据。方法：采用改良的FISH技术检测了30例原发性肠淋巴瘤及10例淋巴结反应性增生患者的石蜡切片中p53基因及13q14染色体变异情况,分析其与原发性肠淋巴瘤预后的关系。结果：①Ⅰ~Ⅱ期患者中22.7%有p53基因缺失,Ⅲ~Ⅳ期患者中75.0%有p53基因缺失（χ2=6.903, P<0.01）;②MALT淋巴瘤中14.3%有p53基因缺失,非MALT淋巴瘤中56.3%有p53基因缺失（χ2=5.662, P<0.05）;③p53基因缺失者平均生存期为13.4月,明显短于p53基因正常者36.1月（t=2.637,P<0.05）;④13q14缺失在原发性肠淋巴瘤中发生率为40%,但在10例淋巴结反应性增生患者的石蜡切片中未检测到。13q14缺失与原发性肠淋巴瘤病理类型、临床分期以及平均生存期的关系不大;⑤p53基因缺失与13q14缺失无明显相关性。结论：p53基因缺失在非MALT淋巴瘤及Ⅲ~Ⅳ期患者中发生率较高。p53基因缺失的原发性肠淋巴瘤病例恶性程度高、预后差,宜早期联合化疗。13q14缺失与患者预后无明显相关性。［中国当代儿科杂志,2009,11（7）：555-558］     

伴DNA修复相关基因胚系突变的遗传易感性小儿白血病5例临床分析

目的探讨DNA修复相关基因胚系突变所致遗传易感性小儿白血病的诊断思路以及这类疾病临床、遗传学特征。方法收集并回顾性分析2017年5月—2020年1月确诊的5例DNA修复相关基因胚系突变的遗传易感性小儿白血病患儿的临床资料及遗传学、分子学资料。结果伴遗传易感性的白血病患儿中涉及DNA修复缺陷者5例,男2例,女3例。5例中1例TP53突变,2例PMS2突变,1例9p21.3p21.1缺失,1例CHEK2突变。结论白血病诊疗中应注意体貌异常及肿瘤家族史,不存在以上也不能除外肿瘤遗传易感性。需甄别结构性变异,重视基因突变及杂合性缺失两种形式,完全缓解后的拷贝数变异检测应更加积极。TP53c. 421T C p. C141R的胚系突变形式为致病性突变。PMS2的单等位基因突变也可导致典型的结构性错配修复综合征发生。DNA修复缺陷相关胚系突变本身不影响化疗反应,体细胞改变特征才是影响化疗疗效的关键因素。     

小儿急性淋巴细胞性白血病与p53基因突变的相关性研究

ｐ５３基因是迄今发现与人类肿瘤相关性最高的一个重要的抑癌基因 ,但 ｐ５３基因一旦突变则成为白血病发生的重要分子生物学机制之一。本研究应用聚合酶链反应结合单链构象多态性分析(ＰＣＲ＿ＳＳＣＰ)技术检测了１６例小儿急性淋巴细胞性白血病 (ＡＬＬ)的ｐ５３基因５、６、７、８外显子的突变 ,以探讨 ｐ５３基因突变与小儿ＡＬＬ发生、治疗效果及预后的关系。对象和方法一、对象ＡＬＬ患儿 (按ＦＡＢ标准诊断 )共１６例 ,年龄１岁～１３岁。其中初诊７例 ,复发期３例 ,缓解期６例。二、方法提取患儿外周血ＤＮＡ后 ,应用上海复旦大学…     

NBS1基因突变与肿瘤发生的相关性研究进展

Nijmegen断裂综合征是一种极其罕见的常染色体隐性遗传病.分子流行病学显示NBS1基因是肿瘤易患基因.迄今共在肿瘤患者的NBSl基因编码区发现了9种杂合子突变,目前关注较多的是657del5、511A→G(I171V)、643C→T(R215W).该文就Nijmegen断裂综合征的症状及细胞特点、NBS1基因定位及蛋白结构、常见的杂合突变及其与肿瘤的关系作一综述.     

p53免疫组化判定肾母细胞瘤预后的研究

目的探讨p53免疫组化的表达与肾母细胞瘤侵袭性的关系,及对术前化疗的评估。方法收集2007年一2009年本院收治的44例肾母细胞瘤患儿,25例患儿未接受化疗而直接手术,19例术前化疗后再做手术。患儿术后病理组织学检查均证实为肾母细胞瘤,年龄0.4~10岁,平均年龄(2.7±2.0)岁。所有病理切片做p53免疫组化。根据p53染色密度和强度进行计分。结果 p53高强度、综合得分在术后和术前化疗患儿之间有统计学意义(P=0.003;P=0.006),综合得分为1的术后化疗患儿死亡、复发及组织结构分型有统计学意义(P值分别为0.034、0.035、0.02)。综合得分为1的术前化疗患儿死亡、复发及组织结构分型无统计学意义(P=0.271)。结论本研究初步表明,肾母细胞瘤术后化疗的肿瘤侵袭性较术前化疗肾母细胞瘤强,p53免疫组化的表达与肾母细胞瘤分期和预后相关,可能成为肾母细胞瘤肿瘤组织病理学分析的补充。     

细胞程序化列亡与肿瘤治疗

细胞程序化死亡是一种不同于细胞坏死的主动死亡方式，它受基因、细胞因子等因素调控，并与肿瘤的发生、发展、转归密切相关，本文讨论了细胞程序化死亡相关基因ｐ５３、ｂｃｌ－２、ｃ－ｍｙｃ和细胞因子在肿瘤细胞程序化死亡中的调控，及细胞程序化死亡在肿瘤发生和治疗中的作用。     

以孤独症为主要表型的MYT1L基因突变嵌合体1例并文献复习北大核心CSCD

对2019年4月河南省儿童医院康复医学科就诊的1例孤独症谱系障碍(ASD)的MYT1L基因突变患儿临床表型和基因型进行回顾性分析。对患儿进行全基因组测序及拷贝数异常(CNVs)检测,并复习相关文献。该患儿存在MYT1L基因15号外显子错义突变(c.2186T>G,p.Met729Arg),患儿为嵌合体,突变率约为10%,该突变未在父母及患儿哥哥中出现。检索到MYT1L相关基因异常报道共18篇文献,共53例患者(含本例),包括22种点突变及30例携带包含MYT1L基因区域在内的2p25.3染色体条带微缺失患者。患者孤独症行为发生率为45.0%(18/40例)、超重/肥胖发生率为70.2%(33/47例)、智力障碍/全面发育迟缓发生率为96.2%(51/53例),嵌合体的症状相对较轻。提示MYT1L基因是ASD重要的易感基因,但嵌合体的症状较轻。ASD患儿共患肥胖或超重时应警惕可能存在MYT1L基因突变,可进行基因检测协助诊断并注意嵌合体存在的可能性,本研究扩大了ASD基因突变谱。     

Molecular epidemiology study of a suspected community cluster of childhood cancers

We investigated the report of a community cluster of cancers in 33 children, which included two siblings known to have dominantly inherited Li-Fraumeni syndrome and a germline p53 mutation. After defining criteria for inclusion in the cluster, the 12 eligible childhood cancer probands diagnosed between 1980 and 1989 were not excessive (expected, ten cases). The corresponding childhood cancer mortality rates for the community fluctuated between 1950 and 1989 and were not increased overall. However, three additional probands had family histories of childhood cancer that suggested a forme fruste of Li-Fraumeni syndrome. The epidemiological data suggested a geographic cluster of this rare hereditary disorder, but absence of germline p53 mutation in the three other multicase families indicates genetic heterogeneity. Laboratory studies can assist analyses of suspected clusters, although investigations of geographic clusters of hereditary cancers raise complex issues of confidentiality and protection of affected individuals, their families, and the community. Med. Pediatr. Oncol. 28:243–247. © 1997 Wiley-Liss, Inc.     

Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation

A child with an unusual association of cancers is described. The patient first presented with a rhabdomyosarcoma of the right scapular muscle, and was successfully treated with chemotherapy. Six years after diagnosis of the first malignancy, the child presented with two synchronous malignancies: osteosarcoma of the jaw and adrenocortical carcinoma. Genetic mutation analysis was performed and revealed a germline p53 mutation of CGT > CAT at codon 273. The family history was negative for any other cancer consistent with the Li-Fraumeni syndrome. This case highlights the need for close surveillance of patients with p53 mutation for malignancy and describes the occurrence of two malignancies synchronously.     

Early detection of adrenocortical carcinoma in a child with Li–Fraumeni syndrome

We report an early detection of cancer in a child with Li–Fraumeni syndrome. The proband was a 3‐year‐old male with a primitive mesenchymal tumor. Genetic analysis showed a germline TP53 mutation in codon 220 exon 6, which changed TAT → TGT and resulted in a tyrosine‐to‐cysteine amino acid substitution (Tyr220Cys). The younger sister at risk was followed, and an asymptomatic adrenal cortical carcinoma was detected 3 years later. The report highlights the importance of genetic counseling and provides an example of early detection of cancers in childhood LFS carriers. Pediatr Blood Cancer 2009;52:541–544. © 2008 Wiley‐Liss, Inc.     

Novel p53 splicing site mutation in Li‐Fraumeni‐like syndrome with osteosarcoma

We describe a 15‐year‐old girl with a novel germline p53 splice site mutation who developed an osteosarcoma. She received several cycles of chemotherapy with complete resection of the primary tumor without amputation, and has maintained remission for 18 months. Li‐Fraumeni‐like syndrome was suspected based on familial history. Sequence analysis revealed the presence of a novel germline p53 gene mutation resulting in a G to A transition at position +1 at the donor splice site of intron 6, creating a 6 amino acid insertion. This case provides interesting insight into the phenotype‐genotype correlation in LFL syndrome with a TP53 splicing mutation.     

Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists.     

Germ-line genetic variation of TP53 in osteosarcoma

BACKGROUND: Osteosarcoma (OS) has been well described in individuals with germ-line TP53 mutations (Li-Fraumeni Syndrome) but typically occurs sporadically in adolescents and young adults. Single nucleotide polymorphisms (SNPs), the most common germ-line genetic variation, have been associated with risk for other types of cancer. We hypothesized that genetic variation in TP53 could be associated with OS risk based on its critical role in cell growth and effect of somatic mutations in OS tumors. PROCEDURE: Twelve common SNPs in TP53 were genotyped in a case-control study of sporadic OS. These SNPs spanned the TP53 locus and captured common haplotypes. Genotype data were analyzed using contingency tables for additive, dominant, and recessive genetic models. PHASEv2.1 and HaploStats were used to evaluate haplotypes. RESULTS: The recessive model suggested an increased risk of OS when two copies of TP53-34 C>G variant (IVS2+38, rs1642785) were present, P = 0.041, odds ratio (OR) 6.70 (95% confidence interval [CI] 1.06-41.6). The TP53-01 variant C>G (Pro72Arg, rs1042522) may also be associated with increased risk for OS, P = 0.028, OR 7.5 (95% CI 1.20-46.3). Common TP53 haplotypes as well as the remaining 10 SNPs were not associated with risk for OS. CONCLUSIONS: These data do not indicate a strong link between variation in TP53 and OS risk, although they provide preliminary evidence of an increased risk of OS associated with variants at IVS2+38 and Pro72Arg. The findings warrant replication in further studies.     

De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system

We present a case of a 14‐year‐old male with a germline TP53 mutation who presented with synchronous primitive neuroectodermal tumor and choroid plexus carcinoma. Identification of synchronous brain tumors prompted genetic testing for predisposition to malignancy. Within 5 months of presentation, the child developed widely metastatic alveolar rhabdomyosarcoma. Patient DNA sequencing showed a TP53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The child's parents, younger brother, paternal grandparents, and maternal grandmother, are without history of malignancy. The patient's brother tested negative for TP53 mutations. This case identifies a rare, de novo, germline TP53 mutation presenting with synchronous CNS malignancies and exhibiting a more fulminant course than typical cases of Li–Fraumeni syndrome. Pediatr Blood Cancer 2009; 53:1352–1354. © 2009 Wiley‐Liss, Inc.     

TP53 codon 72 polymorphisms in favorable histology Wilms tumors

In Wilms tumor (WT), mutations in the gene encoding p53, TP53, are correlated with anaplasia; however TP53 variants have not been studied in favorable histology (FH) WTs. A single nucleotide polymorphism of TP53 encoding either arginine or proline at codon 72 is suggested to alter in vitro p53 behavior. Therefore, we analyzed tissue from 23 consecutive patients with FHWT to determine allelic and genotypic frequencies of Pro72 and Arg72 variants and correlate this with clinical outcomes. Interestingly, our cohort showed a statistically significant over-representation of the Arg allele and Arg/Arg genotype. However, the genotypic and allelic frequencies showed no significant correlation with age, stage, or disease recurrence.     

TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report

Rhabdomyosarcoma (RMS) is a well-described cancer in Li–Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.