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Multiple endocrine neoplasia type 1: a new germline “homozygous” variant (c.201delC) caused by detection errors 1型多发性内分泌瘤:由检测错误引起的一种新的种系“纯合”变异(c.201delC)
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2022-03-07 DOI: 10.1186/s13053-022-00216-2
Zhang, Fan, Yu, Xiaohui, Wang, Xiaoli, Shao, Hua
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary cancer syndrome caused by germline variants in the MEN1 gene located on chromosome 11q13. We found a Chinese woman who had a pancreatic tumor, parathyroid tumor, adrenal tumor, and suspicion of gastrinoma. The proband and her immediate family members underwent genetic detection. The results showed that two of the proband’s six relatives had the same variants as the proband, and her sister also had the typical symptoms of MEN1. However, the first- and second-time genetic detection results showed that they were homozygous variants, which did not conform to Mendelian inheritance laws. Multiplex ligation-dependent probe amplification (MLPA) was used to rule out homozygous variants caused by a deletion of gene fragments in the proband and her immediate family members. The MLPA results showed that the gene deletion was absent in the MEN1. The results from the third genetic detection (redesigned the primer) showed that they had a heterozygous variant. A new MEN1 germline variant [c.201delC (p.Ala68Profs*51)], which could induce MEN1, was found in this study. This newly identified germline variant could improve the identification of clinical phenotypes and the early diagnosis of MEN1. Clinician should consider the present of situation that intron variant causing detection error. Re-designing the primers close to the variant site for gene detection could avoid this situation.
多发性内分泌肿瘤1型(Multiple endocrine neoplasia type 1, MEN1)是一种由染色体11q13上MEN1基因的种系变异引起的遗传性癌症综合征。我们发现了一位中国妇女,她患有胰腺肿瘤、甲状旁腺肿瘤、肾上腺肿瘤和怀疑胃泌素瘤。先证者及其直系亲属接受了基因检测。结果显示,先证者的6个亲属中有2个与先证者有相同的变异,其姐姐也有MEN1的典型症状。然而,第一次和第二次遗传检测结果显示它们是纯合变异,不符合孟德尔遗传规律。多重连接依赖探针扩增(Multiplex lig- dependent probe amplification, MLPA)用于排除先证者及其直系亲属基因片段缺失引起的纯合变异。MLPA结果显示,MEN1中不存在该基因缺失。第三次基因检测(重新设计引物)结果表明,它们具有杂合变异。一种新的MEN1种系变异[c]。201delC (p.Ala68Profs*51)]可以诱导MEN1。这一新发现的种系变异可以提高MEN1临床表型的鉴定和早期诊断。临床医师应考虑内含子变异导致检测错误的情况。重新设计靠近变异位点的引物进行基因检测可以避免这种情况。
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引用次数: 0
Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients. 早发性中东乳腺癌患者种系TP53突变的患病率
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-12-14 DOI: 10.1186/s13053-021-00206-w
Abdul Khalid Siraj, Tariq Masoodi, Rong Bu, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Saud Azam, Maha Al-Rasheed, Dahish Ajarim, Asma Tulbah, Fouad Al-Dayel, Khawla Sami Al-Kuraya

Background: The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited.

Methods: We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing.

Results: Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS.

Conclusions: TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.

背景:TP53生殖系突变在早发性中东乳腺癌(BC)中的患病率和临床相关性数据有限。方法:我们使用基于下一代测序的捕获测序方法检测了来自沙特阿拉伯的464例早发性BC患者的TP53种系突变。结果:1.5%(7/464)的沙特早发性BC患者存在种系TP53致病性突变。在我们的队列中共检测到6个致病性错义突变,1个停止增益突变和2个不确定意义变异(VUS)。463例健康对照未检出TP53致病性突变。TP53突变携带者患双侧乳腺癌的可能性显著增加(p = 0.0008)。在中位随访41个月时,单因素分析显示TP53突变是影响总生存率的不利因素。所有携带TP53突变的患者BRCA1和BRCA2突变均为阴性。多数患者(85.7%;6/7)携带TP53突变,没有提示LFS的家族史,也没有多发性LFS相关肿瘤的个人病史。仅有1例患者有提示LFS的阳性家族史。结论:TP53种系突变筛查检测出该种族早发性BC的临床意义风险,无论癌症家族史如何,都应考虑所有早发性BC,特别是在BRCA突变阴性的年轻患者中。
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引用次数: 2
Retroperitoneal leiomyosarcoma in a female patient with a germline splicing variant RAD51D c.904-2A > T: a case report. 种系剪接变异RAD51D c.904-2A > T女性患者腹膜后平滑肌肉瘤1例报告
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-11-27 DOI: 10.1186/s13053-021-00205-x
Mashu Futagawa, Hideki Yamamoto, Mariko Kochi, Yusaku Urakawa, Reimi Sogawa, Fumino Kato, Mika Okazawa-Sakai, Daisuke Ennishi, Katsunori Shinozaki, Hirofumi Inoue, Hiroyuki Yanai, Akira Hirasawa

Background: RAD51D (RAD51 paralog D) is an intermediate cancer susceptibility gene for primary ovarian cancer, including fallopian tube and peritoneal carcinomas and breast cancer. Although gynecological non-epithelial tumors such as uterine sarcomas are associated with genomic instability, including BRCA impairment, there is no clear evidence of the relationship between RAD51D variants and the risk of sarcoma development.

Case presentation: A Japanese woman in her 50s underwent multiple surgical resections and several regimens of chemotherapy for tumors that originated in the retroperitoneum and recurred in the peritoneum over a clinical course of approximately 4 years. The peritoneal tumor was histologically diagnosed as a leiomyosarcoma and was genetically identified to show a splice variant of RAD51D c.904-2A > T [NM_002878] through tumor profiling performed as a part of cancer precision medicine. The confirmatory genetic test performed after genetic counseling revealed that the RAD51D splicing variant detected in her tumor was of germline origin. In silico analyses supported the possible pathogenicity of the detected splice variant of RAD51D with a predicted attenuation in mRNA transcription and truncated protein production due to frameshifting, which was attributed to a single-nucleotide alteration in the splicing acceptor site at the 3'-end of intron 9 of RAD51D. Considering her unfavorable clinical outcome, which showed a highly aggressive phenotype of leiomyosarcoma with altered RAD51D, this case provided novel evidence for the relationship of a RAD51D splicing variant with malignant tumor development or progression. We report the findings of this rare case with possible involvement of the germline variant of RAD51D c.904-2A > T as a potential predisposing factor for malignant tumors, including leiomyosarcoma.

Conclusions: We present the findings of a case of leiomyosarcoma in the peritoneum of a female patient with a novel germline splicing variant of RAD51D as potential evidence for the pathogenicity of the variant and its involvement in the risk of sarcoma etiology and/or development. To the best of our knowledge, this is the first case report describing a leiomyosarcoma carrying a germline RAD51D splicing variant and elucidating its pathogenicity on the basis of computational prediction of the impairment of normal transcription and the presumed loss of functional protein production.

背景:RAD51D (RAD51 para D)是原发性卵巢癌(包括输卵管癌、腹膜癌和乳腺癌)的中间癌易感基因。尽管妇科非上皮性肿瘤如子宫肉瘤与包括BRCA损伤在内的基因组不稳定性相关,但没有明确的证据表明RAD51D变异与肉瘤发展风险之间存在关系。病例介绍:一名50多岁的日本妇女因肿瘤起源于腹膜后并在腹膜复发,在大约4年的临床过程中接受了多次手术切除和几种化疗方案。腹膜肿瘤经组织学诊断为平滑肌肉瘤,并通过肿瘤谱分析作为癌症精准医学的一部分进行遗传鉴定,显示RAD51D c.904-2A > T [NM_002878]剪接变异。在遗传咨询后进行的确认性基因检测显示,在她的肿瘤中检测到的RAD51D剪接变异是种系起源的。计算机分析支持检测到的RAD51D剪接变体可能的致病性,预测由于移框导致mRNA转录衰减和蛋白产生截短,这归因于RAD51D内含子9 3'端剪接受体位点的单核苷酸改变。考虑到她的不良临床结果,显示出高度侵袭性的平滑肌肉瘤表型并改变RAD51D,本病例为RAD51D剪接变异与恶性肿瘤的发生或进展的关系提供了新的证据。我们报告这一罕见病例的发现,可能涉及RAD51D c.904-2A > T的种系变异,作为恶性肿瘤(包括平滑肌肉瘤)的潜在易感因素。结论:我们报告了一例女性患者腹膜平滑肌肉瘤的发现,该患者携带一种新的种系剪接变异RAD51D,作为该变异的致病性及其参与肉瘤病因和/或发展风险的潜在证据。据我们所知,这是第一个描述携带种系RAD51D剪接变异的平滑肌肉瘤的病例报告,并在正常转录损伤的计算预测和假设的功能蛋白生产损失的基础上阐明了其致病性。
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引用次数: 2
Correction to: Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis. 更正:对患有多种原发肿瘤的个体进行大规模平行测序揭示了重新分析的好处。
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-11-16 DOI: 10.1186/s13053-021-00204-y
Karin Wallander, Håkan Thonberg, Daniel Nilsson, Emma Tham
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引用次数: 0
Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis. 对患有多种原发性肿瘤的个体进行大规模平行测序,揭示了重新分析的益处。
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-28 DOI: 10.1186/s13053-021-00203-z
Karin Wallander, Håkan Thonberg, Daniel Nilsson, Emma Tham

Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.

多发性原发性癌症是指三个或三个以上的原发性肿瘤,这种癌症非常罕见,有关这种癌症的遗传学研究也很少。我们需要进一步了解多发性原发性癌症的遗传性以及基因型与表型之间的相关性。我们对 10 名患有 3 个或更多原发性肿瘤,且之前未进行过标准临床基因检测的患者进行了全基因组/外显子组测序(WGS/WES)。在一名临床诊断为 MEN1 的患者中,我们在 MEN1 基因中检测到了一个可能致病的隐性剪接位点变异。该变异(c.654C > A)是同义变异,但我们在 cDNA 分析中发现,该变异会影响剪接并导致帧移位,其理论上的新氨基酸序列为 p.(Gly219Glufs*13)。在一个同时患有结直肠癌、卵巢癌、子宫内膜癌和慢性淋巴细胞白血病的人身上,我们发现了 MLH1 基因中一个可能的致病变体(c.27G > A),以及 CHEK2 和 HOXB13 基因中的两个风险因子变体。MLH1基因变异是同义的,但先前已证明它与MLH1基因启动子的低度低甲基化有关,并在结直肠癌和子宫内膜癌家族中与疾病分离。研究中的其余 8 人未检测到致病性单核苷酸变异或结构变异。通过 WGS/WES 发现的致病变异位于已在临床上通过 Sanger 测序和 WES 测序的基因中,但没有任何发现。我们的结论是,在临床明确诊断为特定遗传性癌症综合征的个体中,如果标准临床检测未能检测到致病变异,重新分析可能会得出诊断结果。
{"title":"Massive parallel sequencing in individuals with multiple primary tumours reveals the benefit of re-analysis.","authors":"Karin Wallander, Håkan Thonberg, Daniel Nilsson, Emma Tham","doi":"10.1186/s13053-021-00203-z","DOIUrl":"10.1186/s13053-021-00203-z","url":null,"abstract":"<p><p>Multiple primary cancers, defined as three or more primary tumours, are rare, and there are few genetic studies concerning them. There is a need for increased knowledge on the heritability of multiple primary cancers and genotype-phenotype correlations. We have performed whole-genome/exome sequencing (WGS/WES) in ten individuals with three or more primary tumours, with no previous findings on standard clinical genetic investigations. In one individual with a clinical diagnosis of MEN1, a likely pathogenic cryptic splice site variant was detected in the MEN1 gene. The variant (c.654C > A) is synonymous but we showed in a cDNA analysis that it affects splicing and leads to a frameshift, with the theoretical new amino acid sequence p.(Gly219Glufs*13). In one individual with metachronous colorectal cancers, ovarian cancer, endometrial cancer and chronic lymphocytic leukaemia, we found a likely pathogenic variant in the MLH1 gene (c.27G > A), and two risk factor variants in the genes CHEK2 and HOXB13. The MLH1 variant is synonymous but has previously been shown to be associated to constitutional low-grade hypermethylation of the MLH1 promoter, and segregates with disease in families with colorectal and endometrial cancer. No pathogenic single nucleotide or structural variants were detected in the remaining eight individuals in the study. The pathogenic variants found by WGS/WES were in genes already sequenced by Sanger sequencing and WES in the clinic, without any findings. We conclude that, in individuals with an unequivocal clinical diagnosis of a specific hereditary cancer syndrome, where standard clinical testing failed to detect a causative variant, re-analysis may lead to a diagnosis.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"46"},"PeriodicalIF":1.7,"publicationDate":"2021-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39823924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review. 有害的生活方式、肥胖和体重变化会增加BRCA 1和BRCA 2突变携带者患乳腺癌的风险吗?一个小评论。
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-27 DOI: 10.1186/s13053-021-00199-6
A Daniele, R Divella, B Pilato, S Tommasi, P Pasanisi, M Patruno, M Digennaro, C Minoia, M Dellino, S Pisconti, P Casamassima, E Savino, A V Paradiso

Background and aim: The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations.

Methods: Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review.

Results: Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.

背景和目的:BRCA 1和BRCA 2基因与乳腺癌的遗传易感性相关,BRCA 1突变携带者的累积风险为60%,BRCA 2突变携带者的累积风险为30%。一些生活方式因素可能在决定一个人患乳腺癌的风险方面发挥作用。肥胖、体型变化或不健康的生活习惯,如吸烟、饮酒和缺乏体育活动,已被评估为乳腺癌风险的可能决定因素。本研究的目的是探讨目前对BRCA 1/2突变女性携带者中有害生活方式和肥胖或体重变化在乳腺癌发展中的作用的理解。方法:利用相关关键词从MEDLINE检索2020年10月的文章;然后阅读它们,并使用笔记、研究参与者、测量、数据分析和结果来撰写这篇综述。结果:已经进行了大量病例的研究,但只有少数显示出一致的结果。进一步的研究将有助于更好地确定这些因素的实际作用和影响。
{"title":"Can harmful lifestyle, obesity and weight changes increase the risk of breast cancer in BRCA 1 and BRCA 2 mutation carriers? A Mini review.","authors":"A Daniele,&nbsp;R Divella,&nbsp;B Pilato,&nbsp;S Tommasi,&nbsp;P Pasanisi,&nbsp;M Patruno,&nbsp;M Digennaro,&nbsp;C Minoia,&nbsp;M Dellino,&nbsp;S Pisconti,&nbsp;P Casamassima,&nbsp;E Savino,&nbsp;A V Paradiso","doi":"10.1186/s13053-021-00199-6","DOIUrl":"https://doi.org/10.1186/s13053-021-00199-6","url":null,"abstract":"<p><strong>Background and aim: </strong>The BRCA 1 and BRCA 2 genes are associated with an inherited susceptibility to breast cancer with a cumulative risk of 60% in BRCA 1 mutation carriers and of 30% in BRCA 2 mutation carriers. Several lifestyle factors could play a role in determining an individual's risk of breast cancer. Obesity, changes in body size or unhealthy lifestyle habits such as smoking, alcohol consumption and physical inactivity have been evaluated as possible determinants of breast cancer risk. The aim of this study was to explore the current understanding of the role of harmful lifestyle and obesity or weight change in the development of breast cancer in female carriers of BRCA 1/2 mutations.</p><p><strong>Methods: </strong>Articles were identified from MEDLINE in October 2020 utilizing related keywords; they were then read and notes, study participants, measures, data analysis and results were used to write this review.</p><p><strong>Results: </strong>Studies with very large case series have been carried out but only few of them have shown consistent results. Additional research would be beneficial to better determine the actual role and impact of such factors.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"45"},"PeriodicalIF":1.7,"publicationDate":"2021-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8554866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39563774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 19
Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma - a case report. Li-Fraumeni综合征相关骨肉瘤的异常病程和遗传谱- 1例报告
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-20 DOI: 10.1186/s13053-021-00202-0
Alexander Puzik, Markus Uhl, Juri Ruf, Tilmann Schumacher, Udo Kontny

Background: Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research.

Case presentation: We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH.

Conclusion: Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.

背景:骨肉瘤是一种高度恶性肿瘤,与大量复杂的基因改变有关,如拷贝数改变。最近的全基因组研究揭示了几种候选癌基因的不同突变。虽然临床参数将骨肉瘤患者分为危险组,但遗传谱尚未用于定制肿瘤治疗。然而,特异性拷贝数改变似乎对骨肉瘤治疗有预后影响。散发性骨肉瘤常发生体细胞TP53基因突变。当发生种系时,TP53突变可导致Li-Fraumeni综合征,并可能导致早期骨肉瘤。Li-Fraumeni综合征对骨肉瘤遗传谱的影响以及在癌症治疗中对该综合征的考虑是当前研究的主题。病例介绍:我们报告一位25岁女性骨盆骨肉瘤拒绝继续治疗。她根据EURAMOS-1/COSS建议中断新辅助化疗,拒绝局部或进一步辅助治疗。令人惊讶的是,她的骨肉瘤持续缓解,但最终死于新诊断的乳腺癌。在乳腺癌建立后,我们检测了TP53种系突变,并用array-CGH对骨肉瘤材料进行了研究。结论:肿瘤的遗传检查证实了几个拷贝数的改变,与先前报道的数据有显著差异。我们讨论了遗传谱对异常临床病程的可能影响以及Li-Fraumeni综合征对遗传谱的意义。(原)癌基因的特异性缺失可能导致了这一不寻常的病例。进一步对Li-Fraumeni患者进行大规模遗传学研究,并结合详细的临床数据,将有助于确定特定的遗传风险概况并改善治疗。
{"title":"Unusual course of disease and genetic profile in Li-Fraumeni syndrome-associated osteosarcoma - a case report.","authors":"Alexander Puzik,&nbsp;Markus Uhl,&nbsp;Juri Ruf,&nbsp;Tilmann Schumacher,&nbsp;Udo Kontny","doi":"10.1186/s13053-021-00202-0","DOIUrl":"https://doi.org/10.1186/s13053-021-00202-0","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma is a highly malignant tumour associated with numerous and complex genetic alterations like copy number alterations. Recent whole genome studies revealed distinct mutations in several candidate oncogenes. While clinical parameters stratify osteosarcoma patients in risk groups, genetic profiles have not yet been used to tailor tumour treatment. However, specific copy number alterations seem to have a prognostic impact in osteosarcoma treatment. Somatic TP53 gene mutation frequently occurs in sporadic osteosarcoma. When arising germline, TP53 mutation leads to Li-Fraumeni syndrome and may result in early life osteosarcoma. The effect of Li-Fraumeni syndrome on the genetic profile of osteosarcoma and the consideration of the syndrome during cancer treatment are topics of current research.</p><p><strong>Case presentation: </strong>We report a 25-year-old female with pelvic osteosarcoma refusing continuation of therapy. She interrupted neo-adjuvant chemotherapy according to EURAMOS-1/COSS recommendations and declined local or further adjuvant therapy. Surprisingly, she remained in sustained remission for the osteosarcoma but eventually died from newly diagnosed breast cancer. After establishment of breast cancer, we detected TP53 germline mutation and investigated the osteosarcoma material with array-CGH.</p><p><strong>Conclusion: </strong>Genetic examination of the tumour evidenced several copy number alterations with striking differences to previously reported data. We discuss possible influences of the genetic profile on the unusual clinical course and the significance of Li-Fraumeni syndrome for the genetic profile. Specific loss of (proto-) oncogenes might have contributed to the unusual case. Further large-scale genetics of Li-Fraumeni patients combined with detailed clinical data will help to identify specific genetic risk profiles and improve treatment.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"44"},"PeriodicalIF":1.7,"publicationDate":"2021-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39537513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 3
"Left in limbo": Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis. “陷入困境”:探讨结直肠癌患者对疑似Lynch综合征诊断的理解和反应。
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-16 DOI: 10.1186/s13053-021-00201-1
Nicole den Elzen, Sharelle L Joseland, Sibel Saya, Sowmya Jonnagadla, Joanne Isbister, Ingrid Winship, Daniel D Buchanan

Background: A diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis.

Methods: Semi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services.

Results: Participants' interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants' interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received.

Conclusions: Our study findings highlight the variability in patients' interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.

背景:当肿瘤表现出与Lynch综合征(LS)一致的特征时,诊断为疑似Lynch综合征(SLS),但未发现种系致病变异。这种不确定的诊断导致在适当的癌症风险管理方面存在不确定性。本定性研究探讨了CRC患者对SLS诊断的理解和反应。方法:对15名接受SLS诊断的结直肠癌患者进行半结构化电话访谈,这些患者来自澳大利亚的癌症遗传学服务机构。访谈内容逐字记录,并采用专题分析进行分析。参与者的回答与癌症遗传学服务的预约摘要信件进行了比较。结果:参与者对基因检测结果的解释差异很大。虽然这种差异通常与癌症遗传学服务解释的差异一致,但参与者在基因测试结果的复杂性和回忆方面也存在困难。参与者对结果的不确定性有一系列的心理反应,从宽慰到失望和怀疑。对癌症风险的认知也存在很大差异,参与者对基因检测结果的解释只是几个影响因素之一。尽管存在差异,但几乎所有参与者都遵守了癌症风险管理建议,尽管不同的参与者收到了不同的建议。出于保护他们的动机,所有参与者还向一级亲属传达了任何癌症风险管理建议,但传达的信息并不总是与收到的建议一致。结论:我们的研究结果强调了在接受SLS诊断时,患者对其诊断、癌症风险管理和家庭沟通的解释存在差异,并为医疗保健专业人员如何更好地支持SLS患者提供了新的见解。
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引用次数: 2
Germline mutations among Polish patients with acute myeloid leukemia. 波兰急性髓性白血病患者的种系突变
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-12 DOI: 10.1186/s13053-021-00200-2
Aneta Bąk, Katarzyna Skonieczka, Anna Jaśkowiec, Anna Junkiert-Czarnecka, Marta Heise, Maria Pilarska-Deltow, Stanisław Potoczek, Maria Czyżewska, Olga Haus

Background: A small but important proportion of patients (4-10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT).

Methods: 103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations.

Results: In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028).

Conclusions: We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.

背景:一小部分但重要的AML患者(4- 10%)有种系突变。它们可以在更早的年龄导致AML的发展,赋予更高的复发风险或易患继发性白血病,包括治疗相关白血病。如果患者是造血干细胞移植(HSCT)的候选者,分析患者及其家庭的种系突变对于选择合适的家庭供体也至关重要。方法:103例无关联的连续新发AML患者入组研究。对照组由103名普通人群组成。我们对骨髓细胞和口腔拭子的六个基因CEBPA、DDX41、ETV6、TERT、GATA2和IDH2进行了NGS测序,以检测种系致病突变。结果:在调查组中,6个基因共检测到49个变异。其中体细胞26只,种系23只。在所有六个测试基因中均检测到种系变异。在7例AML患者中检测到8种致病种系突变,涉及3个基因:CEBPA、ETV6和IDH2。一名患者有两个致病的生发突变,一个在ETV6基因,一个在CEBPA基因。我们在CEBPA基因中发现了一种新的致病种系突变。各致病种系突变发生频率在试验组(7.77%)与对照组(0.97%)之间的差异有统计学意义(p = 0.046)。在试验组中,有致病性种系突变的患者诊断AML时的中位年龄比没有这种突变的患者低11岁(p = 0.028)。结论:我们发现,与对照组相比,AML患者中CEBPA、ETV6和IDH2种系突变的频率更高,这证实了这些突变在AML发展中的作用。我们还发现,具有致病性种系突变的AML患者发病的中位年龄明显低于没有这些突变的患者。
{"title":"Germline mutations among Polish patients with acute myeloid leukemia.","authors":"Aneta Bąk,&nbsp;Katarzyna Skonieczka,&nbsp;Anna Jaśkowiec,&nbsp;Anna Junkiert-Czarnecka,&nbsp;Marta Heise,&nbsp;Maria Pilarska-Deltow,&nbsp;Stanisław Potoczek,&nbsp;Maria Czyżewska,&nbsp;Olga Haus","doi":"10.1186/s13053-021-00200-2","DOIUrl":"https://doi.org/10.1186/s13053-021-00200-2","url":null,"abstract":"<p><strong>Background: </strong>A small but important proportion of patients (4-10 %) with AML have germline mutations. They can cause the development of AML at an earlier age, confer a higher risk of relapse or predispose to secondary leukemias, including therapy-related leukemias. The analysis of germline mutations in a patient and his/her family is also critical for the selection of suitable family donors if the patient is a candidate for hematopoietic stem cell transplantation (HSCT).</p><p><strong>Methods: </strong>103 unrelated consecutive patients with de novo AML were enrolled in the study. Control group consisted of 103 persons from the general population. We performed NGS sequencing of bone marrow cells and buccal swabs DNA of six genes: CEBPA, DDX41, ETV6, TERT, GATA2, and IDH2 to detect germline pathogenic mutations.</p><p><strong>Results: </strong>In the investigated group, 49 variants were detected in six genes. 26 of them were somatic and 23 germline. Germline variants were detected in all six tested genes. Eight pathogenic germline mutations were detected in 7 AML patients, in three genes: CEBPA, ETV6, and IDH2. One patient had two pathogenic germinal mutations, one in ETV6 and one in CEBPA gene. We identified one novel pathogenic germline mutation in CEBPA gene. The difference in frequency of all pathogenic germline mutations between the tested (7.77 %) and control groups (0.97 %) was statistically significant (p = 0.046). In the tested group, the median age at AML diagnosis was 11 years lower in patients with pathogenic germline mutations than in patients without them (p = 0.028).</p><p><strong>Conclusions: </strong>We showed higher frequency of CEBPA, ETV6, and IDH2 germline mutations in AML patients than in control group, which confirms the role of these mutations in the development of AML. We also showed that the median age at the onset of AML in patients with pathogenic germline mutations is significantly lower than in patients without them.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":"19 1","pages":"42"},"PeriodicalIF":1.7,"publicationDate":"2021-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39512031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
Danish guidelines for management of non-APC-associated hereditary polyposis syndromes. 丹麦非apc相关遗传性息肉病综合征管理指南。
IF 1.7 4区 医学 Q3 ONCOLOGY Pub Date : 2021-10-07 DOI: 10.1186/s13053-021-00197-8
Anne Marie Jelsig, John Gásdal Karstensen, Niels Jespersen, Zohreh Ketabi, Charlotte Lautrup, Karina Rønlund, Lone Sunde, Karin Wadt, Ole Thorlacius-Ussing, Niels Qvist

Hereditary Polyposis Syndromes are a group of rare, inherited syndromes characterized by the presence of histopathologically specific or numerous intestinal polyps and an increased risk of cancer. Some polyposis syndromes have been known for decades, but the development in genetic technologies has allowed the identification of new syndromes.. The diagnosis entails surveillance from an early age, but universal guideline on how to manage and surveille these new syndromes are lacking. This paper represents a condensed version of the recent guideline (2020) from a working group appointed by the Danish Society of Medical Genetics and the Danish Society of Surgery on recommendations for the surveillance of patients with hereditary polyposis syndromes, including rare polyposis syndromes.

遗传性息肉病综合征是一组罕见的遗传性综合征,其特征是存在组织病理学特异性或大量肠息肉,并增加患癌症的风险。一些息肉病综合征已经知道了几十年,但遗传技术的发展已经允许识别新的综合征。诊断需要早期监测,但缺乏关于如何管理和监测这些新综合征的普遍指南。本文是丹麦医学遗传学学会和丹麦外科学会任命的工作组关于遗传性息肉病综合征(包括罕见息肉病综合征)患者监测建议的最新指南(2020年)的浓缩版。
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引用次数: 9
期刊
Hereditary Cancer in Clinical Practice
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