Germline PHOX2B mutation in hereditary neuroblastoma.
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ABSTRACT:
SUBMITTER: Mosse YP
PROVIDER: S-EPMC1182065 | biostudies-literature | 2004 Oct
REPOSITORIES: biostudies-literature
Publications
Germline PHOX2B mutation in hereditary neuroblastoma.
Mosse Yael P YP Laudenslager Marci M Khazi Deepa D Carlisle Alex J AJ Winter Cynthia L CL Rappaport Eric E Maris John M JM
American journal of human genetics 20041001 4
Similar Datasets
Project description:Neuroblastoma (NB) is a frequent pediatric tumor for which recurrent somatic rearrangements are known. Germline mutations of predisposing gene(s) are suspected on the basis of rare familial cases and the association of NB with other genetically determined congenital malformations of neural crest-derived cells--namely, Hirschsprung disease (HSCR) and/or congenital central hypoventilation syndrome (CCHS). We recently identified the paired-like homeobox 2B (PHOX2B) gene as the major disease-causing gene in isolated and syndromic CCHS, which prompted us to regard it as a candidate gene in NB. Here, we report on germline mutations of PHOX2B in both a familial case of NB and a patient with the HSCR-NB association. PHOX2B, therefore, stands as the first gene for which germline mutations predispose to NB.
| S-EPMC1181953 | biostudies-literature
Project description:BackgroundMedulloblastoma is an aggressive brain tumor mostly found in children, few studies on pathogenic germline mutations predisposing this disease was reported.Case presentationWe present an 11-year-old male with medulloblastoma, who harbors a de novo PHOX2B germline mutation as detected by whole exome sequencing (WES). Family history was negative. Sanger sequencing confirmed this mutation in peripheral blood, hair bulbs, urine and saliva. Identification of novel germline mutations is beneficial for childhood cancer screening.ConclusionsThis case revealed a de novo PHOX2B germline mutation as a potential cause of medulloblastoma in a child and suggests familial germline variant screening is useful when an affected family is considering having a second child.
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Project description:Paired like homeobox 2B (PHOX2B) is a minimal residual disease (MRD) marker of neuroblastoma. The presence of MRD, also referred to as micro-metastases, is a powerful marker of poor prognosis in neuroblastoma. Lung metastasis is considered a terminal event in neuroblastoma. Lung micro-metastatic neuroblastoma (MicroNB) cells show high expression levels of PHOX2B and possess a less malignant and metastatic phenotype than lung macro metastatic neuroblastoma (MacroNB) cells, which hardly express PHOX2B. In vitro assays showed that PHOX2B knockdown in MicroNB cells did not affect cell viability; however it decreased the migratory capacity of the MicroNB-shPHOX2B cells. An orthotopic inoculation of MicroNB-shPHOX2B cells into the adrenal gland of nude mice resulted in significantly larger primary tumors and a heavier micro-metastatic load in the lungs and bone-marrow, than when control cells were inoculated. PHOX2B expression was found to be regulated by methylation. The PHOX2B promoter in MacroNB cells is significantly more methylated than in MicroNB cells. Demethylation assays using 5-azacytidine demonstrated that methylation can indeed inhibit PHOX2B transcription in MacroNB cells. These pre-clinical data strongly suggest that PHOX2B functions as a suppressor of neuroblastoma progression.
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Project description:Germline genetic context may play a significant role in the development and evolution of cancer, particularly in childhood cancers such as neuroblastoma. This study investigates the role of putatively functional germline variants in neuroblastoma, even if they do not directly increase disease risk. Our whole-exome sequencing analysis of 125 patients with neuroblastoma reveals a positive correlation between germline variant burden and somatic mutations. Moreover, patients with higher germline variant burden exhibit worse outcomes. Similar findings are observed in the independent neuroblastoma cohort where a higher germline variant burden correlates with a higher somatic mutational burden and a worse overall survival outcome. However, contrasting results emerge in adult-onset cancer, emphasizing the importance of germline genetics in neuroblastoma. The enrichment of putatively functional germline variants in cancer predisposition genes is borderline significant when compared to healthy populations (P = 0.077; Odds Ratio, 1.45; 95% confidence intervals, 0.94-2.21) and significantly more pronounced against adult-onset cancers (P = 0.016; Odds Ratio, 2.13; 95% confidence intervals, 1.10-3.91). Additionally, the presence of these variants proves to have prognostic significance in neuroblastoma (log-rank P < 0.001), and combining germline with clinical risk factors notably improves survival predictions.
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Project description:PurposeCowden syndrome is a hereditary cancer syndrome associated with a germline mutation in PTEN. Patients are predisposed to multiple malignancies including renal cell carcinoma.Materials and methodsPatients with Cowden syndrome were evaluated as part of a clinical protocol. Those with a history of renal cell carcinoma underwent review of clinical features, tumor characteristics and family history. Renal tumors were evaluated for loss of heterozygosity.ResultsAmong 24 patients with Cowden syndrome 4 were identified with renal cell carcinoma (16.7%). Three patients had solitary tumors, 2 with papillary type I histology and 1 with clear cell histology. The fourth patient had bilateral, synchronous chromophobe tumors. No patients had a prior family history of renal cell carcinoma. All patients with renal cell carcinoma had dermatologic manifestations of Cowden syndrome and had macrocephaly. Loss of heterozygosity at the PTEN mutation was identified in 4 tumors (80%). No genotype-phenotype association was found, as the same mutation was identified in different renal cell carcinoma histologies.ConclusionsRenal cell carcinoma is an underappreciated feature of Cowden syndrome. As most patients lack a prior family history or a distinctive renal cell carcinoma histology, recognition of the associated nonrenal features should target referral for genetic counseling. PTEN loss of heterozygosity is common in Cowden syndrome renal tumors. Because loss of PTEN can activate mTOR and mTOR inhibitors are Food and Drug Administration approved to treat renal cell carcinoma, these agents have clinical potential in renal cell carcinoma associated with Cowden syndrome.
| S-EPMC4193347 | biostudies-literature
Project description:The pathogenesis of acute leukemia is still complex and vague. Most types of acute leukemia are related to somatic gene mutations, and familial incidence is rare. Here we report a case of familial leukemia. The proband presented to our hospital with vaginal bleeding and disseminated intravascular coagulation at the age of 42 and was diagnosed with acute promyelocytic leukemia with typical PML-RARα fusion gene caused by t(15;17)(q24;q21) translocation. By taking the history, we found that the patient's second daughter had been diagnosed with B-cell acute leukemia with ETV6-RUNX1 fusion gene at age 6. Then we performed whole exome sequencing in peripheral blood mononuclear cells from these two patients at remission status and identified 8 shared germline gene mutations. Using functional annotation and Sanger sequencing validation, we finally focused on a single nucleotide variant in RecQ like helicase (RECQL), rs146924988, which was negative in the proband's healthy eldest daughter. This gene variant potentially led to a relative lack of RECQL protein, disordered DNA repair and chromatin rearrangement, which may mediate the occurrence of fusion genes, as driving factors for leukemia. This study identified a novel possible leukemia-related germline gene variant and provided a new understanding for the screening and pathogenesis of hereditary predisposition syndromes.
| S-EPMC10043295 | biostudies-literature
Project description:Ovarian immature teratomas (OITs) are malignant tumors originating from the ovarian germ cells that mainly occur during the first 30 y of a female's life. Early age of onset strongly suggests the presence of susceptibility gene mutations for the disease yet to be discovered. Whole exon sequencing was used to screen pathogenic mutations from pedigrees with OITs. A rare missense germline mutation (C262T) in the first exon of the BMP15 gene was identified. In silico calculation suggested that the mutation could impair the formation of mature peptides. In vitro experiments on cell lines confirmed that the mutation caused an 84.7% reduction in the secretion of mature BMP15. Clinical samples from OIT patients also showed a similar pattern of decrease in the BMP15 expression. In the transgenic mouse model, the spontaneous parthenogenetic activation significantly increased in oocytes carrying the T allele. Remarkably, a mouse carrying the T allele developed the phenotype of OIT. Oocyte-specific RNA sequencing revealed that abnormal activation of the H-Ras/MAPK pathway might contribute to the development of OIT. BMP15 was identified as a pathogenic gene for OIT which improved our understanding of the etiology of OIT and provided a potential biomarker for genetic screening of this disorder.
| S-EPMC10927523 | biostudies-literature
Project description:BackgroundGermline CDKN2A mutations are a well-known cause of familial atypical multiple mole melanoma (OMIM #155601) and melanoma-pancreatic cancer syndrome (OMIM #606719). Increased risk of head and neck squamous cell carcinoma (HNSCC), particularly oral squamous cell carcinoma (OSCC) in those with germline CDKN2A mutations, has been described. However, screening for HNSCC is not a routine practice in patients with CDKN2A germline mutations and these mutations are not a conventional test for HNSCC patients without obvious risk factors.Case presentationWe describe a female with no smoking history who developed oral squamous cell carcinoma at age 39 and had a complex clinical course of recurrent multifocal squamous cell carcinoma (SCC) and carcinoma in situ of the oral cavity and oropharynx. Detailed family history demonstrated that her mother was diagnosed with OSCC and melanoma in her 40 s, and her maternal grandfather was diagnosed with metastatic melanoma in his 40 s. Genetic testing of the patient and her mother revealed CDKN2A c.301G>T mutation. She was referred to genetic counseling as well as to dermatology, gastroenterology, and neurology for cancer surveillance. She was treated with resections and has no evidence of disease 3 years after diagnosis.ConclusionsWe report a family with a CDKN2A c.301 G>T mutation who also have significant history of OSCC, adding to the growing body of literature suggesting increased risk of HNSCC, particularly OSCC, in CDKN2A germline mutation carriers. It is important to consider CDKN2A mutation testing in familial HNSCC and young patients without obvious risk factors. Moreover, surveillance for HNSCC should be routine practice in those with a CDKN2A germline mutation.
| S-EPMC8818223 | biostudies-literature
Project description:Hirschsprung disease (HSCR) is a heterogeneous congenital disorder that affects the enteric nervous system, while neuroblastoma is an embryonal tumor of the sympathetic nervous system. Familial cases of both HSCR and neuroblastoma appear to be functionally linked to PHOX2B, which plays a key role in the development of neural crest derivatives. However, the association between common PHOX2B variants and disease risk is contested. Additionally, large-scale examination for pleiotropy or shared genetic susceptibility in sporadic HSCR and neuroblastoma cases lacks theoretical support. Here, we report the first examination of PHOX2B in 1470 HSCR and 469 neuroblastoma patients with matched healthy controls. The PHOX2B rs28647582 polymorphism was found to be associated with HSCR (P = 2.21E-03, OR = 1.26), and each subtype of the ailment (3.22E-03 ≤ P ≤ 0.43, 1.11 ≤ OR ≤ 2.32). The association between rs28647582 and NB risk was consistent with HSCR in a recessive model, though the P value was marginal (P = 0.06). These new genetic findings indicate the potential pleiotropic effects of PHOX2B in both HSCR and neuroblastoma, which could guide the development of therapeutic targets for the treatment of related neurodevelopmental disorders.
| S-EPMC6402522 | biostudies-literature
Project description:A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient's parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novoALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient.
| S-EPMC9498070 | biostudies-literature