Paternal bias in parental origin ofHRASmutations in Costello syndrome

Sol‐Church, Katia; Stabley, Deborah L.; Nicholson, Linda; Gonzalez, Iris L.; Gripp, Karen W.

doi:10.1002/humu.20381

Cited by 68 publications

(77 citation statements)

References 21 publications

(24 reference statements)

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“…The previous survey (10) identified two tumors with FGFR3 c.1948A>G (p.K650E) mutations and five tumors with HRAS mutations [three samples with c.182A>G (p.Q61R) and two with c.181C>T (p.Q61K)]. The finding of acquired HRAS mutations was noteworthy because heterozygous germline mutations cause CS, which exhibits the epidemiological characteristics of a PAE disorder (11,19,20). However, whereas all mutations previously identified in SpS affect the p.Q61 codon, 88% of published CS mutations localize to the p. G12 codon (Fig.…”

Section: Significancementioning

confidence: 99%

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Giannoulatou

McVean

Taylor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

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The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.paternal age effect | male mutation bias | RASopathy | testis

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Section: Significancementioning

confidence: 99%

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Giannoulatou

McVean

Taylor

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

117

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“…7,8 The phenotype of patients with mosaicism may differ and the clinical manifestations could occur along a spectrum depending on the affected tissue compartments. 9 In a recently published case report, mutant HRAS mosaicism was also described in relation to BC.…”

Section: Resultsmentioning

confidence: 99%

HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome

2013

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Bladder tumours of patients o20 years have a low incidence of genetic aberrations typically found in tumours in older patients. In this study, we investigated oncogene mutations in patients with bladder cancer (BC) o20 years and compared them to older age groups. Interestingly, we observed a relatively high number of HRAS mutations in tumour from young patients. These mutations were also highly uncommon in BCs of older patients, ie, p.(Gly12Ser) and p.(Gly12Ala). Germline mutations in the HRAS gene, especially p.(Gly12Ser/Ala), cause Costello Syndrome (CS), a severe congenital disorder. Indeed, one of the patients had been diagnosed with CS. We hypothesized that some of the other patients might be mosaic for the HRAS mutation and therefore could express some of the clinical features of CS, like tumour predisposition. Hence, we isolated DNA from microdissected stroma and analysed it for HRAS mutations. In the CS patient and in patient X, the mutation was also highly expressed in normal stroma. We conclude that patient X is possibly mosaic for the HRAS mutation. These results suggest that mosaicism for oncogenic HRAS mutations may increase the risk for developing BC at a young age. (BC) is a disease of the elderly with a peak incidence in the sixth decade of life and only 1-2.4% of all cases present under the age of 40 years. BC in patients younger than 20 years is even more uncommon with reported incidence rates of only 0.1-0.4%. 1 Previous studies demonstrated that tumours of patients o20 years lack or have a much lower incidence of epigenetic and genetic aberrations typical of BC in elderly patients. 2 Together with mutations in FGFR3 and PIK3CA, mutations in the RAS genes are the most common mutations found in BC and up to 13% of all bladder tumours harbour a mutation in HRAS, KRAS or NRAS. 3 There is limited data available regarding these oncogenic mutations in BC of patients o20 years. Therefore, we aimed to investigate FGFR3, PIK3CA, and RAS mutations in BC of patients o20 years and compared the results with the mutation status of a control group consisting of patients with BC 420 years.

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“…In the current study, a high frequency of silent mutations in codon 27 (c.81T>C, H27H) was found in H-ras exon 1. The mutation was first reported in Costello syndrome and found in strong linkage disequilibrium with the hexanucleotide repeat region [27], but had not previously been reported in bladder cancer. The mutations were present in 25 tumors (29.1%), comprising 13 (22.0%) in primary tumors and 12 (44.4%) in recurrent tumors.…”

Section: Discussionmentioning

confidence: 99%

H-ras Mutation Detection in Bladder Cancer by COLD-PCR Analysis and Direct Sequencing

Wang

Chang²,

Li³

et al. 2012

Urol Int

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Objective: A sensitive mutation detection method called co-amplification at lower denaturation temperature-polymerase chain reaction (COLD-PCR) was applied to improve the detection frequencies of expressive mutations in the H-ras gene, including exons 1 and 2, in a group of Chinese patients diagnosed with bladder cancer. Materials and Methods: The expressive mutations in the H-ras gene in 86 fresh tissues of human bladder cancer were identified by COLD-PCR or conventional PCR, followed by direct sequencing. Results: A high frequency of silent mutations of 29.1% (25 of 86) in exon 1 (c.81T>C, H27H) and activating mutations of 8.1% (7 of 86) were detected by COLD-PCR, yielding a 36% improvement in mutation detection compared with conventional PCR. No significant association was shown between activating mutations and clinicopathologic parameters, but the frequencies of silent mutations in recurrent tumors were higher than those in primary tumors (p = 0.034). Conclusions: COLD-PCR is a highly sensitive, reliable, and convenient clinical assay for mutation detection. The adoption of the method is straightforward and requires no additional reagents or instruments. Silent mutations might be important genomic alterations in bladder cancer, and play a role in bladder cancer recurrence.

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Paternal bias in parental origin ofHRASmutations in Costello syndrome

Cited by 68 publications

References 21 publications

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

Contributions of intrinsic mutation rate and selfish selection to levels of de novo HRAS mutations in the paternal germline

HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome

<b><i>H-ras</i></b> Mutation Detection in Bladder Cancer by COLD-PCR Analysis and Direct Sequencing

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