Dataset Information

Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

ABSTRACT: Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating with breast cancer susceptibility both in familial (5/145, 3.4%, P = 0.003, OR 8.3) and unselected cases (16/1150, 1.4%, P = 0.016, OR 3.3). A total of 21 mutation positive families were identified, of which one-third exhibited also brain tumors and/or sarcomas (P = 0.0007). Mutation carriers exhibited significant increase in genomic instability assessed by cytogenetic analysis for spontaneous chromosomal rearrangements in peripheral blood lymphocytes (P = 0.0007), suggesting an effect for MCPH1 haploinsufficiency on cancer susceptibility. Furthermore, 40% of the mutation carrier tumors exhibited loss of the wild-type allele. These findings collectively provide strong evidence for MCHP1 being a novel breast cancer susceptibility gene, which warrants further investigations in other populations.

SUBMITTER: Mantere T

PROVIDER: S-EPMC4731077 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

Mantere Tuomo T Winqvist Robert R Kauppila Saila S Grip Mervi M Jukkola-Vuorinen Arja A Tervasmäki Anna A Rapakko Katrin K Pylkäs Katri K

PLoS genetics 20160128 1

Breast cancer is strongly influenced by hereditary risk factors, a majority of which still remain unknown. Here, we performed a targeted next-generation sequencing of 796 genes implicated in DNA repair in 189 Finnish breast cancer cases with indication of hereditary disease susceptibility and focused the analysis on protein truncating mutations. A recurrent heterozygous mutation (c.904_916del, p.Arg304ValfsTer3) was identified in early DNA damage response gene, MCPH1, significantly associating w ...[more]

PMID: 26820313

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Project description:RationaleEpidermolysis bullosa (EB) refers to a group of rare inherited mechanobullous disorders that present with great clinical and genetic heterogeneity. Its severity ranges from mild blistering to life-threatening. However, the clinical symptoms of different types of EB overlap significantly, especially at an early stage. Thus it is important to clarify the diagnosis for prognostic implications, patient management, and genetic counseling.Patient concernsHere, we report a 10-day-old male neonate from a nonconsanguineous Chinese family. He showed a bulla on the left lower limb lasting for 3 days, erosions around fingertips and toe tips at birth (predominantly on fingers), with the progressive spread of generalized blisters over the body as well as the development of the illness.DiagnosisThe patient was diagnosed with suspected epidermolysis bullosa according to the blisters and erosions of the body as well as the pyogenic fingernails and toenails.InterventionsThe patient was performed targeted next-generation sequencing (NGS) with 9 candidate known genes, subsequently, his parents were screened for the mutations identified in the patient by Sanger sequencing. Then, prenatal diagnosis with amniotic fluid was performed in the subsequent pregnancy by Sanger sequencing.OutcomesTargeted NGS revealed a previously unreported splice site variant c.822+1G>A (IVS 8) and a known recurrent nonsense variant c.124C>T (p.Arg42Ter, exon 3) in LAMB3 gene. The patient's father possessed a heterozygous c.822+1G>A mutation, his mother possessed a heterozygous c.124C>T mutation. For the subsequent pregnancy, the analyses of amniotic fluid sample indicated that the fetus carried neither of the mutations.LessonsOur finding will further enlarge LAMB3 genotype-phenotype correlations spectrum. Targeted capture sequencing is a valuable method to illustrate precise molecular pathology in patients with EB disorders, especially at an early stage of the clinical evaluation of complex disorders to avoid unnecessary and economically wasteful tests.

Dataset Information

Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

Publications

Targeted Next-Generation Sequencing Identifies a Recurrent Mutation in MCPH1 Associating with Hereditary Breast Cancer Susceptibility.

Similar Datasets

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