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Next Generation Sequencing Analysis in Early Onset Dementia Patients.

ABSTRACT: BACKGROUND:Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. OBJECTIVE:To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed. METHODS:We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. RESULTS:We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN, VCP, MAPT, FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP), and one did not show any risk mutation/variant. Overall, 69% (n?=?9) of our early onset Alzheimer's disease (EAOD) patients, compared with 34% (n?=?13) of sporadic late onset Alzheimer's disease (LOAD) patients and 27% (n?=?73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. CONCLUSION:This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.

SUBMITTER: Bonvicini C

PROVIDER: S-EPMC6398561 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Next Generation Sequencing Analysis in Early Onset Dementia Patients.

Bonvicini Cristian C Scassellati Catia C Benussi Luisa L Di Maria Emilio E Maj Carlo C Ciani Miriam M Fostinelli Silvia S Mega Anna A Bocchetta Martina M Lanzi Gaetana G Giacopuzzi Edoardo E Ferraboli Sergio S Pievani Michela M Fedi Virginia V Defanti Carlo Alberto CA Giliani Silvia S Frisoni Giovanni Battista GB Ghidoni Roberta R Gennarelli Massimo M

Journal of Alzheimer's disease : JAD 20190101 1

<h4>Background</h4>Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia.<h4>Objective</h4>To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE) and prion protein (PRNP) genes were also assessed.<h4>Methods</h4>We studied 22 EOD pat ...[more]

PMID: 30530974

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Project description:BackgroundAround 5%-7% of breast cancer cases are diagnosed in women younger than 40, making it the leading cause of female cancer in the 25- to 39-year-old age group. Unfortunately, young age at diagnosis is linked to a more aggressive tumor biology and a worse clinical outcome. The identification of the mutational landscape of breast cancer in this age group could optimize the management.MethodsWe performed NGS analysis in paraffin blocks and blood samples of 32 young patients with breast cancer [<40 years] and 90 older patients during the period 2019 through 2021. All patients were treated in a single institution at the Oncology Department of "Alexandra" Hospital, Medical School, University of Athens, Greece.ResultsBreast tumors were characterized more frequently by HER2 overexpression [25% vs 18.9%], higher ki67 levels [75% vs 61%] and lower differentiation [71.9% vs 60%] in the younger group. PIK3CA [6/20; 30%] and TP53 [6/20; 30%] were the most frequent pathogenic somatic mutations identified in young patients, while one case of BRCA2 somatic mutation [1/20; 5%] and one case of PTEN somatic mutation [1/20; 5%] were also identified. PIK3CA mutations [16/50; 32%] and TP53 mutations [20/50; 40%] were the most common somatic mutations identified in older patients, however other somatic mutations were also reported (ATM, AKT, CHEK2, NRAS, CDKN2A, PTEN, NF1, RB1, FGFR1, ERBB2). As for germline mutations, CHEK2 [3/25; 12%] was the most common pathogenic germline mutation in younger patients followed by BRCA1 [2/25; 8%]. Of note, CHEK2 germline mutations were identified less frequently in older patients [2/61; 3%] among others [BRCA1 (2/61; 3%), ATM (2/61; 3%), APC (1/61; 1,6%) and BRCA2 (1/61; 1,6%)].ConclusionWe here report the mutational profile identified via NGS in patients with early-onset breast cancer compared to their older counterparts. Although the sample size is small and no statistically significant differences were detected, we highlight the need of genetic testing to most patients in this subgroup.

Dataset Information

Next Generation Sequencing Analysis in Early Onset Dementia Patients.

Publications

Next Generation Sequencing Analysis in Early Onset Dementia Patients.

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