Portal de investigação
The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing
Data de publicação:
Autores da FMUP
Participantes de fora da FMUP
- Barbosa Matos, R
- Silva, RL
- Garrido, L
- Aguiar, AC
- Garcia Pelaez, J
- Andre, A
- Seixas, S
- Sousa, SP
- Ferro, L
- Vilarinho, L
- Devezas, V
- Oliveira, R
- Costa, SC
- Magalhaes, A
- Baptista, M
- Pinheiro, H
Unidades de investigação
Abstract
Simple Summary An unexpectedly high number of early-onset diffuse gastric and lobular breast cancer in apparently unrelated families carrying the same CDH1 c.1901C>T variant (formerly known as missense p.A634V) in Northern Portugal suggested a founder effect in this region. We demonstrated that c.1901C>T is a truncating variant triggered by cryptic splicing, calculated its mutational age, and characterized the tumour spectrum and age of onset in affected families. Hereditary diffuse gastric cancer (HDGC) caused by CDH1 variants predisposes to early-onset diffuse gastric (DGC) and lobular breast cancer (LBC). In Northern Portugal, the unusually high number of HDGC cases in unrelated families carrying the c.1901C>T variant (formerly known as p.A634V) suggested this as a CDH1-founder variant. We aimed to demonstrate that c.1901C>T is a bona fide truncating variant inducing cryptic splicing, to calculate the timing of a potential founder effect, and to characterize tumour spectrum and age of onset in carrying families. The impact in splicing was proven by using carriers' RNA for PCR-cloning sequencing and allelic expression imbalance analysis with SNaPshot. Carriers and noncarriers were haplotyped for 12 polymorphic markers, and the decay of haplotype sharing (DHS) method was used to estimate the time to the most common ancestor of c.1901C>T. Clinical information from 58 carriers was collected and analysed. We validated the cryptic splice site within CDH1-exon 12, which was preferred over the canonical one in 100% of sequenced clones. Cryptic splicing induced an out-of-frame 37bp deletion in exon 12, premature truncation (p.Ala634ProfsTer7), and consequently RNA mediated decay. The haplotypes carrying the c.1901C>T variant were found to share a common ancestral estimated at 490 years (95% Confidence Interval 445-10,900). Among 58 carriers (27 males (M)-31 females (F); 13-83 years), DGC occurred in 11 (18.9%; 4M-7F; average age 33 +/- 12) and LBC in 6 females (19.4%; average age 50 +/- 8). Herein, we demonstrated that the c.1901C>T variant is a loss-of-function splice-site variant that underlies the first CDH1-founder effect in Portugal. Knowledge on this founder effect will drive genetic testing of this specific variant in HDGC families in this geographical region and allow intrafamilial penetrance analysis and better estimation of variant-associated tumour risks, disease age of onset, and spectrum.
Dados da publicação
- ISSN/ISSNe:
- 2072-6694, 2072-6694
- Tipo:
- Article
- Páginas:
- 4464-
- Link para outro recurso:
- www.scopus.com
Cancers Multidisciplinary Digital Publishing Institute (MDPI)
Citações Recebidas na Web of Science: 6
Citações Recebidas na Scopus: 7
Documentos
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Filiações
Keywords
- HDGC; CDH1; founder effect; missense variants; cryptic splicing
Financiamento
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Citar a publicação
Barbosa R,Silva RL,Garrido L,Aguiar AC,Garcia J,Andre A,Seixas S,Sousa SP,Ferro L,Vilarinho L,Gullo I,Devezas V,Oliveira R,Fernandes S,Costa SC,Magalhaes A,Baptista M,Carneiro F,Pinheiro H,Castedo S,Oliveira C. The <i>CDH1</i> c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing. Cancers. 2021. 13. (17):p. 4464-4464. IF:6,575. (1).
