The CDH1 c.1901C>T Variant: A Founder Variant in the Portuguese Population with Severe Impact in mRNA Splicing

• Type: Article in International Scientific Journal
• Date: 2021

Authors

Barbosa Matos, R (Author) Other; Silva, RL (Author) Other; Garrido, L (Author) Other; Aguiar, AC (Author) Other; Garcia Pelaez, J (Author) Other; Andre, A (Author) Other; Seixas, S (Author) Other; Sousa, SP (Author) Other; Ferro, L (Author) Other; Vilarinho, L (Author) Other; Gullo, I (Author) FMUP; Devezas, V (Author) Other; Oliveira, R (Author) ICBAS; Fernandes, S (Author) Other; Costa, SC (Author) Other; Magalhaes, A (Author) Other; Baptista, M (Author) Other; Carneiro F (Author) FMUP; Pinheiro, H (Author) Other; CASTEDO, S (Author) FMUP; Oliveira, C (Author) Other

Journal

Title: Cancers

Vol. 13

Final page: 4464

ISSN: 2072-6694

Publisher: MDPI

Indexing

ISI Web of Knowledge - 6 Citations

Scopus - 7 Citations

Other information

Authenticus ID: P-00V-BED

DOI: 10.3390/cancers13174464

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 18