Τίτλος:
BRCA1 and BRCA2 germline testing in Cretan isolates reveals novel and strong founder effects
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Germline BRCA1 and BRCA2 loss-of-function variants have been linked to increased breast and ovarian cancer risk, with more than 5,000 distinct pathogenic variants being reported worldwide. Among individuals of Greek descent, the BRCA1/2 variant spectrum is heterogeneous, but characterized by strong founder effects. As patients from certain geographical regions of Greece (like Crete) were underrepresented in previous studies, we hypothesized that isolated Cretans, a southern Greece islanders' population with distinct demographic, cultural and genetic features, could harbor founder BRCA1/2 mutations. A total of 304 breast or/and ovarian cancer patients of Cretan descent, fulfilling NCCN criteria for genetic testing, were tested by NGS or Sanger sequencing, followed by MLPA. Haplotype analysis was subsequently performed to investigate potential founder effects of recurrent alleles. Overall, 16.5% (50/304) of the tested patients carried 22 different pathogenic variants; 48% in BRCA1, 52% in BRCA2. Three variants, namely two in BRCA2 (Δexons 12 and 13 and c.7806-2A>T) and one in BRCA1 (c.5492del), constituting approximately half (48%) of all detected pathogenic variants, were shown to have a founder effect, with all carriers sharing common haplotypes. Remarkably, these variants were confined to Cretans and have not been identified in other regions of Greece. The high prevalence of specific BRCA1/2 pathogenic variants among Cretans, provides the possibility of cost- and time-efficient screening of the Cretan population. Integrating this knowledge in local public health services may have a significant impact on cancer prevention, and may serve as a starting point for the implementation of testing on a population level. © 2020 UICC
Συγγραφείς:
Apostolou, P.
Fostira, F.
Kouroussis, C.
Kalfakakou, D.
Delimitsou, A.
Agelaki, S.
Androulakis, N.
Christodoulou, C.
Kalbakis, K.
Kalykaki, A.
Sanidas, E.
Papadimitriou, C.
Vamvakas, L.
Georgoulias, V.
Mavroudis, D.
Yannoukakos, D.
Konstantopoulou, I.
Saloustros, E.
Περιοδικό:
International Journal of Cancer
Εκδότης:
Wiley-Liss, Inc.
Λέξεις-κλειδιά:
adult; aged; allele; Article; BRCA2 gene; breast cancer; clinical feature; cultural factor; exon; female; gene; genetic association; genetic screening; genetic variability; germline mutation; Greece; haplotype; high throughput sequencing; human; major clinical study; male; ovary cancer; prevalence; priority journal; risk factor; Sanger sequencing; sequence alignment; tumor suppressor gene; breast tumor; epidemiology; founder effect; genetic predisposition; genetic screening; genetics; germline mutation; middle aged; ovary tumor; pathology; pedigree; young adult, BRCA1 protein; BRCA1 protein, human; BRCA2 protein; BRCA2 protein, human, Adult; Aged; Alleles; BRCA1 Protein; BRCA2 Protein; Breast Neoplasms; Female; Founder Effect; Genetic Predisposition to Disease; Genetic Testing; Germ-Line Mutation; Greece; Haplotypes; Humans; Male; Middle Aged; Ovarian Neoplasms; Pedigree; Prevalence; Young Adult
