PALB2 c.2257C>T truncating variant is a Greek founder and is associated with high breast cancer risk

PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>...

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Bibliographic Details
Published in:Journal of human genetics 2019-08, Vol.64 (8), p.767-773
Main Authors: Vagena, Andromachi, Papamentzelopoulou, Myrto, Kalfakakou, Despoina, Kollia, Panagoula, Papadimitriou, Christos, Psyrri, Amanda, Apostolou, Paraskevi, Fountzilas, George, Konstantopoulou, Irene, Yannoukakos, Drakoulis, Fostira, Florentia
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Alleles
Amino Acid Substitution
Breast cancer
Breast Neoplasms - diagnosis
Breast Neoplasms - epidemiology
Breast Neoplasms - genetics
Case-Control Studies
DNA Mutational Analysis
Fanconi Anemia Complementation Group N Protein - genetics
Female
Founder Effect
Gastric cancer
Gene Frequency
Genetic markers
Genetic Predisposition to Disease
Genetic screening
Genotype
Germ-Line Mutation
Greece - epidemiology
Haplotypes
Health risk assessment
Hereditary Breast and Ovarian Cancer Syndrome - diagnosis
Hereditary Breast and Ovarian Cancer Syndrome - epidemiology
Hereditary Breast and Ovarian Cancer Syndrome - genetics
Humans
Loss of Function Mutation
Microsatellites
Middle Aged
Neoplasm Grading
Neoplasm Staging
Ovarian cancer
Pancreas
Pedigree
Risk Assessment
Risk Factors
Sequence Deletion
Young Adult
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Summary:PALB2 loss-of-function variants play an important role in breast, pancreatic and possibly, ovarian and gastric cancer susceptibility. Their frequency can be influenced by founder effects, already described in some populations. Herein, we have assessed the possible founder effect of PALB2 c.2257C>T (p.Arg753*) truncating variant among Greek breast cancer patients, while investigating possible correlations with cancer diagnoses. Following a lead deriving from a background study of highly selected Greek breast cancer patients, a total of 2496 breast and 697 ovarian cancer patients were directly genotyped for the PALB2 c.2257C>T truncating variant. Consequently, haplotype analysis was conducted on identified carriers, using seven microsatellite markers. The prevalence of the PALB2 variant was 0.24% (6/2496) and 0.14% (1/697) among breast and ovarian cases, respectively. Family history seems to be an important factor for the variant identification, although not reaching statistical significance. Microsatellite analysis on 12 carriers revealed a common shared haplotype, spanning a chromosomal region of ~1.2 Mb; the variant was possibly introduced in the Greek population ~1600 years ago. The variant confers high breast cancer risk, as illustrated by comparison with publicly available control groups. Genetic testing for PALB2, especially for the Greek founder c.2257C>T truncating variant, should be seriously considered in Greek breast cancer cases, since such findings could assist appropriate clinical management for the patients and their families.
ISSN:1434-5161
1435-232X
DOI:10.1038/s10038-019-0612-6