Frequency and molecular characteristics of PALB2-associated cancers in Russian patients.
Adolescent
Adult
Age of Onset
Aged
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ diagnosis
Carcinoma
/ diagnosis
DNA Mutational Analysis
Drug Resistance, Neoplasm
/ genetics
Fanconi Anemia Complementation Group N Protein
/ genetics
Female
Genetic Predisposition to Disease
Germ-Line Mutation
Humans
Loss of Heterozygosity
Male
Mastectomy
Medical History Taking
Middle Aged
Neoadjuvant Therapy
/ methods
Ovarian Neoplasms
/ diagnosis
Pancreatic Neoplasms
/ diagnosis
Point Mutation
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Russia
Young Adult
NGS
PALB2
PCR
hereditary breast cancer
mutation
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 01 2021
01 01 2021
Historique:
received:
15
06
2020
revised:
15
09
2020
accepted:
18
09
2020
pubmed:
1
10
2020
medline:
11
6
2021
entrez:
30
9
2020
Statut:
ppublish
Résumé
PALB2 is а high-penetrance gene for hereditary breast cancer (BC). Our study aimed to investigate the spectrum of PALB2 mutations in Russian cancer patients. PALB2 sequencing revealed pathogenic variants in 3/190 (1.6%) young-onset and/or familial and/or bilateral BC cases but none in 96 ovarian cancer (OC) or 172 pancreatic cancer patients. Subsequently, seven recurrent PALB2 pathogenic alleles were selected from this and previous Slavic studies and tested in an extended patient series. PALB2 pathogenic variants were detected in 5/585 (0.9%) "high-risk" BC, 10/1508 (0.7%) consecutive BC and 5/1802 (0.3%) OC cases. Haplotyping suggested that subjects with Slavic alleles c.509-510delGA (n = 10) and c.172-175delTTGT (n = 4) as well as carriers of Finnish c.1592delT mutation (n = 4) originated from a single founder each, while PALB2 p.R414X allele (n = 4) had at least two independent founders. Somatic loss of heterozygosity (LOH) was revealed in 5/10 chemonaive BCs and in 0/2 BC samples obtained after neoadjuvant therapy. Multigene sequencing identified somatic PALB2 inactivating point mutation in one out of two tumors without PALB2 LOH but in none of four BCs with PALB2 LOH. Genomic instability, as determined by NGS, was observed in four out of five tumors with biallelic PALB2 inactivation but not in the BC sample with the preserved wild-type PALB2 allele. PALB2 germ-line mutations contribute to a small fraction of cancer cases in Russia. The majority although not all PALB2-driven BCs have somatic inactivation of the remaining PALB2 allele and therefore potential sensitivity to platinum compounds and PARP inhibitors.
Substances chimiques
Fanconi Anemia Complementation Group N Protein
0
PALB2 protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
203-210Informations de copyright
© 2020 Union for International Cancer Control.
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