Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2.
Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2 c.2167_2168delAT have each been observed multiple times in breast cancer families of Italian ancestry. More recently, the c2167_2168delAT mutation was identified in unrelated breast cancer cases of various ancestries. For each mutation, we investigated whether the origin was multiple mutational events (a "hot-spot") or a single event (a founder allele).



We genotyped and reconstructed haplotypes for 36 participants of Italian, Italian-American, Hispanic, and Nigerian ancestries, using seven short tandem repeat (STR) markers that covered 3 Megabases within and flanking PALB2 on chromosome 16.



For PALB2 c.1027C>T, a shared haplotype with a minimum size of 150 kb was shared by all 19 carriers investigated, all of Italian ancestry. This result suggests that this allele arose as a single event in a shared ancestor. For PALB2 c.2167_2168delAT, all 12 carriers from American-Italian and Italian families shared a 1-Mb haplotype, the 3 Hispanic carriers shared a different haplotype of size 2 Mb, and the Nigerian carrier had different alleles at all 7 STR markers. These results suggest that PALB2 c.2167_2168delAT arose multiple times, but that within each population, PALB2 c.2167_2168delAT likely represents a single mutational event.



We identified two PALB2 mutations that are founder alleles in Italian families, one of which is, independently, also a founder mutation in American-Hispanic breast cancers.
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
Irene
I
Catucci
Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Silvia
S
Casadei
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Yuan Chun
YC
Ding
Cogentech, Cancer Genetic Test Laboratory, Milan, Italy.
Sara
S
Volorio
Cogentech, Cancer Genetic Test Laboratory, Milan, Italy.
Filomena
F
Ficarazzi
Department of Immunohematology and Transfusion Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Anna
A
Falanga
Department of Immunohematology and Transfusion Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Marina
M
Marchetti
Unit of Oncology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Carlo
C
Tondini
Unit of Oncology, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
Michela
M
Franchi
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Aaron
A
Adamson
Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Jessica
J
Mandell
Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Tom
T
Walsh
Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, IL, USA.
Olufunmilayo I
OI
Olopade
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Siranoush
S
Manoukian
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Paolo
P
Radice
Department Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA.
Charite
C
Ricker
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Jeffrey
J
Weitzel
Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Mary-Claire
MC
King
IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy.
Paolo
P
Peterlongo
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. sneuhausen@coh.org.
Susan L
0000-0001-5053-0390
SL
Neuhausen
D000483:Alleles; D001943:Breast Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D000076164:Fanconi Anemia Complementation Group N Protein / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007558:Italy; D018895:Microsatellite Repeats; D009154:Mutation; D010375:Pedigree
D000076164:Fanconi Anemia Complementation Group N Protein
Breast cancer; Founder mutations, Haplotype; PALB2