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.
KeywordsBreast cancer PALB2 Founder mutations, Haplotype
Work in Italy was partially supported by funds from Ministero della Salute, Italy; Ricerca Finalizzata (RF-2010-2316374 to PP and CT); AIRC Associazione Italiana per la Ricerca sul Cancro (IG 12821 to PP and “5xmille” n. 12237 to AF), and from Italian citizens who allocated a 5/1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori (SM and PR). Work at University of Washington was supported by NIH R01CA175716 (M-CK) and R35CA197458 (M-CK). Work at City of Hope (COH) was supported by R01CA184585 (SLN), a COH Excellence Award (SLN), and the Morris and Horowitz Families Professorship (SLN). Work performed in the Integrative Genomics Core was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. Work at University of Chicago was supported by American Cancer Society CRP-10-119-01 –CCE (OIO) and the Susan G. Komen Foundation (OIO). The City of Hope Clinical Cancer Genetics Community Research Network was supported in part by Award Number RC4A153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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