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Breast Cancer Research and Treatment

, Volume 160, Issue 1, pp 121–129 | Cite as

Haplotype analyses of the c.1027C>T and c.2167_2168delAT recurrent truncating mutations in the breast cancer-predisposing gene PALB2

  • Irene Catucci
  • Silvia Casadei
  • Yuan Chun Ding
  • Sara Volorio
  • Filomena Ficarazzi
  • Anna Falanga
  • Marina Marchetti
  • Carlo Tondini
  • Michela Franchi
  • Aaron Adamson
  • Jessica Mandell
  • Tom Walsh
  • Olufunmilayo I. Olopade
  • Siranoush Manoukian
  • Paolo Radice
  • Charite Ricker
  • Jeffrey Weitzel
  • Mary-Claire King
  • Paolo Peterlongo
  • Susan L. Neuhausen
Epidemiology

Abstract

Purpose

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).

Methods

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.

Results

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.

Conclusion

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.

Keywords

Breast cancer PALB2 Founder mutations, Haplotype 

Notes

Funding

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.

Ethical approval

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.

Supplementary material

10549_2016_3981_MOESM1_ESM.pdf (47 kb)
Supplementary material 1 (PDF 47 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Irene Catucci
    • 1
  • Silvia Casadei
    • 2
  • Yuan Chun Ding
    • 3
  • Sara Volorio
    • 4
  • Filomena Ficarazzi
    • 4
  • Anna Falanga
    • 5
  • Marina Marchetti
    • 5
  • Carlo Tondini
    • 6
  • Michela Franchi
    • 6
  • Aaron Adamson
    • 3
  • Jessica Mandell
    • 2
  • Tom Walsh
    • 2
  • Olufunmilayo I. Olopade
    • 7
  • Siranoush Manoukian
    • 8
  • Paolo Radice
    • 9
  • Charite Ricker
    • 10
  • Jeffrey Weitzel
    • 3
  • Mary-Claire King
    • 2
  • Paolo Peterlongo
    • 1
  • Susan L. Neuhausen
    • 3
  1. 1.IFOM, the FIRC Institute of Molecular OncologyMilanItaly
  2. 2.Departments of Medicine and Genome SciencesUniversity of Washington School of MedicineSeattleUSA
  3. 3.Department of Population SciencesBeckman Research Institute of City of HopeDuarteUSA
  4. 4.Cogentech, Cancer Genetic Test LaboratoryMilanItaly
  5. 5.Department of Immunohematology and Transfusion MedicineOspedale Papa Giovanni XXIIIBergamoItaly
  6. 6.Unit of OncologyOspedale Papa Giovanni XXIIIBergamoItaly
  7. 7.Department of Medicine, Center for Clinical Cancer Genetics and Global HealthUniversity of ChicagoChicagoUSA
  8. 8.Unit of Medical Genetics, Department of Preventive and Predictive MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  9. 9.Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  10. 10.Department MedicineKeck School of Medicine at University of Southern CaliforniaLos AngelesUSA

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