Irene Catucci1, Silvia Casadei2, Yuan Chun Ding3, Sara Volorio4, Filomena Ficarazzi4, Anna Falanga5, Marina Marchetti5, Carlo Tondini6, Michela Franchi6, Aaron Adamson3, Jessica Mandell2, Tom Walsh2, Olufunmilayo I Olopade7, Siranoush Manoukian8, Paolo Radice9, Charite Ricker10, Jeffrey Weitzel3, Mary-Claire King2, Paolo Peterlongo1, Susan L Neuhausen11. 1. IFOM, the FIRC Institute of Molecular Oncology, Milan, Italy. 2. Departments of Medicine and Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA. 3. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. 4. Cogentech, Cancer Genetic Test Laboratory, Milan, Italy. 5. Department of Immunohematology and Transfusion Medicine, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 6. Unit of Oncology, Ospedale Papa Giovanni XXIII, Bergamo, Italy. 7. Department of Medicine, Center for Clinical Cancer Genetics and Global Health, University of Chicago, Chicago, IL, USA. 8. Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 9. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 10. Department Medicine, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA. 11. Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA. sneuhausen@coh.org.
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.
PURPOSE:Breast cancer-predisposing mutations PALB2 c.1027C>T (p.Gln343*) and PALB2c.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 PALB2c.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 PALB2c.2167_2168delAT arose multiple times, but that within each population, PALB2c.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.
Entities:
Keywords:
Breast cancer; Founder mutations, Haplotype; PALB2
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