Familial Cancer

, Volume 10, Issue 2, pp 225–231 | Cite as

PALB2 mutations in familial breast and pancreatic cancer

  • Erin W. Hofstatter
  • Susan M. Domchek
  • Alexander Miron
  • Judy Garber
  • Molin Wang
  • Kathryn Componeschi
  • Leigh Boghossian
  • Penelope L. Miron
  • Katherine L. Nathanson
  • Nadine Tung
Article

Abstract

PALB2 (Partner And Localizer of BRCA2) binds to and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1–2% of familial breast cancer and 3–4% of familial pancreatic cancer cases. The goal of this study was to evaluate the prevalence of PALB2 mutations in women with breast cancer without BRCA1/2 mutations who also had a personal or family history of pancreatic cancer. PALB2 mutation analysis was performed in 94 non-BRCA1/2 breast cancer patients with a personal or family history of pancreatic cancer. Two truncating PALB2 mutations, c.3549C>CA and c.2962C>CT, were identified resulting in a mutation prevalence of 2.1%. The proband found to carry the c.3549C>CA PALB2 mutation had a mother diagnosed with both breast and pancreatic cancer; this relative was subsequently confirmed to carry the identical mutation. The proband with the c.2962C>CT mutation had a father and paternal aunt diagnosed with pancreatic cancer; neither relative was available for testing. Two novel PALB2 missense variants were also found, one of which was deemed potentially deleterious. The prevalence rate of PALB2 mutations in a non-BRCA1/2 breast cancer population specifically selected for a family history of pancreatic cancer does not appear to be significantly increased compared to that observed in other breast cancer populations studied thus far. Further evaluation is needed to determine the prevalence of PALB2 mutations and the clinical utility of such testing in those individuals affected with both breast and pancreatic cancers.

Keywords

BRCA2 Breast cancer PALB2 Pancreatic cancer 

References

  1. 1.
    Ferlay J, Shin HR, Bray F et al (2008) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. doi:10.1002/ijc.25516
  2. 2.
    Buchholz TA, Wazer DE (2002) Molecular biology and genetics of breast cancer development: a clinical perspective. Semin Radiat Oncol 12:285–295. doi:10.1053/srao.2002.35248 PubMedCrossRefGoogle Scholar
  3. 3.
    Tan DSP, Marchio C, Reis-Filho JS (2008) Hereditary breast cancer: from molecular pathology to tailored therapies. J Clin Pathol 61:1073–1082. doi:10.1136/jcp.2008.057950 PubMedCrossRefGoogle Scholar
  4. 4.
    Walsh T, King MC (2007) Ten genes for inherited breast cancer. Cancer Cell 11:103. doi:10.1016/j.ccr.2007.01.010 PubMedCrossRefGoogle Scholar
  5. 5.
    Ford D, Easton DF, Stratton M (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Amer J Hum Genet 62:676–689. pii: S0002-9297(07)63848-8PubMedCrossRefGoogle Scholar
  6. 6.
    Rahman N, Seal S, Thompson D et al (2007) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39:165–167. doi:10.1038/ng1959 PubMedCrossRefGoogle Scholar
  7. 7.
    Xia B, Sheng Q, Nakanishi K et al (2006) Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 22:719–729. doi:10.1016/j.molcel.2006.05.022 PubMedCrossRefGoogle Scholar
  8. 8.
    Reid S, Schindler D, Hanenberg H et al (2007) Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet 39:162–164. doi:10.1038/ng1947 PubMedCrossRefGoogle Scholar
  9. 9.
    Zhang F, Ma J, Wu J et al (2009) PALB2 Links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol 19:524–529. doi:10.1016/j.cub.2009.02.018 PubMedCrossRefGoogle Scholar
  10. 10.
    Sy SM, Huen MS, Chen J (2009) PALB2 is an integral component of the BRCA complex required for homologous recombination repair. Proc Natl Acad Sci USA 106:7155–7160. doi:10.1073/pnas.0811159106 PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang F, Fan Q, Ren K, Andreassen PR (2009) PALB2 functionally connects the breast cancer susceptibility proteins BRCA1 and BRCA2. Mol Cancer Res 7:1110–1118. doi:10.1158/1541-7786.MCR-09-0123 PubMedCrossRefGoogle Scholar
  12. 12.
    Tischkowitz M, Xia B (2010) PALB2/FANCN: recombining cancer and Fanconi anemia. Cancer Res 70:7353–7359. doi:10.1158/0008-5472.CAN-10-1012 PubMedCrossRefGoogle Scholar
  13. 13.
    Hirshfield KM, Rebbeck TR, Levine AJ (2010) Germline mutations and polymorphisms in origins of cancers in women. J Oncol 1–11. doi:10.1155/2010/297671
  14. 14.
    Tischkowitz M, Xia B, Sabbaghian N et al (2007) Analysis of PALB2/FANCN-associated breast cancer families. Proc Natl Acad Sci 104:6788–6793. doi:10.1073/pnas.0701724104 PubMedCrossRefGoogle Scholar
  15. 15.
    Byrnes GB, Southey MC, Hopper JL (2008) Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res 10:208–214. doi:10.1186/bcr2099 PubMedCrossRefGoogle Scholar
  16. 16.
    Heikkinen T, Karkkainen H, Aaltonen K et al (2009) The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype. Clin Cancer Res 15:3214–3222. doi:10.1158/1078-0432.CCR-08-3128 PubMedCrossRefGoogle Scholar
  17. 17.
    Tischkowitz MD, Sabbaghian N, Hamel N et al (2009) Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology 137:1183–1186. doi:10.1053/j.gastro.2009.06.055 PubMedCrossRefGoogle Scholar
  18. 18.
    Jones S, Hruban RH, Kamiyama M et al (2009) Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324:217. doi:10.1126/science.1171202 PubMedCrossRefGoogle Scholar
  19. 19.
    Slater EP, Langer P, Niemczyk E et al (2010) PALB2 mutations in European familial pancreatic cancer families. Clin Genet. doi:10.1111/j.1399-0004.2010.01425.x
  20. 20.
    The Breast Cancer Linkage Consortium (1999) Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 91:1310–1316CrossRefGoogle Scholar
  21. 21.
    van Asperen CJ, Brohet RM, Meijers-Heijboer EJ et al (2005) Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711–719. doi:10.1136/jmg.2004.028829 PubMedCrossRefGoogle Scholar
  22. 22.
    Velasco E, Infante M, Durán M et al (2007) Heteroduplex analysis by capillary array electrophoresis for rapid mutation detection in large multiexon genes. Nat Protoc 2(1):237–246. doi:10.1038/nprot.2006.482 PubMedCrossRefGoogle Scholar
  23. 23.
    Davies H, Dicks E, Stephens P et al (2006) High throughput DNA sequence variant detection by conformation sensitive capillary electrophoresis and automated peak comparison. Genomics 87(3):427–432. doi:10.1016/j.ygeno.2005.11.008 PubMedCrossRefGoogle Scholar
  24. 24.
    Mehta CR, Patel NR (1983) A network algorithm for the exact treatment of Fisher’s exact test in rxc contingency tables. J Am Stat Assoc 78:427–434CrossRefGoogle Scholar
  25. 25.
    Oliver AW, Swift S, Lord CJ et al (2009) Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep 10:990–996. doi:10.1038/embor.2009.126 PubMedCrossRefGoogle Scholar
  26. 26.
    Adank MA, van Mil SE, Gille JJ et al (2010) PALB2 analysis in BRCA2-like families. Breast Cancer Res Treat. doi:10.1007/s10549-010-1001-1
  27. 27.
    Verna EC, Hwang C, Stevens PD et al (2010) Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics. Clin Cancer Res 16:OF1–OF10. doi:10.1158/1078-0432.CCR-09-3209 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Erin W. Hofstatter
    • 1
  • Susan M. Domchek
    • 2
  • Alexander Miron
    • 3
  • Judy Garber
    • 4
  • Molin Wang
    • 5
  • Kathryn Componeschi
    • 6
  • Leigh Boghossian
    • 2
  • Penelope L. Miron
    • 3
  • Katherine L. Nathanson
    • 2
  • Nadine Tung
    • 6
  1. 1.Section of Medical OncologyYale Cancer Center, Yale School of MedicineNew HavenUSA
  2. 2.Division of Medical Oncology, Abramson Cancer CenterUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Cancer BiologyDana-Farber Cancer InstituteBostonUSA
  4. 4.Division of Population Sciences and Adult OncologyDana-Farber Cancer InstituteBostonUSA
  5. 5.Department of Biostatistics and Computational BiologyDana-Farber Cancer InstituteBostonUSA
  6. 6.Division of Hematology-OncologyBeth Israel Deaconess Medical CenterBostonUSA

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