Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene
Open accessAbstract
Through complete sequencing of the protein-coding genes in a patient with familial pancreatic cancer, we identified a germline, truncating mutation in PALB2 that appeared responsible for this patient's predisposition to the disease. Analysis of 96 additional patients with familial pancreatic cancer revealed three distinct protein-truncating mutations, thereby validating the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner for BRCA2. These results illustrate that complete, unbiased sequencing of protein-coding genes can lead to the identification of a gene responsible for a hereditary disease.
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Pancreatic surveillance is recommended for carriers of germline deleterious variants in BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.
“Pancreatic surveillance is recommended for carriers of germline deleterious variants in cancer susceptibility gene,22–26: BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.”
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“, where three of four FPC families in their report also had cases of breast cancer (8), and Tischkowitz et al.”
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“the protein-coding genes in a single patient’s cancer [42,43].”
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“PALB2–BRCA2 signaling still plays an indispensable role in this HR restoration.”
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“These include BRCA1 and BRCA2 (Lal et al, 2000), TP53 (Caldas et al, 1994), PALB2 (Jones et al, 2009), p16/CDKN2A (Redston et al, 1994; Ghiorzo et al, 2012), SMAD4 (Hahn et al, 1996), STK 11 (Sato et al, 2001), ataxia-telangiectasia-mutated (ATM) gene (Roberts et al, 2011) and the mismatch repair genes (MMR) (Win et a…”
Villarroel, M. C., Rajeshkumar, N. V., Garrido‐Laguna, I., Jesus‐Acosta, A. D., Jones, S., Maitra, A., Hruban, R. H., Eshleman, J. R., Klein, A. P., Laheru, D. A., et al. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-10-0893 · Cited by 249 · see citing works
“Whenever a variant was identified in the cancer, the patient’s germline DNA was also sequenced, revealing information about germline variations in this patient (10).”
Self-citationContribution of Inherited Mutations in the BRCA2-Interacting Protein PALB2 to Familial Breast Cancer
Casadei, S., Norquist, B. M., Walsh, T., Stray, S. M., Mandell, J. B., Lee, M. K., Stamatoyannopoulos, J. A., & King, M. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-3958 · Cited by 242 · see citing works
“Cancer profiles of these families are also consistent with the suggestion that PALB2 is a susceptibility gene for pancreatic cancer (22).”
Genetic susceptibility to pancreatic cancer
Klein, A. P. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.20855 · Cited by 235 · see citing works
“Approximately 1% of non-BRCA1/BRCA2 deficient familial breast cancers are caused by germline defects in PALB2 [31].”
BackgroundInfluentialSelf-citationDiagnostic, prognostic, and predictive biomarkers in pancreatic cancer
Winter, J. M., Yeo, C. J., & Brody, J. R. (2012) · Journal of Surgical Oncology · doi:10.1002/jso.23192 · Cited by 228 · see citing works
“A separate study in a single patient with a PDA and a PALB2 mutation demonstrated a durable response to mitomycin C even after progression on gemcitabine [81].”
BackgroundArchitecture of inherited susceptibility to common cancer
Fletcher, O., & Houlston, R. S. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2840 · Cited by 221 · see citing works
“Exomic screening was recently used to identify PALB2 mutations in familial pancreatic cance”
MethodAdvanced-stage pancreatic cancer: therapy options
Werner, J., Combs, S. E., Springfeld, C., Hartwig, W., Hackert, T., & Büchler, M. W. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.66 · Cited by 217 · see citing works
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The Predictive Capacity of Personal Genome Sequencing
Roberts, N. J., Vogelstein, J. T., Parmigiani, G., Kinzler, K. W., Vogelstein, B., & Velculescu, V. E. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3003380 · Cited by 213 · see citing works
“shown that whole-genome sequencing can prove highly informative [for example, (8, 9)].”
BackgroundSelf-citationThompson, E. R., Doyle, M., Ryland, G. L., Rowley, S. M., Choong, D. Y. H., Tothill, R. W., Thorne, H., kConFab, Barnes, D. R., Li, J., et al. (2012) · PLoS Genetics · doi:10.1371/journal.pgen.1002894 · Cited by 211 · see citing works
Increased Prevalence of Precursor Lesions in Familial Pancreatic Cancer Patients
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Self-citationEarly detection of pancreatic cancer: Where are we now and where are we going?
Zhou, B., Xu, J., Cheng, Y., Gao, J., Hu, S., Wang, L., & Zhan, H. (2017) · International Journal of Cancer · doi:10.1002/ijc.30670 · Cited by 209 · see citing works
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“As with BRCA2, heterozygotes PALB2 mutations have been associated with an increased risk of pancreatic cancer (43).”
BackgroundVerna, E. C., Hwang, C., Stevens, P. D., Rotterdam, H., Stavropoulos, S. N., Sy, C. D., Prince, M. A., Chung, W. K., Fine, R. L., Chabot, J. A., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3209 · Cited by 201 · see citing works
Hereditary Breast and Ovarian Cancer
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Identification of germline genetic mutations in patients with pancreatic cancer
Salo‐Mullen, E. E., O'Reilly, E. M., Kelsen, D. P., Ashraf, A. M., Lowery, M. A., Yu, K. H., Reidy‐Lagunes, D. L., Epstein, A. S., Lincoln, A., Saldia, A., et al. (2015) · Cancer · doi:10.1002/cncr.29664 · Cited by 198 · see citing works
“Although the majority of cases of pancreatic adenocarcinoma (PAC) appear to be sporadic, approximately 5% to 10% occur in the presence of a family history of the disease.1,2 Pancreatic cancer has been linked to inherited cancer susceptibility syndromes including hereditary breast and ovarian cancer (HBOC) syndrome (BR…”
BackgroundPALB2/FANCN: Recombining Cancer and Fanconi Anemia
Tischkowitz, M. D., & Xia, B. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1012 · Cited by 196 · see citing works
“It is therefore possible that the second PALB2 allele is somatically mutated in the tumors, as was observed in a PALB2-related pancreas cancer (27).”
Diagnosis and management of pancreatic cancer
Kanji, Z. S., & Gallinger, S. (2013) · Canadian Medical Association Journal · doi:10.1503/cmaj.121368 · Cited by 196 · see citing works
PALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function
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Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer
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“For example, methods for detecting BNC1 or ADAMTS1 promoter methylation could be carried out before or concurrently with testing for mutations common to pancreatic cancer such as KRAS (57), PALB2 (58), or GNAS (59)”
BackgroundSelf-citationCancer systems biology: embracing complexity to develop better anticancer therapeutic strategies
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Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics
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“Other transposable elements have contributed functional noncoding sequence, for example, as regulatory elements [Jordan et al., 2003; Thornburg et al., 2006], microRNAs [Piriyapongsa et al.”
BackgroundStructural basis for recruitment of BRCA2 by PALB2
Oliver, A. W., Swift, S., Lord, C. J., Ashworth, A., & Pearl, L. H. (2009) · EMBO Reports · doi:10.1038/embor.2009.126 · Cited by 181 · see citing works
“Structural basis for recruitment of BRCA2 by PALB2”
BackgroundSampson, J. N., Wheeler, W. A., Yeager, M., Panagiotou, O. A., Wang, Z., Berndt, S. I., Qing Lan, B., Abnet, C. C., Amundadottir, L. T., Figueroa, J. D., et al. (2015) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djv279 · Cited by 181 · see citing works
Vincent, A., Omura, N., Hong, S., Jaffe, A. E., Eshleman, J. R., & Goggins, M. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-3431 · Cited by 177 · see citing works
“Identifying those at risk of developing pancreatic cancer (1, 2) and developing better diagnostic markers of pancreatic neoplasia (3, 4) could improve the early diagnosis of pancreatic cancer and its precursors (5) and allow more patients to undergo curative surgical resection.”
BackgroundSelf-citationBhagat, T. D., Ahrens, D. V., Dawlaty, M. M., Zou, Y., Baddour, J., Achreja, A., Zhao, H., Yang, L., Patel, B., Kwak, C., et al. (2019) · eLife · doi:10.7554/elife.50663 · Cited by 170 · see citing works
Self-citationKanda, M., Knight, S., Topazian, M. D., Syngal, S., Farrell, J. J., Lee, J. D., Kamel, I. R., Lennon, A. M., Borges, M. W., Young, A., et al. (2012) · Gut · doi:10.1136/gutjnl-2012-302823 · Cited by 170 · see citing works
Self-citationSkoulidis, F., Cassidy, L. D., Pisupati, V., Jonasson, J. G., Bjarnason, H., Eyfjord, J. E., Karreth, F. A., Lim, M., Barber, L. M., Clatworthy, S. A., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.10.015 · Cited by 167 · see citing works
“More recently, PALB2, which encodes a BRCA2-interacting protein also essential for homology-directed DNA repair, has emerged as a pancreatic cancer-susceptibility allele (Jones et al., 2009).”
BackgroundPetersen, G. M. (2016) · Seminars in Oncology · doi:10.1053/j.seminoncol.2016.09.002 · Cited by 157 · see citing works
PALB2 mutations in familial breast and pancreatic cancer
Hofstatter, E. W., Domchek, S. M., Miron, A., Garber, J. E., Wang, M., Componeschi, K. P., Boghossian, L., Miron, P. L., Nathanson, K. L., & Tung, N. (2011) · Familial Cancer · doi:10.1007/s10689-011-9426-1 · Cited by 155 · see citing works
“2962C[CT PALB2 mutations identified in our sample have been previously described in breast cancer and Fanconi anemia patients, respectively [8, 18].”
Iacobuzio–Donahue, C. A. (2011) · Gut · doi:10.1136/gut.2010.236026 · Cited by 158 · see citing works
“PALB2 germline mutations, whose protein product interacts with Brca2, have also recently been identified in patients with familial pancreatic cancer.(8) While CDKN2A is a known tumour suppressor gene in sporadic pancreatic cancers, germline mutations in CDKN2A cause familial atypical multiple mole melanoma syndrome (F…”
BackgroundSelf-citationPatient‐derived xenografts for individualized care in advanced sarcoma
Stebbing, J., Paz, K., Schwartz, G. K., Wexler, L. H., Maki, R. G., Pollock, R. E., Morris, R., Cohen, R., Shankar, A., Blackman, G., et al. (2014) · Cancer · doi:10.1002/cncr.28696 · Cited by 156 · see citing works
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“More recently, germline mutations in the gene PALB2, which encodes a protein critical for the initiation of homologous recombination (HR), have also been identified in patients with PDAC and a personal or family history of breast cancer[8].”
BackgroundClinical Validation of KRAS, BRAF, and EGFR Mutation Detection Using Next-Generation Sequencing
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Self-citationKlein, A. P., Lindström, S., Mendelsohn, J. B., Steplowski, E., Arslan, A. A., Bueno-de-Mesquita, H. B., Fuchs, C. S., Gallinger, S., Gross, M., Helzlsouer, K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072311 · Cited by 148 · see citing works
Self-citationFamilial pancreatic cancer—current knowledge
Bartsch, D. K., Gress, T. M., & Langer, P. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2012.111 · Cited by 151 · see citing works
Chaffee, K. G., Oberg, A. L., McWilliams, R. R., Majithia, N., Allen, B. A., Kidd, J., Singh, N., Hartman, A.-R., Wenstrup, R. J., & Petersen, G. M. (2018) · Genetics in Medicine · doi:10.1038/gim.2017.85 · Cited by 144 · see citing works
“Twenty-seven individuals were found to carry a PV in a gene associated with increased risk of breast cancer (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, NBN).”
InfluentialIacobuzio–Donahue, C. A., Velculescu, V. E., Wolfgang, C. L., & Hruban, R. H. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0315 · Cited by 149 · see citing works
“germline PALB2 mutations were identified in a validation set of 96 familial pancreatic cancer patients, establishing PALB2 as a familial pancreatic cancer gene (23, 24).”
Self-citationHu, H.-F., Ye, Z., Qin, Y., Xu, X.-W., Yu, X.-J., Zhuo, Q.-F., & Ji, S.-R. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00584-2 · Cited by 149 · see citing works
- Authors
- Jones, S., Hruban, R. H., Kamiyama, M., Borges, M., Zhang, X., Parsons, D. W., Lin, J. C.-H., Palmisano, E., Brune, K., Jaffee, E. M., Iacobuzio-Donahue, C. A., Maitra, A., Parmigiani, G., Kern, S. E., Velculescu, V. E., Kinzler, K. W., Vogelstein, B., Eshleman, J. R., Goggins, M., & Klein, A. P.
- Affiliations
- Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Baltimore, MD 21231, USA.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eshleman, James R.
- Goggins, Michael
- Klein, Alison P.
- ORCID
- Venue
- Science
- Published
- 2009-04-10
- Volume
- 324
- Issue
- 5924
- Pages
- 217-217
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2684332
- OpenAlex
- W2140872369
- Cited by
- 826
- References
- 10
- Citations by year
- 2026: 13 · 2025: 7 · 2024: 18 · 2023: 19 · 2022: 66 · 2021: 43 · 2020: 34 · 2019: 53 · 2018: 48 · 2017: 50 · 2016: 50 · 2015: 69 · 2014: 81 · 2013: 53 · 2012: 67
- FWCI
- 42.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca121113-15)
- National Cancer Institute (R01CA-97075, CA123483, R01CA123483, R01-CA121113, R37CA043460, P50CA102701, R01CA097075, P50CA062924, R37CA057345, CA 62924)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- PALB2, pancreatic cancer, hereditary cancer predisposition, germline mutations, truncating mutations, familial pancreatic cancer, BRCA2, exome sequencing
- MeSH terms
- Fanconi Anemia Complementation Group N Protein, Breast Neoplasms, Female, Humans, Male, Nuclear Proteins, Pancreatic Neoplasms, Pedigree, Sequence Deletion, Sequence Analysis, DNA, Germ-Line Mutation, Codon, Terminator, Genetic Predisposition to Disease, Tumor Suppressor Proteins
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