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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 cancer susceptibility gene,22–26: BRCA2, ATM, BRCA1, PALB2, CDKN2A, STK11, MLH1 and MSH2.”
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Self-citationWhole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
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“and of germline mutations in the gene encoding partner and localizer of BRCA2 ( PALB2 ) in patients with pancreatic carcinom”
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Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis
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Recent progress in pancreatic cancer
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“The partner and localizer of BRCA2 ( PALB2 ) gene, which is associated with Fanconi anemia and breast cancer predisposition, has also been identified as a candidate pancreatic cancer susceptibility gene”
BackgroundHereditary Diffuse Gastric Cancer Syndrome
Hansford, S., Kaurah, P., Li-Chang, H. H., Woo, M., Senz, J., Pinheiro, H. C., Schrader, K. A., Schaeffer, D. F., Shumansky, K., Zogopoulos, G., et al. (2015) · JAMA Oncology · doi:10.1001/jamaoncol.2014.168 · Cited by 695
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Self-citationFrequent detection of pancreatic lesions in asymptomatic high-risk individuals
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Self-citationPetersen, G. M., Amundadottir, L. T., Fuchs, C. S., Kraft, P. L., Stolzenberg‐Solomon, R. Z., Jacobs, K. B., Arslan, A. A., Bueno-de-Mesquita, H. B., Gallinger, S., Gross, M. D., et al. (2010) · Nature Genetics · doi:10.1038/ng.522 · Cited by 598
“Truncating mutations and deletions in PALB2 have also recently been shown to be involved in familial pancreatic cance”
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“1%, for BRCA1 and BRCA2 carriers, respectively),(7,8) hereditary pancreatitis (lifetime risk, 40%),(9) and the newly described familial pancreatic cancer due to mutations in the PALB2 gene (risk not specified).(10) Pancreatic cancer has also been observed in Lynch syndrome, an autosomal dominant condition caused by de…”
Genetics and biology of pancreatic ductal adenocarcinoma
Ying, H., Dey, P., Yao, W., Kimmelman, A. C., Draetta, G. F., Maitra, A., & DePinho, R. A. (2016) · Genes & Development · doi:10.1101/gad.275776.115 · Cited by 527
“Germline mutations of some DDR genes, such as BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, and MSH6, have been linked to an increased predisposition to PDAC (Goggins et al. 1996; Thompson et al. 2002; Jones et al. 2009; Roberts et al. 2012; Grant et al. 2015; Holter et al. 2015).”
Diabetes, pancreatogenic diabetes, and pancreatic cancer
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“Susceptibility genes that have been identified range from rare mutations in genes associated with cancer syndromes to common SNPs. Designs that include familybased and case-control studies have uncovered mutations in known syndrome-related genes, such as BRCA1, BRCA2, CDKN2A, and CFTR. Next-generation sequencing has i…”
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Self-citationATM Mutations in Patients with Hereditary Pancreatic Cancer
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“Unbiased, genome-wide sequencing can be used to identify familial pancreatic genes, as demonstrated by the finding that PALB2 is a pancreatic cancer susceptibility gene (3).”
BackgroundSelf-citationDeleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma
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“1 , 51 81 (9) 79 (23) 51-60 199 (23) 80 (24) 61-70 297 (35) 95 (28) 71-80 220 (26) 69 (20) $ 80 57 (7) 16 (5) Sex Male 455 (53) 181 (53) Female 399 (47) 158 (47) Race White 756 (89) 280 (83) African American 52 (6) 31 (9) Other 46 (5) 28 (8) Family history of pancreatic cancer 109 (12.”
Self-citationNext-Generation Sequencing in Oncology: Genetic Diagnosis, Risk Prediction and Cancer Classification
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“Previous observational studies of PALB2 in familial PaC reported conflicting results.(8,9,33-36) The current analysis confirms the association with PaC and is the first in our knowledge to quantify it, with an RR estimate of 2.”
ResultTung, N., Battelli, C., Allen, B. A., Kaldate, R., Bhatnagar, S., Bowles, K. R., Timms, K. M., Garber, J. E., Herold, C. I., Ellisen, L. W., et al. (2014) · Cancer · doi:10.1002/cncr.29010 · Cited by 442
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“This process led, as recently reported, to the discovery of PALB2 mutations in a mitomycin C–responsive patient (12, 15).”
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“Sequencing all known coding DNA, known as exomic sequencin”
BackgroundGermline BRCA Mutations in a Large Clinic-Based Cohort of Patients With Pancreatic Adenocarcinoma
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What can exome sequencing do for you?
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“(the gene encoding partner and localiser of BRCA2) in patients with pancreatic carcinoma,”
BackgroundSusceptibility Pathways in Fanconi's Anemia and Breast Cancer
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Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer
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“Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern, while Fanconi anaemia is an autosomal recessive condition [82, 83].”
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“Recently, PALB2 has also been linked to pancreatic cancer susceptibility, being the second most frequently mutated gene in affected people, after BRCA2 (ref”
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Self-citationImportance of Age of Onset in Pancreatic Cancer Kindreds
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Self-citationPALB2 mutations in European familial pancreatic cancer families
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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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Self-citationUpdate on Familial Pancreatic Cancer
Hruban, R. H., Canto, M. I., Goggins, M., Schulick, R. D., & Klein, A. P. (2010) · Advances in Surgery · doi:10.1016/j.yasu.2010.05.011 · Cited by 278
“the protein-coding genes in a single patient’s cancer [42,43].”
InfluentialSelf-citationGenome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
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Self-citationPARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications
Zhu, H., Wei, M., Xu, J., Hua, J., Chen, L., Meng, Q., Zhang, Y., Liu, J., Zhang, B., Yu, X., et al. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01167-9 · Cited by 263
“PALB2–BRCA2 signaling still plays an indispensable role in this HR restoration.”
BackgroundInfluentialThe incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers
T. H. B. C. S. G., Iqbal, J., Ragone, A., Lubinski, J., Lynch, H. T., Moller, P., Ghadirian, P., Foulkes, W. D., Armel, S., Eisen, A., et al. (2012) · British Journal of Cancer · doi:10.1038/bjc.2012.483 · Cited by 252
“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
“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
“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 240
“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 234
“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 227
“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 220
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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 216
“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 218
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 218
Lalloo, F. I., & Evans, D. G. (2012) · Clinical Genetics · doi:10.1111/j.1399-0004.2012.01859.x · Cited by 220
“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
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
“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 199
“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
PALB2 Interacts with KEAP1 To Promote NRF2 Nuclear Accumulation and Function
Ma, J., Cai, H., Wu, T., Sobhian, B., Huo, Y., Alcivar, A. L., Mehta, M., Cheung, K. L., Ganesan, S., Kong, A. T., et al. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06271-11 · Cited by 193
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Novel Methylation Biomarker Panel for the Early Detection of Pancreatic Cancer
Yi, J. M., Guzzetta, A. A., Bailey, V. J., Downing, S. R., Neste, L. V., Chiappinelli, K. B., Keeley, B. P., Stark, A., Herrera, A., Wolfgang, C. L., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-3224 · Cited by 188
“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 188
“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
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“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 178
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
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 169
“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
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
“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
“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 157
Lowery, M. A., Kelsen, D. P., Capanu, M., Smith, S., Lee, J. W., Stadler, Z. K., Moore, M. J., Kindler, H. L., Golan, T., Segal, A., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2017.11.004 · Cited by 159
“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
Lin, M., Mosier, S. L., Thiess, M., Beierl, K. F., Debeljak, M., Tseng, L., Chen, G., Yegnasubramanian, S., Ho, H., Cope, L., et al. (2014) · American Journal of Clinical Pathology · doi:10.1309/ajcpmwgwgo34egod · Cited by 152
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 153
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“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 155
“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
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Self-citation
Metadata
- 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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