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Epidemiology

Family history of cancer, Ashkenazi Jewish ancestry, and pancreatic cancer risk

Abstract

Background

Individuals with a family history of cancer may be at increased risk of pancreatic cancer. Ashkenazi Jewish (AJ) individuals carry increased risk for pancreatic cancer and other cancer types.

Methods

We examined the association between family history of cancer, AJ heritage, and incident pancreatic cancer in 49 410 male participants of the prospective Health Professionals Follow-up Study. Hazard ratios (HRs) were estimated using multivariable-adjusted Cox proportional hazards models.

Results

During 1.1 million person-years (1986–2016), 452 participants developed pancreatic cancer. Increased risk of pancreatic cancer was observed in individuals with a family history of pancreatic (HR, 2.79; 95% confidence interval [CI], 1.28–6.07) or breast cancer (HR, 1.40; 95% CI, 1.01–1.94). There was a trend towards higher risk of pancreatic cancer in relation to a family history of colorectal cancer (HR, 1.21; 95% CI, 0.95–1.55) or AJ heritage (HR, 1.29; 95% CI, 0.94–1.77). The risk was highly elevated among AJ men with a family history of breast or colorectal cancer (HR, 2.61 [95% CI, 1.41–4.82] and 1.92 [95% CI, 1.05–3.49], respectively).

Conclusion

Family history of pancreatic cancer was associated with increased risk of this malignancy. Family history of breast or colorectal cancer was associated with the increased risk among AJ men.

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References

  1. 1.

    Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin. 69, 7–34 (2019).

  2. 2.

    Kleeff, J., Korc, M., Apte, M., La Vecchia, C., Johnson, C. D. & Biankin, A. V. et al. Pancreatic cancer. Nat. Rev. Dis. Prim. 2, 16022 (2016).

  3. 3.

    Brune, K. A., Lau, B., Palmisano, E., Canto, M., Goggins, M. G. & Hruban, R. H. et al. Importance of age of onset in pancreatic cancer kindreds. J. Natl. Cancer Inst. 102, 119–126 (2010).

  4. 4.

    Coughlin, S. S., Calle, E. E., Patel, A. V. & Thun, M. J. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 11, 915–923 (2000).

  5. 5.

    Hemminki, K. & Li, X. Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. Int. J. Cancer 103, 525–530 (2003).

  6. 6.

    Jacobs, E. J., Chanock, S. J., Fuchs, C. S., Lacroix, A., McWilliams, R. R. & Steplowski, E. et al. Family history of cancer and risk of pancreatic cancer: a pooled analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int. J. Cancer 127, 1421–1428 (2010).

  7. 7.

    Schulte, A., Pandeya, N., Fawcett, J., Fritschi, L., Klein, K. & Risch, H. A. et al. Association between family cancer history and risk of pancreatic cancer. Cancer Epidemiol. 45, 145–150 (2016).

  8. 8.

    Jacobs, E. J., Rodriguez, C., Newton, C. C., Bain, E. B., Patel, A. V. & Feigelson, H. S. et al. Family history of various cancers and pancreatic cancer mortality in a large cohort. Cancer Causes Control 20, 1261–1269 (2009).

  9. 9.

    Wang, L., Brune, K. A., Visvanathan, K., Laheru, D., Herman, J. & Wolfgang, C. et al. Elevated cancer mortality in the relatives of patients with pancreatic cancer. Cancer Epidemiol. Biomark. Prev. 18, 2829–2834 (2009).

  10. 10.

    McWilliams, R. R., Rabe, K. G., Olswold, C., De Andrade, M. & Petersen, G. M. Risk of malignancy in first-degree relatives of patients with pancreatic carcinoma. Cancer 104, 388–394 (2005).

  11. 11.

    Antwi, S. O., Fagan, S. E., Chaffee, K. G., Bamlet, W. R., Hu, C., & Polley, E. C. et al. Risk of different cancers among first-degree relatives of pancreatic cancer patients: influence of probands’ susceptibility gene mutation status. J. Natl Cancer Inst. (2018).

  12. 12.

    Zhen, D. B., Rabe, K. G., Gallinger, S., Syngal, S., Schwartz, A. G. & Goggins, M. G. et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet. Med. 17, 569–577 (2015).

  13. 13.

    Jones, S., Hruban, R. H., Kamiyama, M., Borges, M., Zhang, X. & Parsons, D. W. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009).

  14. 14.

    Petersen, G. M. Familial pancreatic adenocarcinoma. Hematol. Oncol. Clin. North. Am. 29, 641–653 (2015).

  15. 15.

    Roberts, N. J., Norris, A. L., Petersen, G. M., Bondy, M. L., Brand, R. & Gallinger, S. et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 6, 166–175 (2016).

  16. 16.

    Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J. Natl Cancer Inst. 91, 1310–1316 (1999).

  17. 17.

    Thompson, D. & Easton, D. F. Cancer Incidence in BRCA1 mutation carriers. J. Natl Cancer Inst. 94, 1358–1365 (2002).

  18. 18.

    Klein, A. P. Genetic susceptibility to pancreatic cancer. Mol. Carcinog. 51, 14–24 (2012).

  19. 19.

    Syngal, S., Brand, R. E., Church, J. M., Giardiello, F. M., Hampel, H. L. & Burt, R. W. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 110, 223–262 (2015).

  20. 20.

    Win, A. K., Young, J. P., Lindor, N. M., Tucker, K. M., Ahnen, D. J. & Young, G. P. et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J. Clin. Oncol. 30, 958–964 (2012).

  21. 21.

    Matsubayashi, H., Takaori, K., Morizane, C., Maguchi, H., Mizuma, M. & Takahashi, H. et al. Familial pancreatic cancer: Concept, management and issues. World J. Gastroenterol. 23, 935–948 (2017).

  22. 22.

    Mocci, E., Milne, R. L., Mendez-Villamil, E. Y., Hopper, J. L., John, E. M. & Andrulis, I. L. et al. Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. Cancer Epidemiol. Biomark. Prev. 22, 803–811 (2013).

  23. 23.

    Borg, A., Sandberg, T., Nilsson, K., Johannsson, O., Klinker, M. & Masback, A. et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl Cancer Inst. 92, 1260–1266 (2000).

  24. 24.

    Carmi, S., Hui, K. Y., Kochav, E., Liu, X., Xue, J. & Grady, F. et al. Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins. Nat. Commun. 5, 4835 (2014).

  25. 25.

    Behar, D. M., Yunusbayev, B., Metspalu, M., Metspalu, E., Rosset, S. & Parik, J. et al. The genome-wide structure of the Jewish people. Nature 466, 238–242 (2010).

  26. 26.

    Bray, S. M., Mulle, J. G., Dodd, A. F., Pulver, A. E., Wooding, S. & Warren, S. T. Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population. Proc. Natl Acad. Sci. USA 107, 16222–16227 (2010).

  27. 27.

    Stadler, Z. K., Salo-Mullen, E., Patil, S. M., Pietanza, M. C., Vijai, J. & Saloustros, E. et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi Jewish families with breast and pancreatic cancer. Cancer 118, 493–499 (2012).

  28. 28.

    Metcalfe, K. A., Poll, A., Royer, R., Llacuachaqui, M., Tulman, A. & Sun, P. et al. Screening for founder mutations in BRCA1 and BRCA2 in unselected Jewish women. J. Clin. Oncol. 28, 387–391 (2010).

  29. 29.

    Abeliovich, D., Kaduri, L., Lerer, I., Weinberg, N., Amir, G. & Sagi, M. et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am. J. Hum. Genet. 60, 505–514 (1997).

  30. 30.

    Ponti, G., Castellsague, E., Ruini, C., Percesepe, A. & Tomasi, A. Mismatch repair genes founder mutations and cancer susceptibility in Lynch syndrome. Clin. Genet. 87, 507–516 (2015).

  31. 31.

    Eldridge, R. C., Gapstur, S. M., Newton, C. C., Goodman, M., Patel, A. V. & Jacobs, E. J. Jewish ethnicity and pancreatic cancer mortality in a large U.S. cohort. Cancer Epidemiol. Biomark. Prev. 20, 691–698 (2011).

  32. 32.

    Salo-Mullen, E. E., O’Reilly, E. M., Kelsen, D. P., Ashraf, A. M., Lowery, M. A. & Yu, K. H. et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 121, 4382–4388 (2015).

  33. 33.

    Lynch, H. T., Deters, C. A., Lynch, J. F. & Brand, R. E. Familial pancreatic carcinoma in Jews. Fam. Cancer 3, 233–240 (2004).

  34. 34.

    Laitman, Y., Keinan Boker, L., Liphsitz, I., Weissglas-Volkov, D., Litz-Philipsborn, S. & Schayek, H. et al. Cancer risks in Jewish male BRCA1 and BRCA2 mutation carriers. Breast Cancer Res. Treat. 150, 631–635 (2015).

  35. 35.

    Yeo, T. P. Demographics, epidemiology, and inheritance of pancreatic ductal adenocarcinoma. Semin. Oncol. 42, 8–18 (2015).

  36. 36.

    Tempero, M. A., Malafa, M. P., Al-Hawary, M., Asbun, H., Bain, A. & Behrman, S. W. et al. Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 15, 1028–1061 (2017).

  37. 37.

    Michaud, D. S., Liu, Y., Meyer, M., Giovannucci, E. & Joshipura, K. Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol. 9, 550–558 (2008).

  38. 38.

    Rich-Edwards, J. W., Corsano, K. A. & Stampfer, M. J. Test of the national death index and equifax nationwide death search. Am. J. Epidemiol. 140, 1016–1019 (1994).

  39. 39.

    Kamisawa, T., Wood, L. D., Itoi, T. & Takaori, K. Pancreatic cancer. Lancet 388, 73–85 (2016).

  40. 40.

    Permuth-Wey, J. & Egan, K. M. Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis. Fam. Cancer 8, 109–117 (2009).

  41. 41.

    Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K. A., Mooij, T. M. & Roos-Blom, M. J. et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 317, 2402–2416 (2017).

  42. 42.

    Grant, R. C., Selander, I., Connor, A. A., Selvarajah, S., Borgida, A. & Briollais, L. et al. Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer. Gastroenterology 148, 556–564 (2015).

  43. 43.

    Underhill, M. L., Germansky, K. A. & Yurgelun, M. B. Advances in hereditary colorectal and pancreatic cancers. Clin. Ther. 38, 1600–1621 (2016).

  44. 44.

    Lindstrom, S., Finucane, H., Bulik-Sullivan, B., Schumacher, F. R., Amos, C. I. & Hung, R. J. et al. Quantifying the genetic correlation between multiple cancer types. Cancer Epidemiol. Biomark. Prev. 26, 1427–1435 (2017).

  45. 45.

    Foulkes, W. D., Thiffault, I., Gruber, S. B., Horwitz, M., Hamel, N. & Lee, C. et al. The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am. J. Hum. Genet. 71, 1395–1412 (2002).

  46. 46.

    Raskin, L., Schwenter, F., Freytsis, M., Tischkowitz, M., Wong, N. & Chong, G. et al. Characterization of two Ashkenazi Jewish founder mutations in MSH6 gene causing Lynch syndrome. Clin. Genet. 79, 512–522 (2011).

  47. 47.

    Ziogas, A., Horick, N. K., Kinney, A. Y., Lowery, J. T., Domchek, S. M. & Isaacs, C. et al. Clinically relevant changes in family history of cancer over time. JAMA 306, 172–178 (2011).

  48. 48.

    Acheson, L. S. Recording, interpreting, and updating the family history of cancer: implications for cancer prevention. JAMA 306, 208–210 (2011).

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Acknowledgements

We would like to thank the participants and staff of the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. We assume full responsibility for analyses and interpretation of the data. The HPFS is supported by U.S. National Institutes of Health (NIH) grants (UM1 CA167552 and U01 CA167552). This work was additionally supported by NIH R01 CA205406 and the Broman Fund for Pancreatic Cancer Research to K.N.; by NIH R01 CA124908 and P50 CA127003, the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, and Pappas Family Research Fund for Pancreatic Cancer to C.S.F.; by NIH R35 CA197735 to S.O.; and by Hale Center for Pancreatic Cancer Research, NIH/National Cancer Institute (NCI) U01 CA210171, Department of Defense CA130288, Lustgarten Foundation, Stand Up to Cancer, Pancreatic Cancer Action Network, Noble Effort Fund, Wexler Family Fund, and Promises for Purple to B.M.W. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

T.H., C.Y., and B.M.W. drafted the manuscript. T.H., C.Y., N.K., V.M.O., A.B., C.S.F., S.O., and B.M.W. planned and conducted the study. All authors collected, analysed, and interpreted the data. M.B.Y., K.P., N.K., V.M.O., A.B., J.A.N., D.A.R., M.G., K.N., P.K., M.J.S., E.L.G., C.S.F., S.O., and B.M.W. edited the manuscript. C.S.F., S.O., and B.M.W. supervised the study. All authors approved the final submitted draft.

Author information

Competing interests

C.S.F. declares consulting for Agios Inc., Bain Capital L.P., Bayer A.G., Celgene Inc., Dicerna Inc., Eli Lilly, Entrinsic Health Solutions Inc., Five Prime Therapeutics Inc., Genentech Inc., Gilead Sciences Inc., KEW Inc., Merck Inc., Merrimack Pharmaceuticals Inc., Pfizer Inc., Sanofi Inc., Taiho Ltd., and Unum Therapeutics Inc. He also serves as a director for CytomX Therapeutics Inc. and owns unexercised stock options for CytomX Therapeutics Inc. and Entrinsic Health Solutions Inc. B.M.W. declares research funding from Celgene Inc., and consulting for BioLineRx Ltd., G1 Therapeutics Inc., and GRAIL Inc. The remaining authors declare no competing interests.

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

Informed consent was obtained from all participants at study enrolment, and the HPFS was approved by the institutional review board at Harvard T.H. Chan School of Public Health (Boston, MA, USA). The study was conducted in accordance with the Declaration of Helsinki.

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).

Correspondence to Brian M. Wolpin.

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