Abstract
The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.
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References
Alter, B. P., Rosenberg, P. S., & Brody, L. C. (2007). Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. Journal of Medical Genetics, 44(1), 1–9. doi:https://doi.org/10.1136/jmg.2006.043257
American College of Obstetricians and Gynocologists. (2011). Committee Opinion: Update on carrier screening for cystic fibrosis. Opinion 486. Retrieved from https://doi.org/www.acog.org/~/media/Committee Opinions/Committee on Genetics/co486.pdf?dmc = 1&ts = 20140721 T1321334730
Association for Molecular Pathology v. Myriad Genetics. (2013). Retrieved from https://doi.org/www.aclu.org/files/assets/12-398_8njq.pdf
Berliner, J. L., Fay, A. M., Cummings, S. A., Burnett, B., & Tillmanns, T. (2013). NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer,". Journal of Genetic Counseling, 22(2), 155–163.
Berwick, M., Satagopan, J. M., Ben-Porat, L., Carlson, A., Mah, K., Henry, R., et al. (2007). Genetic heterogeneity among fanconi anemia heterozygotes and risk of cancer. Cancer Research, 67(19), 9591–9596. doi:https://doi.org/10.1158/0008-5472.CAN-07-1501.
Boder, E., & Sedgwick, R. P. (1958). Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics, 21(4), 526–554.
Bogdanova, N., Feshchenko, S., Schürmann, P., Waltes, R., Wieland, B., Hillemanns, P., et al. (2008). Nijmegen breakage syndrome mutations and risk of breast cancer. International Journal of Cancer, 122(4), 802–806. doi:https://doi.org/10.1002/ijc.23168.
Brown, K. L., Moglia, D. M., Grumet, S. (2007). Genetic counseling for breast cancer risk: general concepts, challenging themes and future directions. Breast Disease, 27, 69--96.
Butturini, A., Gale, R. P., Verlander, P. C., Adler-Brecher, B., Gillio, A. P., & Auerbach, A. D. (1994). Hematologic abnormalities in fanconi anemia: an international fanconi anemia registry study. Blood, 84(5), 1650–1655.
Casadei, S., Norquist, B. M., Walsh, T., Stray, S., Mandell, J. B., Lee, M. K., et al. (2011). Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Research, 71(6), 2222–2229. doi:https://doi.org/10.1158/0008-5472.CAN-10-3958.
Domchek, S. M., Bradbury, A., Garber, J. E., Offit, K., & Robson, M. E. (2013). Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? Journal of Clinical Oncology, 31(10), 1267–1270. doi:https://doi.org/10.1200/JCO.2012.46.9403.
Fanconi Anemia Research Fund. (2014). Fanconi anemia : guidelines for diagnosis and management (4th ed., pp. 307–332). Eugene, Oregon. Retrieved from http://fanconi.org/images/uploads/other/FA_Guidelines_Final.pdf
Giampietro, P. F., Verlander, P. C., Davis, J. G., & Auerbach, A. D. (1997). Diagnosis of fanconi anemia in patients without congenital malformations: an international fanconi anemia registry study. American Journal of Medical Genetics, 68(1), 58–61. doi:https://doi.org/10.1002/(SICI)1096-8628(19970110)68:1<58::AID-AJMG11>3.0.CO;2-N.
Hilbers, F. S. M., Vreeswijk, M. P. G., van Asperen, C. J., & Devilee, P. (2013). The impact of next generation sequencing on the analysis of breast cancer susceptibility: a role for extremely rare genetic Variation? Clinical Genetics, 84(5), 407–414. doi:https://doi.org/10.1111/cge.12256.
Hiraki, S., Rinella, E. S., Schnabel, F., Oratz, R., & Ostrer, H. (2014). Cancer risk assessment using genetic panel testing: considerations for clinical application. Journal of Genetic Counseling, 23(4), 604–617. doi:https://doi.org/10.1007/s10897-014-9695-6.
Howlett, N. G., Taniguchi, T., Olson, S., Cox, B., Waisfisz, Q., De Die-Smulders, C., et al. (2002). Biallelic inactivation of BRCA2 in fanconi anemia. Science, 297(5581), 606–609. doi:https://doi.org/10.1126/science.1073834.
Jiao, L., Hassan, M. M., Bondy, M. L., Wolff, R. a, Evans, D. B., Abbruzzese, J. L., & Li, D. (2008). XRCC2 and XRCC3 gene polymorphism and risk of pancreatic cancer. The American Journal of Gastroenterology, 103(2), 360–367. doi:https://doi.org/10.1111/j.1572-0241.2007.01615.x
King, M.-C., Marks, J. H., & Mandell, J. B. (2003). Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science, 302(5645), 643–646. doi:https://doi.org/10.1126/science.1088759.
Kohli-Kumar, M., Morris, C., DeLaat, C., Sambrano, J., Masterson, M., Mueller, R., et al. (1994). Bone marrow transplantation in fanconi anemia using matched sibling donors. Blood, 84(6), 2050–2054.
Kurian, A. W., Hare, E. E., Mills, M. A., Kingham, K. E., McPherson, L., Whittemore, A. S., et al. (2014). Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. Journal of Clinical Oncology, 32(19), 2001–2009. doi:https://doi.org/10.1200/JCO.2013.53.6607.
Levitus, M., Rooimans, M. a, Steltenpool, J., Cool, N. F. C., Oostra, A. B., Mathew, C. G., et al. (2004). Heterogeneity in fanconi anemia: evidence for 2 new genetic subtypes. Blood, 103(7), 2498–2503. doi:https://doi.org/10.1182/blood-2003-08-2915
Lynch, H. T., & Smyrk, T. (1996). Hereditary nonpolyposis colorectal cancer (lynch syndrome). an updated review. Cancer, 78(6), 1149–1167. doi:https://doi.org/10.1002/(SICI)1097-0142(19960915)78:6<1149::AID-CNCR1>3.0.CO;2-5.
MacMillan, M. L., & Wagner, J. E. (2010). Haematopoeitic cell transplantation for fanconi anaemia - when and how? British Journal of Haematology, 149(1), 14–21. doi:https://doi.org/10.1111/j.1365-2141.2010.08078.x.
Mauer, C. B., Pirzadeh-Miller, S. M., Robinson, L. D., & Euhus, D. M. (2013). The integration of next-generation sequencing panels in the clinical cancer genetics practice: an institutional experience. Genetics in Medicine, 16(5), 407–412. doi:https://doi.org/10.1038/gim.2013.160.
Meyer, S., Tischkowitz, M., Chandler, K., Gillespie, A., Birch, J. M., & Evans, D. G. (2014). Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling. Journal of Medical Genetics, 51(2), 71–75. doi:https://doi.org/10.1136/jmedgenet-2013-101642
Myriad Genetics. (2013). Rapid decline in VUS rates. Retrieved September 03, 2014, from https://doi.org/www.myriadpro.com/for-your-practice/myvision-2/rapid-decline-in-vus-rates/
National Comprehensive Cancer Network. (2014). Genetic/familial high-risk assessment: breast and ovarian. Retrieved from https://doi.org/www.nccn.org/professionals/physician_gls/PDF/genetics_screening.pdf
National Society of Genetic Counselors. (2014). 2014 Professional Status Survey. Retrieved from https://doi.org/nsgc.org/p/cm/ld/fid=68. Accessed June 2014
Nowak, J., Mosor, M., Ziółkowska, I., Wierzbicka, M., Pernak-Schwarz, M., Przyborska, M., et al. (2008). Heterozygous carriers of the I171V mutation of the NBS1 gene have a significantly increased risk of solid malignant tumours. European Journal of Cancer, 44(4), 627–630. doi:https://doi.org/10.1016/j.ejca.2008.01.006.
Oddoux, C., Struewing, J. P., Clayton, C. M., Neuhausen, S., Brody, L. C., Kaback, M., et al. (1996). The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1 %. Nature Genetics, 14(2), 188–190. doi:https://doi.org/10.1038/ng1096-188.
Patton, Michael Quinn. Qualitative research and evaluation methods (3rd ed). Thousand Oaks, Calif.: Sage Publications, 2001. Print.
Pelttari, L. M., Heikkinen, T., Thompson, D., Kallioniemi, A., Schleutker, J., Holli, K., et al. (2011). RAD51C is a susceptibility gene for ovarian cancer. Human Molecular Genetics, 20(16), 3278–3288. doi:https://doi.org/10.1093/hmg/ddr229.
Qualtrics Research Suite. Computer software. Vers. 58612. Qualtrics, Provo, Utah, USA. Copyright 2015. Web. https://doi.org/www.qualtrics.com.
Rafii, S., O’Regan, P., Xinarianos, G., Azmy, I., Stephenson, T., Reed, M., et al. (2002). A potential role for the XRCC2 R188H polymorphic site in DNA-damage repair and breast cancer. Human Molecular Genetics, 11(12), 1433–1438. doi:https://doi.org/10.1093/hmg/11.12.1433.
Rafnar, T., Gudbjartsson, D. F., Sulem, P., Jonasdottir, A., Sigurdsson, A., Jonasdottir, A., et al. (2011). Mutations in BRIP1 confer high risk of ovarian cancer. Nature Genetics, 43(11), 1104–1107. doi:https://doi.org/10.1038/ng.955.
Rainville, I. R., & Rana, H. Q. (2014). Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. Current Oncology Reports, 16(3), 371. doi:https://doi.org/10.1007/s11912-013-0371-z.
Richards, C. S., Bradley, L. A., Amos, J., Allitto, B., Grody, W. W., Maddalena, A., et al. (2002). Standards and guidelines for CFTR mutation testing. Genetics in Medicine, 4(5), 379–391. doi:https://doi.org/10.1097/00125817-200209000-00010.
Ripperger, T., Gadzicki, D., Meindl, A., & Schlegelberger, B. (2009). Breast cancer susceptibility: current knowledge and implications for genetic counselling. European Journal of Human Genetics, 17(6), 722–731. doi:https://doi.org/10.1038/ejhg.2008.212.
Risch, H. a, McLaughlin, J. R., Cole, D. E., Rosen, B., Bradley, L., Kwan, E., et al. (2001). Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. American Journal of Human Genetics, 68(3), 700–710. doi:https://doi.org/10.1086/318787.
Scherr, C. L., Lindor, N. M., Malo, T. L., Couch, F. J., & Vadaparampil, S. T. (2015). Genetic counselors' practices and confidence regarding variant of uncertain significance results and reclassification from BRCA testing. Clinical Genetics. doi:https://doi.org/10.1111/cge.12563.
Scott, R. H., Mansour, S., Pritchard-Jones, K., Kumar, D., MacSweeney, F., & Rahman, N. (2007). Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations. Nature Clinical Practice. Oncology, 4(2), 130–134. doi:https://doi.org/10.1038/ncponc0719.
Seal, S., Thompson, D., Renwick, A., Elliott, A., Kelly, P., Barfoot, R., et al. (2006). Truncating mutations in the fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nature Genetics, 38(11), 1239–1241. doi:https://doi.org/10.1038/ng1902.
Steffen, J., Varon, R., Mosor, M., Maneva, G., Maurer, M., Stumm, M., et al. (2004). Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland. International Journal of Cancer, 111(1), 67–71. doi:https://doi.org/10.1002/ijc.20239.
Strathdee, C. A., Gavish, H., Shannon, W. R., & Buchwald, M. (1992). Cloning of cDNAs for fanconi’s anaemia by functional complementation. Nature, 356(6372), 763–7. doi:https://doi.org/10.1038/356763a0.
Swift, M., Morrell, D., Massey, R. B., & Chase, C. L. (1991). Incidence of cancer in 161 families affected by ataxia-telangiectasia. The New England Journal of Medicine, 325(26), 1831–6. doi:https://doi.org/10.1056/NEJM199112263252602.
Thompson, D., Duedal, S., Kirner, J., McGuffog, L., Last, J., Reiman, A., et al. (2005). Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute, 97(11), 813–822. doi:https://doi.org/10.1093/jnci/dji141.
Tischkowitz, M. D., Sabbaghian, N., Hamel, N., Borgida, A., Rosner, C., Taherian, N., et al. (2009). Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology, 137(3), 1183–1186. doi:https://doi.org/10.1053/j.gastro.2009.06.055.
Van der Heijden, M. S., Yeo, C. J., Hruban, R. H., & Kern, S. E. (2003). Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Research, 63(10), 2585–2588.
Vaz, F., Hanenberg, H., Schuster, B., Barker, K., Wiek, C., Erven, V., et al. (2010). Mutation of the RAD51C gene in a fanconi anemia-like disorder. Nature Genetics, 42(5), 406–409. doi:https://doi.org/10.1038/ng.570.
Wagner, J. E., Tolar, J., Levran, O., Scholl, T., Deffenbaugh, A., Satagopan, J., et al. (2004). Germline mutations in BRCA2: shared genetic susceptibility to breast cancer, early onset leukemia, and fanconi anemia. Blood, 103(8), 3226–3229. doi:https://doi.org/10.1182/blood-2003-09-3138.
Wagner, J. E., Eapen, M., MacMillan, M. L., Harris, R. E., Pasquini, R., Boulad, F., et al. (2007). Unrelated donor bone marrow transplantation for the treatment of fanconi anemia. Blood, 109(5), 2256–2262. doi:https://doi.org/10.1182/blood-2006-07-036657.
Wagner, J. E., Ishida-Yamamoto, A., McGrath, J. a, Hordinsky, M., Keene, D. R., Woodley, D. T., et al. (2010). Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. The New England Journal of Medicine, 363(7), 629–639. doi:https://doi.org/10.1056/NEJMoa0910501
Weemaes, C. M., Hustinx, T. W., Scheres, J. M., van Munster, P. J., Bakkeren, J. a, & Taalman, R. D. (1981). A new chromosomal instability disorder: the Nijmegen breakage syndrome. Acta Paediatrica Scandinavica, 70(4), 557–564. doi:https://doi.org/10.1111/j.1651-2227.1981.tb05740.x.
Wimmer, K., & Etzler, J. (2008). Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg? Human Genetics, 124(2), 105–122. doi:https://doi.org/10.1007/s00439-008-0542-4.
Wooster, R., Bignell, G., Lancaster, J., Swift, S., Seal, S., Mangion, J., et al. (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature, 378(6559), 789–792. doi:https://doi.org/10.1038/378789a0.
Xia, B., Dorsman, J. C., Ameziane, N., de Vries, Y., Rooimans, M. a, Sheng, Q., et al. (2007). Fanconi anemia is associated with a defect in the BRCA2 partner PALB2. Nature Genetics, 39(2), 159–161. doi:https://doi.org/10.1038/ng1942.
Acknowledgments
This study was completed in partial fulfillment of the requirements for the first author’s Masters of Science degree from the University of Minnesota. Dr. Christina Palmer served as Action Editor on the manuscript review process and publication decision.
Conflict of Interest
Sarah Mets, Rebecca Tryon, Patricia McCarthy Veach, and Heather Zierhut declare they have no conflict of interest.
Human Studies and Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent information was supplied and implied through participation in the on-line survey.
Animal Studies
No animal studies were carried out by the authors for this article.
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Mets, S., Tryon, R., Veach, P.M. et al. Genetic Counselors’ Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels. J Genet Counsel 25, 359–372 (2016). https://doi.org/10.1007/s10897-015-9892-y
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DOI: https://doi.org/10.1007/s10897-015-9892-y