Which genetic syndromes increase the risk of breast cancer?

Answer

Li-Fraumeni syndrome, caused by TP53 mutations, is responsible for approximately 1% of cases of familial breast cancer. Bilateral breast cancer is noted in up to 25% of patients. Li-Fraumeni syndrome is also associated with multiple cancers, including the SBLLA syndrome (sarcoma, breast and brain tumors, leukemia, and laryngeal and lung cancer). Cancer susceptibility is transmitted in an autosomal dominant pattern, with a 90% lifetime risk of breast cancer (and a 56% risk by age 45), necessitating earlier screening in TP53 mutation carriers.)^[17]

Cowden disease is a rare genetic syndrome caused by PTEN mutations. It is associated with intestinal hamartoma, cutaneous lesions, and thyroid cancer. The lifetime risk of breast cancer ranges from 25-50%. Benign mammary abnormalities (eg, fibroadenomas, fibrocystic breast disease, ductal epithelial hyperplasia, and nipple malformations) are also common.^[17]

Other rare genetic disorders, such as Peutz-Jeghers syndrome and hereditary nonpolyposis colorectal carcinoma (HNPCC), are associated with an increased risk of breast cancer.

Hereditary syndromes may also affect the response to treatment in breast cancer. A study by Mangoni et al found an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in patients with breast cancer. The authors propose a hypothesis that mismatch repair mechanisms may be involved in the cellular response to radiotherapy and that genetic polymorphisms warrant further study as candidates for predicting acute radiosensitivity.^[18]

The table below lists the most prevalent genetically determined breast cancer syndromes.

Table 3. Genetic Breast Cancer Syndromes (Open Table in a new window)

Syndrome	Gene	Inheritance	Cancers	Other Features
Breast/ovarian	BRCA1	AD	Breast, ovarian, prostate, pancreatic	~1-2% risk of male breast cancer
Breast/ovarian	BRCA2	AD	Breast, ovarian, prostate, pancreatic, melanoma	Fanconi anemia in homozygotes.~8% risk of male breast cancer
Li-Fraumeni syndrome	TP53	AD	Breast, brain, soft-tissue sarcomas, leukemia, adrenocortical, others
Cowden disease	PTEN	AD	Breast, ovary, follicular thyroid, colon	Adenomas of thyroid, fibroids, GI polyps
Peutz-Jeghers syndrome	STKII/LKB1	AD	GI, breast	Hamartomas of bowel, pigmentation of buccal mucosa
Ataxia-telangiectasia	ATM	AD	Breast	Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias
Hereditary Diffuse Gastic Cancer Syndrome	CDH1	AD	Gastric, Breast (Lobular)
Site-specific	CHEK2	AD	Breast	Low penetrance
Muir-Torre syndrome	MSH2/MLH1	AD	Colorectal, breast
Breast/ovarian	BARD1	AD	Breast, ovarian, neuroblastoma	Unclear if male breast cancer risk is elevated
AD = autosomal dominant; GI = gastrointestinal.

Did this answer your question?

Yes No

Additional feedback? (Optional)

Thank you for your feedback!

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019 Jan. 69 (1):7-34. [Medline]. [Full Text].
U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999-2015). Centers for Disease Control and Prevention. Available at https://nccd.cdc.gov/uscs/. June 2018; Accessed: March 13, 2019.
Feuer EJ. Modeling the impact of adjuvant therapy and screening mammography on U.S. breast cancer mortality between 1975 and 2000: introduction to the problem. J Natl Cancer Inst Monogr. 2006. 364(25):2-6. [Medline].
Dossus L, Benusiglio PR. Lobular breast cancer: incidence and genetic and non-genetic risk factors. Breast Cancer Res. 2015 Mar 13. 17:37. [Medline]. [Full Text].
Morrow M, Burstein HJ, Harris JR. Malignant Tumors of the Breast. DeVita VT Jr, Lawrence TS, Rosenberg SA. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology. 10th ed. Philadelphia PA: Wolters Kluwer Health; 2015. 1117-19.
Breast Cancer Facts & Figures 2017-2018. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed: April 3, 2019.
Reeves GK, Beral V, Green J, Gathani T, Bull D; Million Women Study Collaborators. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol. Nov 2006. 7(11):910-8.
[Guideline] National Comprehensive Cancer Network. Breast Cancer Risk Reduction. NCCN Clinical Practice Guidelines in Oncology. Available at https://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf. Version 1.2019 — December 11, 2018; Accessed: April 3, 2019.
Mørch LS, Skovlund CW, Hannaford PC, Iversen L, Fielding S, Lidegaard Ø. Contemporary Hormonal Contraception and the Risk of Breast Cancer. N Engl J Med. 2017 Dec 7. 377 (23):2228-2239. [Medline]. [Full Text].
Hamajima N, et al; Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer. 2002 Nov 18. 87 (11):1234-45. [Medline]. [Full Text].
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA, eds. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute; April 2017. [Full Text].
Hereditary Breast and Ovarian Cancer: Breast and Ovarian Cancer and Family History Risk Categories. Centers for Disease Control and Prevention. Available at https://www.cdc.gov/genomics/resources/diseases/breast_ovarian_cancer/risk_categories.htm. July 29, 2016; Accessed: April 3, 2019.
PDQ Cancer Genetics Editorial Board. Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. Updated March 21, 2019. [Medline]. [Full Text].
Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Fan I, et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada. J Natl Cancer Inst. 2006 Dec 6. 98 (23):1694-706. [Medline]. [Full Text].
Breast Cancer Linkage Consortium. Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst. 1999 Aug 4. 91 (15):1310-6. [Medline]. [Full Text].
[Guideline] U.S. Preventive Services Task Force. BRCA-Related Cancer: Risk Assessment, Genetic Counseling, and Genetic Testing. USPSTF. Available at https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/brca-related-cancer-risk-assessment-genetic-counseling-and-genetic-testing. December 2013; Accessed: April 3, 2019.
Allain DC. Genetic counseling and testing for common hereditary breast cancer syndromes: a paper from the 2007 William Beaumont hospital symposium on molecular pathology. J Mol Diagn. 2008 Sep. 10 (5):383-95. [Medline]. [Full Text].
Mangoni M, Bisanzi S, Carozzi F, Sani C, Biti G, Livi L, et al. Association between genetic polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT genes and radiosensitivity in breast cancer patients. Int J Radiat Oncol Biol Phys. 2011 Sep 1. 81 (1):52-8. [Medline].
Breast Cancer Rates by Race and Ethnicity. Centers for Disease Control and Prevention. Available at http://www.cdc.gov/cancer/breast/statistics/race.htm. June 2018; Accessed: November 5, 2018.
Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign breast disease and the risk of breast cancer. N Engl J Med. 2005 Jul 21. 353 (3):229-37. [Medline]. [Full Text].
Devesa SS, Diamond EL. Association of breast cancer and cervical cancer incidence with income and education among whites and blacks. J Natl Cancer Inst. 1980 Sep. 65 (3):515-28. [Medline].
Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet. 1996 Jun 22. 347 (9017):1713-27. [Medline].
Kubba AA. Breast cancer and the pill. J R Soc Med. 2003 Jun. 96 (6):280-3. [Medline]. [Full Text].
Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet. 1997 Oct 11. 350 (9084):1047-59. [Medline].
Reeves GK, Beral V, Green J, Gathani T, Bull D, Million Women Study Collaborators. Hormonal therapy for menopause and breast-cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol. 2006 Nov. 7 (11):910-8. [Medline].
Chlebowski RT, Anderson GL, Gass M, Lane DS, Aragaki AK, Kuller LH, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA. 2010 Oct 20. 304 (15):1684-92. [Medline].
Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019 Sep 28. 394 (10204):1159-1168. [Medline]. [Full Text].
Ingram I. HRT Has 20-Year Impact on Breast Cancer Risks. MedPage Today. Available at https://www.medpagetoday.com/meetingcoverage/sabcs/83882. December 13, 2019; Accessed: December 16, 2019.
Hoover RN, Hyer M, Pfeiffer RM, Adam E, Bond B, Cheville AL, et al. Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med. 2011 Oct 6. 365 (14):1304-14. [Medline]. [Full Text].
Gaudet MM, Gapstur SM, Sun J, Diver WR, Hannan LM, Thun MJ. Active smoking and breast cancer risk: original cohort data and meta-analysis. J Natl Cancer Inst. 2013 Apr 17. 105 (8):515-25. [Medline]. [Full Text].
Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care. 2003 Jun. 26 (6):1752-8. [Medline].
Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011 Nov 2. 306 (17):1884-90. [Medline]. [Full Text].
Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES. Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer. 2005 Sep. 41 (13):2023-32. [Medline].
Foraker RE, Abdel-Rasoul M, Kuller LH, Jackson RD, Van Horn L, Seguin RA, et al. Cardiovascular Health and Incident Cardiovascular Disease and Cancer: The Women's Health Initiative. Am J Prev Med. 2016 Feb. 50 (2):236-40. [Medline].
Chen Z, Arendell L, Aickin M, Cauley J, Lewis CE, Chlebowski R, et al. Hip bone density predicts breast cancer risk independently of Gail score: results from the Women's Health Initiative. Cancer. 2008 Sep 1. 113 (5):907-15. [Medline]. [Full Text].
Grenier D, Cooke AL, Lix L, Metge C, Lu H, Leslie WD. Bone mineral density and risk of postmenopausal breast cancer. Breast Cancer Res Treat. 2011 Apr. 126 (3):679-86. [Medline].
Qu X, Zhang X, Qin A, Liu G, Zhai Z, Hao Y, et al. Bone mineral density and risk of breast cancer in postmenopausal women. Breast Cancer Res Treat. 2013 Feb. 138 (1):261-71. [Medline].
Coogan PF. Calcium-channel blockers and breast cancer: a hypothesis revived. JAMA Intern Med. 2013 Sep 23. 173 (17):1637-8. [Medline].
Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med. 2013 Sep 23. 173 (17):1629-37. [Medline]. [Full Text].
Kelly JC. Some Antihypertensives Linked to Breast Cancer Risk. Medscape Medical News. Available at http://www.medscape.com/viewarticle/808935. August 5, 2013; Accessed: November 1 ,2017.
Wilson LE, D'Aloisio AA, Sandler DP, Taylor JA. Long-term use of calcium channel blocking drugs and breast cancer risk in a prospective cohort of US and Puerto Rican women. Breast Cancer Res. 2016 Jul 5. 18 (1):61. [Medline]. [Full Text].
Llanos AAM, Rabkin A, Bandera EV, Zirpoli G, Gonzalez BD, Xing CY, et al. Hair product use and breast cancer risk among African American and White women. Carcinogenesis. 2017 Sep 1. 38 (9):883-892. [Medline]. [Full Text].
Cohen R. Dark Hair Dye and Chemical Relaxers Linked to Breast Cancer. Medscape Medical News. Available at https://www.medscape.com/viewarticle/882833. July 13, 2017; Accessed: November 1, 2017.
Permanent hair dye and straighteners may increase breast cancer risk. National Institutes of Health. Available at https://www.nih.gov/news-events/news-releases/permanent-hair-dye-straighteners-may-increase-breast-cancer-risk. December 4, 2019; Accessed: December 5, 2019.
Lancaster JM, Powell CB, Kauff ND, Cass I, Chen LM, Lu KH, et al. Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol. 2007 Nov. 107 (2):159-62. [Medline].
Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K, American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010 Feb 10. 28 (5):893-901. [Medline].
[Guideline] Berliner JL, Fay AM, Cummings SA, Burnett B, Tillmanns T. NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns. 2013 Apr. 22 (2):155-63. [Medline].
[Guideline] Paluch-Shimon S, Cardoso F, Sessa C, Balmana J, Cardoso MJ, Gilbert F, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol. 2016 Sep. 27 (suppl 5):v103-v110. [Medline].
[Guideline] National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast and Ovarian. NCCN. Available at https://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf. Version 3.2019 — January 18, 2019; Accessed: April 3, 2019.
Pankratz VS, Hartmann LC, Degnim AC, Vierkant RA, Ghosh K, Vachon CM, et al. Assessment of the accuracy of the Gail model in women with atypical hyperplasia. J Clin Oncol. 2008 Nov 20. 26 (33):5374-9. [Medline]. [Full Text].
Adams-Campbell LL, Makambi KH, Frederick WA, Gaskins M, Dewitty RL, McCaskill-Stevens W. Breast cancer risk assessments comparing Gail and CARE models in African-American women. Breast J. 2009 Sep-Oct. 15 Suppl 1:S72-5. [Medline]. [Full Text].
Berry DA, Iversen ES Jr, Gudbjartsson DF, Hiller EH, Garber JE, Peshkin BN, et al. BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol. 2002 Jun 1. 20 (11):2701-12. [Medline]. [Full Text].
Tyrer J, Duffy SW, Cuzick J. A breast cancer prediction model incorporating familial and personal risk factors. Stat Med. 2004 Apr 15. 23 (7):1111-30. [Medline].
Amir E, Evans DG, Shenton A, Lalloo F, Moran A, Boggis C, et al. Evaluation of breast cancer risk assessment packages in the family history evaluation and screening programme. J Med Genet. 2003 Nov. 40 (11):807-14. [Medline]. [Full Text].
Boughey JC, Hartmann LC, Anderson SS, Degnim AC, Vierkant RA, Reynolds CA, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol. 2010 Aug 1. 28 (22):3591-6. [Medline]. [Full Text].

Media Gallery

Breast cancer incidence by ethnicity. In the United States in 2013, the rate of breast cancer was highest in white women, followed by black, Hispanic, Asian/Pacific Islander (A/PI), and American Indian/Alaska Native (AI/AN) women. Courtesy of CDC (National Program of Cancer Registries and National Cancer Institute Surveillance, Epidemiology, and End Results program).

of 1

Table 3. Genetic Breast Cancer Syndromes

Table 3. Genetic Breast Cancer Syndromes

Syndrome	Gene	Inheritance	Cancers	Other Features
Breast/ovarian	BRCA1	AD	Breast, ovarian, prostate, pancreatic	~1-2% risk of male breast cancer
Breast/ovarian	BRCA2	AD	Breast, ovarian, prostate, pancreatic, melanoma	Fanconi anemia in homozygotes.~8% risk of male breast cancer
Li-Fraumeni syndrome	TP53	AD	Breast, brain, soft-tissue sarcomas, leukemia, adrenocortical, others
Cowden disease	PTEN	AD	Breast, ovary, follicular thyroid, colon	Adenomas of thyroid, fibroids, GI polyps
Peutz-Jeghers syndrome	STKII/LKB1	AD	GI, breast	Hamartomas of bowel, pigmentation of buccal mucosa
Ataxia-telangiectasia	ATM	AD	Breast	Homozygotes: leukemia, lymphoma, cerebella ataxia, immune deficiency, telangiectasias
Hereditary Diffuse Gastic Cancer Syndrome	CDH1	AD	Gastric, Breast (Lobular)
Site-specific	CHEK2	AD	Breast	Low penetrance
Muir-Torre syndrome	MSH2/MLH1	AD	Colorectal, breast
Breast/ovarian	BARD1	AD	Breast, ovarian, neuroblastoma	Unclear if male breast cancer risk is elevated
AD = autosomal dominant; GI = gastrointestinal.

Back to List

Author

Jessica Katz, MD, PhD, FACP Senior Medical Director, Immuno-Oncology, Oncology R&D, GlaxoSmithKline

Jessica Katz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: for: Currently employed at GSK.

Coauthor(s)

Anand D Patel, MD Hematologist/Oncologist, Ascension Wisconsin

Anand D Patel, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Student National Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Marie Catherine Lee, MD, FACS Associate Professor, Department of Oncologic Sciences, Department of Surgery (Joint Appointment), University of South Florida Morsani College of Medicine; Associate Member, Comprehensive Breast Program, Moffitt McKinley Outpatient Center

Marie Catherine Lee, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, Association of Women Surgeons, Florida Society of Clinical Oncology, Society of Surgical Oncology, Society of University Surgeons

Disclosure: Received research grant from: National Cancer Institute/National Institutes of Health; Department of Defense.

Additional Contributors

Robert C Shepard, MD, FACP Associate Professor of Medicine in Hematology and Oncology at University of North Carolina at Chapel Hill; Vice President of Scientific Affairs, Therapeutic Expertise, Oncology, at PRA International

Robert C Shepard, MD, FACP is a member of the following medical societies: American Association for Cancer Research, American Association for Physician Leadership, European Society for Medical Oncology, Association of Clinical Research Professionals, American Federation for Clinical Research, Eastern Cooperative Oncology Group, Society for Immunotherapy of Cancer, American Medical Informatics Association, American College of Physicians, American Federation for Medical Research, American Medical Association, American Society of Hematology, Massachusetts Medical Society

Disclosure: Nothing to disclose.

Alison T Stopeck, MD Professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center; Director of Clinical Breast Cancer Program, Arizona Cancer Center; Medical Director of Coagulation Laboratory, University Medical Center; Director of Arizona Hemophilia and Thrombosis Center

Alison T Stopeck, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, SWOG, American Society of Clinical Oncology, Hemophilia and Thrombosis Research Society

Disclosure: Received honoraria from Genentech for speaking and teaching; Received honoraria from AstraZeneca for speaking and teaching; Received grant/research funds from AstraZeneca for other.

Leona Downey, MD Assistant Professor of Internal Medicine, Section of Oncology and Hematology, University of Arizona, Arizona Cancer Center

Leona Downey, MD is a member of the following medical societies: American Geriatrics Society, SWOG, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Robert B Livingston, MD Professor of Clinical Medicine and Director, Clinical Research Shared Services, Arizona Cancer Center

Robert B Livingston, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, American Federation for Clinical Research

Disclosure: Nothing to disclose.

Patricia A Thompson, PhD Assistant Professor, Department of Pathology, University of Arizona College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Julie Lang, MD Associate Professor of Surgery, Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California

Julie Lang, MD is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, American Society of Clinical Oncology, Association for Academic Surgery, and Society of Surgical Oncology

Disclosure: Genomic Health, Grant/research funds, Speaking and teaching; Agendia, Grant/research funds, Speaking and teaching; Surgical Tools, Grant/research funds, Research; Sysmex, Grant/research funds, Research

Rachel Swart, MD, PhD Assistant Professor of Medicine, Department of Hematology and Oncology, Arizona Cancer Center, University of Arizona

Rachel Swart, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, Arizona Medical Association, and Southwest Oncology Group

Disclosure: Roche Grant/research funds Other

Which genetic syndromes increase the risk of breast cancer?

Answer

Related Questions:

References

Tables

Contributor Information and Disclosures