Germline pathogenic variants in BRCA1 (FANCD1) and BRCA2 (FANCS) do not explain all familial or sporadic cases with breast cancer. Several reports indicate a role for pathogenic variants in other genes in the Fanconi anemia/breast cancer DNA repair pathway; the strengths of these associations vary widely. Publications from 2006 through 2017 were reviewed to provide a better estimate of the role of pathogenic variants in genes in this pathway in breast cancer.
We identified cohorts and case–control reports describing heterozygous pathogenic variants in Fanconi anemia genes in breast cancer cases with high risk of a germline pathogenic variant in a non-BRCA1/2 breast cancer susceptibility gene (“familial”), and cases unselected for family history (“unselected”). Meta-analysis and meta-regression were used to estimate the frequencies of pathogenic variants in cohorts and the odds ratios (OR) in case–control studies.
Meta-analysis of more than 100 reports of FANCN/PALB2 in familial breast cancer cases provided an overall pathogenic variant prevalence of 1.29% and an OR of 8.45. The prevalence in unselected cohorts was 0.64%, and the OR was 4.76. Pathogenic variants in FANCJ/BRIP1 had a prevalence of 0.5% in familial cases, and an OR of 1.62; their prevalence in unselected cases was 0.39%. FANCO/RAD51C, FANCP/SLX4, FANCU/XRCC2, FANCD2, and other FA-related genes all had prevalences of ≤ 0.5% among familial cases, and even lower in unselected cases.
Heterozygous pathogenic variants in FANCN/PALB2 and possibly FANCJ/BRIP1 may account for 1–2% of familial non-BRCA1/2 breast cancer cases and 0.5–1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.
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The search terms for the literature review are included in the Methods section of the manuscript, and the studies included in the meta-analysis are listed and referenced in the supplementary material.
American Cancer Society (2019–2020) Breast Cancer Facts & Figures 2019–2020. American Cancer Society, Inc., Atlanta
Wang AT, Smogorzewska A (2015) SnapShot: Fanconi anemia and associated proteins. Cell 160:354–354
Borenstein M, Hedges LV, Higgins JPT, Rothstein HR (2009) Introduction to meta-analysis. Wiley, West Sussex
Ioannidis JP, Ntzani EE, Trikalinos TA, Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nat Genet 29:306–309. https://doi.org/10.1038/ng749
Zeng D, Lin DY (2015) On random-effects meta-analysis. Biometrika 102:281–294. https://doi.org/10.1093/biomet/asv011
Easton DF, Pharoah PD, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, Devilee P, Meindl A, Couch FJ, Southey M, Goldgar DE, Evans DG, Chenevix-Trench G, Rahman N, Robson M, Domchek SM, Foulkes WD (2015) Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372:2243–2257. https://doi.org/10.1056/NEJMsr1501341
Ellsworth DL, Turner CE, Ellsworth RE (2019) A review of the hereditary component of triple negative breast cancer: high- and moderate-penetrance breast cancer genes, low-penetrance loci, and the role of nontraditional genetic elements. J Oncol 2019:4382606. https://doi.org/10.1155/2019/4382606
R Core Team (2018) R: a language and environment for statistical computing. R. Foundation for Statistical Computing, Vienna
Viechtbauer W (2010) Conducting meta-analyses in R with the metafor package. J Stat Softw 36:1–48
Rahman N, Seal S, Thompson D, Kelly P, Renwick A, Elliott A, Reid S, Spanova K, Barfoot R, Chagtai T, Jayatilake H, McGuffog L, Hanks S, Evans DG, Eccles D, Easton DF, Stratton MR (2006) PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet 39:165–167
Slavin TP, Maxwell KN, Lilyquist J, Vijai J, Neuhausen SL, Hart SN, Ravichandran V, Thomas T, Maria A, Villano D, Schrader KA, Moore R, Hu C, Wubbenhorst B, Wenz BM, D'Andrea K, Robson ME, Peterlongo P, Bonanni B, Ford JM, Garber JE, Domchek SM, Szabo C, Offit K, Nathanson KL, Weitzel JN, Couch FJ (2017) The contribution of pathogenic variants in breast cancer susceptibility genes to familial breast cancer risk. NPJ Breast Cancer 3:22. https://doi.org/10.1038/s41523-017-0024-8
Skol AD, Sasaki MM, Onel K (2016) The genetics of breast cancer risk in the post-genome era: thoughts on study design to move past BRCA and towards clinical relevance. Breast Cancer Res 18:99. https://doi.org/10.1186/s13058-016-0759-4
Antoniou AC, Casadei S, Heikkinen T, Barrowdale D, Pylkas K, Roberts J, Lee A, Subramanian D, De LK, Fostira F, Tomiak E, Neuhausen SL, Teo ZL, Khan S, Aittomaki K, Moilanen JS, Turnbull C, Seal S, Mannermaa A, Kallioniemi A, Lindeman GJ, Buys SS, Andrulis IL, Radice P, Tondini C, Manoukian S, Toland AE, Miron P, Weitzel JN, Domchek SM, Poppe B, Claes KB, Yannoukakos D, Concannon P, Bernstein JL, James PA, Easton DF, Goldgar DE, Hopper JL, Rahman N, Peterlongo P, Nevanlinna H, King MC, Couch FJ, Southey MC, Winqvist R, Foulkes WD, Tischkowitz M (2014) Breast-cancer risk in families with mutations in PALB2. N Engl J Med 371:497–506
Weber-Lassalle N, Hauke J, Ramser J, Richters L, Gross E, Blumcke B, Gehrig A, Kahlert AK, Muller CR, Hackmann K, Honisch E, Weber-Lassalle K, Niederacher D, Borde J, Thiele H, Ernst C, Altmuller J, Neidhardt G, Nurnberg P, Klaschik K, Schroeder C, Platzer K, Volk AE, Wang-Gohrke S, Just W, Auber B, Kubisch C, Schmidt G, Horvath J, Wappenschmidt B, Engel C, Arnold N, Dworniczak B, Rhiem K, Meindl A, Schmutzler RK, Hahnen E (2018) BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res 20:7. https://doi.org/10.1186/s13058-018-0935-9
Yang X, Leslie G, Doroszuk A, Schneider S, Allen J, Decker B, Dunning AM, Redman J, Scarth J, Plaskocinska I, Luccarini C, Shah M, Pooley K, Dorling L, Lee A, Adank MA, Adlard J, Aittomaki K, Andrulis IL, Ang P, Barwell J, Bernstein JL, Bobolis K, Borg A, Blomqvist C, Claes KBM, Concannon P, Cuggia A, Culver JO, Damiola F, de Pauw A, Diez O, Dolinsky JS, Domchek SM, Engel C, Evans DG, Fostira F, Garber J, Golmard L, Goode EL, Gruber SB, Hahnen E, Hake C, Heikkinen T, Hurley JE, Janavicius R, Kleibl Z, Kleiblova P, Konstantopoulou I, Kvist A, Laduca H, Lee ASG, Lesueur F, Maher ER, Mannermaa A, Manoukian S, McFarland R, McKinnon W, Meindl A, Metcalfe K, Mohd Taib NA, Moilanen J, Nathanson KL, Neuhausen S, Ng PS, Nguyen-Dumont T, Nielsen SM, Obermair F, Offit K, Olopade OI, Ottini L, Penkert J, Pylkas K, Radice P, Ramus SJ, Rudaitis V, Side L, Silva-Smith R, Silvestri V, Skytte AB, Slavin T, Soukupova J, Tondini C, Trainer AH, Unzeitig G, Usha L, van Overeem HT, Whitworth J, Wood M, Yip CH, Yoon SY, Yussuf A, Zogopoulos G, Goldgar D, Hopper JL, Chenevix-Trench G, Pharoah P, George SHL, Balmana J, Houdayer C et al (2020) Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol 38:674–685. https://doi.org/10.1200/JCO.19.01907
Alter BP, Rosenberg PS, Brody LC (2007) Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet 44:1–9
Hunter JE, Schmidt FL (2000) Fixed effects vs random effects meta-analysis. Int J Select Assess 8:275–292
Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, Hallberg E, Moore R, Thomas A, Lilyquist J, Feng B, McFarland R, Pesaran T, Huether R, LaDuca H, Chao EC, Goldgar DE, Dolinsky JS (2017) Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 3:1190–1196. https://doi.org/10.1001/jamaoncol.2017.0424
Lu HM, Li S, Black MH, Lee S, Hoiness R, Wu S, Mu W, Huether R, Chen J, Sridhar S, Tian Y, McFarland R, Dolinsky J, Tippin Davis B, Mexal S, Dunlop C, Elliott A (2018) Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.2956
Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M (2018) Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun 9:4083. https://doi.org/10.1038/s41467-018-06581-8
Shimelis H, LaDuca H, Hu C, Hart SN, Na J, Thomas A, Akinhanmi M, Moore RM, Brauch H, Cox A, Eccles DM, Ewart-Toland A, Fasching PA, Fostira F, Garber J, Godwin AK, Konstantopoulou I, Nevanlinna H, Sharma P, Yannoukakos D, Yao S, Feng BJ, Tippin Davis B, Lilyquist J, Pesaran T, Goldgar DE, Polley EC, Dolinsky JS, Couch FJ (2018) Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst 110:855–862. https://doi.org/10.1093/jnci/djy106
Deng M, Chen HH, Zhu X, Luo M, Zhang K, Xu CJ, Hu KM, Cheng P, Zhou JJ, Zheng S, Chen YD (2019) Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer 145:1517–1528. https://doi.org/10.1002/ijc.32184
Kurian AW, Ward KC, Howlader N, Deapen D, Hamilton AS, Mariotto A, Miller D, Penberthy LS, Katz SJ (2019) Genetic testing and results in a population-based cohort of breast cancer patients and ovarian cancer patients. J Clin Oncol 37:1305–1315. https://doi.org/10.1200/jco.18.01854
Briggs TA, Abdel-Salam GM, Balicki M, Baxter P, Bertini E, Bishop N, Browne BH, Chitayat D, Chong WK, Eid MM, Halliday W, Hughes I, Klusmann-Koy A, Kurian M, Nischal KK, Rice GI, Stephenson JB, Surtees R, Talbot JF, Tehrani NN, Tolmie JL, Toomes C, van der Knaap MS, Crow YJ (2008) Cerebroretinal microangiopathy with calcifications and cysts (CRMCC). Am J Med Genet A 146A:182–190
Vagena A, Papamentzelopoulou M, Kalfakakou D, Kollia P, Papadimitriou C, Psyrri A, Apostolou P, Fountzilas G, Konstantopoulou I, Yannoukakos D, Fostira F (2019) PALB2 c.2257C>T truncating variant is a Greek founder and is associated with high breast cancer risk. J Hum Genet 64:767–773. https://doi.org/10.1038/s10038-019-0612-6
Weitzel JN, Neuhausen SL, Adamson A, Tao S, Ricker C, Maoz A, Rosenblatt M, Nehoray B, Sand S, Steele L, Unzeitig G, Feldman N, Blanco AM, Hu D, Huntsman S, Castillo D, Haiman C, Slavin T, Ziv E (2019) Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer 125:2829–2836. https://doi.org/10.1002/cncr.32083
We thank Megan N Frone MS CGC, Mark H Greene MD, and Philip S Rosenberg PhD, for reviewing the manuscript.
This work was supported by the intramural research program of the National Cancer Institute of the National Institutes of Health, Bethesda, MD. The views presented in this article are those of the authors and should not be viewed as official opinions or positions of the National Cancer Institute, National Institutes of Health, or U.S. Department of Health and Human Services.
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Alter, B.P., Best, A.F. Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis. Breast Cancer Res Treat 182, 465–476 (2020). https://doi.org/10.1007/s10549-020-05710-6
- Breast cancer
- Fanconi anemia
- Germline pathogenic variants