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. 2022 Feb;59(2):115-121.
doi: 10.1136/jmedgenet-2020-107347. Epub 2021 Mar 23.

High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

D Gareth Evans #  1   2   3 , Elke Maria van Veen #  4   2 , Helen J Byers  4   2 , Sarah J Evans  2   5 , George J Burghel  4 , Emma Roisin Woodward  4   2 , Elaine F Harkness  3   6 , Diana M Eccles  7 , Stephanie L Greville-Haygate  7 , Jamie M Ellingford  4   2 , Naomi L Bowers  4 , Marta Pereira  4 , Andrew J Wallace  4 , Sasha J Howell  3   8 , Anthony Howell  3   8 , Fiona Lalloo  4 , William G Newman  4   2 , Miriam Jane Smith  4   2
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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

D Gareth Evans et al. J Med Genet. 2022 Feb.

Abstract

Background: While the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.

Methods: Sequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.

Results: Testing 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26-30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).

Conclusion: The rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

Keywords: genetic testing; genetics; human genetics.

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Conflict of interest statement

Competing interests: JME is funded by a postdoctoral research fellowship from the Health Education England Genomics Education Programme (HEE GEP). SGH is funded by a research fellowship from the Health Education England Genomics Education Programme (HEE GEP). DGE has received travel grants from AstraZeneca.

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References

    1. 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. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017;3:1190–6. 10.1001/jamaoncol.2017.0424 - DOI - PMC - PubMed
    1. Lu H-M, 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. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol 2019;5:51–7. 10.1001/jamaoncol.2018.2956 - DOI - PMC - PubMed
    1. 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 B-J, Tippin Davis B, Lilyquist J, Pesaran T, Goldgar DE, Polley EC, Dolinsky JS, Couch FJ. Triple-Negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst 2018;110:855–62. 10.1093/jnci/djy106 - DOI - PMC - PubMed
    1. Hauke J, Horvath J, Groß E, Gehrig A, Honisch E, Hackmann K, Schmidt G, Arnold N, Faust U, Sutter C, Hentschel J, Wang-Gohrke S, Smogavec M, Weber BHF, Weber-Lassalle N, Weber-Lassalle K, Borde J, Ernst C, Altmüller J, Volk AE, Thiele H, Hübbel V, Nürnberg P, Keupp K, Versmold B, Pohl E, Kubisch C, Grill S, Paul V, Herold N, Lichey N, Rhiem K, Ditsch N, Ruckert C, Wappenschmidt B, Auber B, Rump A, Niederacher D, Haaf T, Ramser J, Dworniczak B, Engel C, Meindl A, Schmutzler RK, Hahnen E. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for hereditary breast and ovarian cancer. Cancer Med 2018;7:1349–58. 10.1002/cam4.1376 - DOI - PMC - PubMed
    1. Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, Hartman A-R, Winer EP, Garber JE. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016;34:1460–8. 10.1200/JCO.2015.65.0747 - DOI - PMC - PubMed

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