Genetic trends and common BRCA1/2 pathogenic sequence variants in black African and Indian breast cancer patients presenting at Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal, South Africa

Authors

  • M Makhetha Department of Clinical Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa
  • C Aldous Department of Genetics, Inkosi Albert Luthuli Central Hospital, Durban, South Africa
  • N Chabilal Department of Clinical Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa

DOI:

https://doi.org/10.7196/SAMJ.2024.v114i6.1094

Keywords:

Breast cancer, Pathogenic sequence variants, South Africa, Genetic Testing, BRCA1/2

Abstract

Background. Hereditary breast cancer is characterised by the presence of a pathogenic sequence variant passed from one generation to the next. These cancers are aggressive, develop early, and account for 5 - 10% of all breast cancer cases. In South Africa (SA), the common variants that predispose to hereditary breast cancer have been well documented among white patients and form part of screening panels during targeted testing. For non-white patients, common variants are not well understood, and as such, all populations are offered the same test optimised for white patients. This carries a risk of misdiagnosis, the consequences of which include recurrence and increased mortality.

Objectives. To retrospectively describe genetic trends in the black African and Indian breast cancer patients from KwaZulu-Natal Province, SA.

Methods. We reviewed clinical and genetic data of breast cancer and high-risk patients who consulted at Inkosi Albert Luthuli Central Hospital between 2011 and 2021. Inclusion criteria were based on clinical and demographic characteristics as defined by SA clinical guidelines.

Results. Black African patients were young (mean 37.6 years, standard deviation 11.16) and had the majority of triple-negative tumours (37.5%). Indians represented 50% of bilateral breast cancers and of high-risk individuals. We identified 30 pathogenic BRCA1/2 sequence variants, four large genomic rearrangements and 13 variants of unknown significance. Twenty black patients carried 12, 13 white patients carried 4, 25 Indian patients carried 16, and 3 coloured patients carried 3 pathogenic sequence variants. The most frequent variants were BRCA2 c.5771_5774del, p.Ile1924fs among black patients, BRCA2 c.7934del, p.Arg2645fs among white patients, and BRCA2 c.8754+1G>A among Indian patients. None of the founder mutations common in white patients was reported in either black, Indian or coloured patients, which explains why black, Coloured and Indian SA patients consistently test negative during targeted screening.

Conclusion. This study highlights unique genetic trends for SA populations and the need for more inclusive targeted tests that are optimal for these populations.

References

Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209-249. https:// doi.org/10.3322/caac.21660

Kuchenbaecker KB, Hopper JL, Barnes DR, et al. Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA 2017;317(23):2402-2416. https://doi. org/10.1001/jama.2017.7112

Guan Z, Huang T, McCarthy AM, et al. Combining breast cancer risk prediction models. Cancers 2023;15(4):1090. https://doi.org/10.3390/cancers15041090

National Cancer Registry. South African Department of Health. Cancer in South Africa 2020 full report. Pretoria: NDoH, 2023. https://www.nicd.ac.za/wp-content/uploads/2023/04/The-National- Pathology-Cancer-Incidence-Report-2020.pdf . (accessed 16 May 2023).

Pegoraro JR, Nirmul D, Bryer JV, Jordaan JP, Joubert SM. Clinical patterns of presentation of breast cancer in women of different racial groups in South Africa. S Afr Med J 1985;63:808-810. https://doi. org/10.10520/AJA20785135_5347

Mthembu JG, Bhuiyan MMZU. Profile of molecular subtyping of breast cancer and clinicopathological features in Mankweng Hospital breast oncology clinic, Limpopo Province, South Africa. S Afr Med J 2021;111(11b):1132-1135. https://doi.org/10.7196/SAMJ.2021.v111i11b.16104

Murugan N, Dickens C, Pisa PT, et al. Down-staging of breast cancer in the pre-screening era: Experiences from Chris Hani Baragwanath Academic Hospital, Soweto, South Africa. S Afr Med J 2014;104(5):380. https://doi.org/10.7196/samj.8243

Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77(11):2318-2324. https://doi.org/10.1002/(SICI)1097- 0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z.

Mitrunen K, Hirvonen A. Molecular epidemiology of sporadic breast cancer. The role of polymorphic genes involved in oestrogen biosynthesis and metabolism. Mutat Res 2003;544(1):9-41. https://doi. org/10.1016/s1383-5742(03)00016-4

Newman LA. Disparities in breast cancer and African ancestry: A global perspective. Breast J 2015;21(2):133-139. https://doi.org/10.1111/tbj.12369

Godet I, Gilkes DM. BRCA1 and BRCA2 mutations and treatment strategies for breast cancer. Integr Cancer Sci Ther 2017;4(1):10.15761/ICST.1000228. https://doi.org/10.15761/ICST.1000228

Venkitaraman AR. How do mutations affecting the breast cancer genes BRCA1 and BRCA2 cause cancer susceptibility? DNA Repair 2019;81:102668. https://doi.org/10.1016/j.dnarep.2019.102668

Van der Groep P, Bouter A, van der Zanden R, et al. Distinction between hereditary and sporadic

breast cancer on the basis of clinicopathological data. J Clin Pathol 2006;59(6):611-617. https://doi.

org/10.1136/jcp.2005.032151

Sokolova A, Johnstone KJ, McCart Reed AE, Simpson PT, Lakhani SR. Hereditary breast cancer: Syndromes, tumour pathology and molecular testing. Histopathology 2023;82(1):70-82. https://doi. org/10.1111/his.14808

Loke J, Pearlman A, Upadhyay K, Tesfa L, Shao Y, Ostrer H. Functional variant analyses (FVAs) predict pathogenicity in the BRCA1 DNA double-strand break repair pathway. Hum Mol Genet 2015;24(11):3030-3037. https://doi.org/10.1093/hmg/ddv048

Collignon J, Lousberg L, Schroeder H, Jerusalem G. Triple-negative breast cancer: Treatment challenges and solutions. Breast Cancer 2016;8:93-107. https://doi.org/10.2147/BCTT.S69488

Weren RD, Mensenkamp AR, Simons M, et al. Novel BRCA1 and BRCA2 tumor test as basis for treatment decisions and referral for genetic counselling of patients with ovarian carcinomas. Hum Mutat 2017;38(2):226-235. https://doi.org/10.1002/humu.23137

Adams BG, van de Vijver FJR, de Bruin GP. Identity in South Africa: Examining self-descriptions across ethnic groups. Int J Intercult Relat 2012;36(3):377-388. https://doi.org/10.1016/j.ijintrel.2011.11.008

Department of Statistics, South Africa. Mid-year population estimates 2022. Pretoria: Department of Statistics, 2023. https://www.statssa.gov.za/publications/P0302/P03022022.pdf (accessed 12 February 2023).

Pillay K. Indian identity in South Africa. In: Ratuva, S, ed. The Palgrave Handbook of Ethnicity. Singapore: Palgrave Macmillan, 2019:77-92. https://doi.org/10.1007/978-981-13-2898-5_9

Matatiele PR, van den Heever WMJ. Breast cancer profiles of women presenting with newly diagnosed breast cancer at Universitas Hospital (Bloemfontein, South Africa): Scientific letter. South Afr Fam Prac 2008;50(6):48-49. https://doi.org/10.1080/20786204.2008.10873786

Herd O, Francies FZ, Cairns A, Mulle, X, Slabbert JP, Baeyens A. Ethnical differences in breast cancer characteristics in South African population. Breast J 2015:21(4);447-449. https://doi.org/10.1111/ tbj.12434

Singh E, Joffe M, Cubasch H, Ruff P, Norris SA, Pisa PT. Breast cancer trends differ by ethnicity: A report from the South African National Cancer Registry (1994 - 2009). European J Pub Health 2017;27(1):173-178. https://doi.org/10.1093/eurpub/ckw191

Churpek JE, Walsh T, Zheng Y, et al. Inherited predisposition to breast cancer among African American women. Breast Cancer Res Treat 2015;149(1):31-39. https:/doi.org/10.1007/s10549-014-3195-0

Sinha S, Bhatia R, Narasimamurthy M, Rayne S, Grover S. Epidemiology of breast cancer presentation in Botswana, South Africa, and the United States. J Surg Res 2022;279:533-539. https://doi.org/10.1016/j. jss.2022.04.071

McCormack VA, Joffe M, van den Berg E, et al. Breast cancer receptor status and stage at diagnosis in over 1,200 consecutive public hospital patients in Soweto, South Africa: A case series. Breast Cancer Res 2013;15(5):R84. https://doi.org/10.1186/bcr3478

Seymour HJ, Wainstein T, Macaulay S, Haw T, Krause A. Breast cancer in high-risk Afrikaner families: Is BRCA founder mutation testing sufficient? S Afr Med J 2016;106(3):264-267. https://doi. org/10.7196/SAMJ.2016.v106i3.10285

Reeves MD, Yawitch TM, van der Merwe NC, van den Berg HJ, Dreyer G, van Rensburg EJ. BRCA1 mutations in South African breast and/or ovarian cancer families: Evidence of a novel founder mutation in Afrikaner families. Int J Cancer 2004;110(5):677-682. https://doi.org/10.1002/ijc.20186

Francies FZ, Wainstein T, De Leeneer K, et al. BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. BMC Cancer 2015;15:912. https://doi.org/10.1186/s12885-015-1913-6

Gardiner SA, Smith D, Loubser F, Raimond P, Gerber J, Conradie M. New recurring BRCA1 variant: An additional South African founder mutation? S Afr Med J 2019;109(8):12676. https://doi.org/10.7196/ SAMJ.2019.v109i8.14187

Schoeman M, Apffelstaedt JP, Baatjes K, Urban M. Implementation of a breast cancer genetic service in South Africa – lessons learned. S Afr Med J 2013;103(8):529-533. https://doi.org/10.7196/samj.6814 32. Van der Merwe NC, Hamel N, Schneider SR, Apffelstaedt JP, Wijnen JT, Foulkes WD. A founder BRCA2 mutation in non-Afrikaner breast cancer patients of the Western Cape of South Africa. Clin

Genet 2012;81(2):179-184. https://doi.org/10.1111/j.1399-0004.2010.01617.x

Yawitch TM, van Rensburg EJ, Mertz M, Falkson CI. Absence of commonly recurring BRCA1

mutations in black South African women with breast cancer. S Afr Med J 2000;90(8):788.

Combrink HM, Oosthuizen J, Visser B, et al. Mutations in BRCA-related breast and ovarian cancer in the South African Indian population: A descriptive study. Cancer Genet 2021;258-259:1-6. https://doi.

org/10.1016/j.cancergen.2021.06.002

National Department of Health, South Africa. Clinical guidelines for breast cancer control and management. Pretoria: NDoH, 2019. https://cansa.org.za/files/2019/08/DOH-Breast-Cancer- Guidelines-Final.pdf (accessed 17 January 2023).

Smith DC, Gardiner SA, Conradie M, Gerber J, Loubser F. Genetic testing approaches for hereditary breast cancer: Perspectives from a private diagnostic laboratory. S Afr Med J 2020;110(10):988-992. https://doi.org/10.7196/SAMJ.2020.v110i10.14709

Prapa M, Solomons J, Tischkowitz M. The use of panel testing in familial breast and ovarian cancer. Clin Med 2017;17(6):568-572. https://doi.org/10.7861/clinmedicine.17-6-568

Oosthuizen J, Kotze MJ, van der Merwe N, Myburgh EJ, Bester P, van der Merwe NC. Globally rare BRCA2 variants with founder haplotypes in the South African population: Implications for point-of- care testing based on a single-institution BRCA1/2 Next-Generation Sequencing study. Front Oncol 2021;10:619469. https://doi.org/10.3389/fonc.2020.619469

Van der Merwe NC, Combrink HM, Ntaita KS, Oosthuizen J. Prevalence of clinically relevant germline BRCA variants in a large unselected South African breast and ovarian cancer cohort: A public sector experience. Front Genet 2022;13:834265. https://doi.org/10.3389/fgene.2022.834265

Feben C, Spencer C, Lochan A, et al. Biallelic BRCA2 mutations in two black South African children with Fanconi anaemia. Fam Cancer 2017;16(3):441-446. https://doi.org/10.1007/s10689-017-9968-y

Van der Merwe NC, Oosthuizen J, Theron M, Chong G, Foulkes WD. The contribution of large genomic rearrangements in BRCA1 and BRCA2 to South African familial breast cancer. BMC Cancer 2020;20(1):391. https://doi.org/10.1186/s12885-020-06917-y

Janavičius R. Founder BRCA1/2 mutations in Europe: Implications for hereditary breast-ovarian cancer prevention and control. EPMA J 2010;1(3):397-412. https://doi.org/10.1007/s13167-010-0037-y 43. Thomassen M, Hansen TV, Borg A, et al. BRCA1 and BRCA2 mutations in Danish families with hereditary breast and/or ovarian cancer. Acta Oncol 2008;47(4):772-777. https://doi.org/10.1080/02841860802004974 44. Hogervorst FB, Nederlof PM, Gille JJ, et al. Large genomic deletions and duplications in the BRCA1

gene identified by a novel quantitative method. Cancer Res 2003;63(7):1449-1453.

Rudnicka H, Debniak T, Cybulski C, et al. Large BRCA1 and BRCA2 genomic rearrangements in Polish high-risk breast and ovarian cancer families. Mol Biol Rep 2013;40;6619-6623. https://doi.org/10.1007/

s11033-013-2775-0

Rashid MU, Muhammad N, Amin A, Loya A, Hamann U. Contribution of BRCA1 large genomic rearrangements to early-onset and familial breast/ovarian cancer in Pakistan. Breast Cancer Res Treat 2017;161(2):191-201. https://doi.org/10.1007/s10549-016-4044-0

Vasickova P, Machackova E, Lukesova M, et al. High occurrence of BRCA1 intragenic rearrangements in hereditary breast and ovarian cancer syndrome in the Czech Republic. BMC Med Genet 2007;8:32. https://doi.org/10.1186/1471-2350-8-32

Zámborszky J, Szikriszt B, Gervai JZ, et al. Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions. Oncogene 2017;36(6):746- 755. https://doi.org/10.1038/onc.2016.243

Scaglione GL, Concolino P, de Bonis M, et al. A whole germline BRCA2 gene deletion: How to learn from CNV in silico analysis. Int J Mol Sci 2018;19(4):961. https://doi.org/10.3390/ ijms19040961

CeruttiR,SahnaneN,CarnevaliI,etal.IdentificationofthefirstcaseofgermlineduplicationofBRCA1 exon 13 in an Italian family. Familial Cancer 2010;9:275-282. https://doi.org/10.1007/s10689-009-9315-z

Kremeyer B, Soller M, Lagerstedt K, et al. The BRCA1 exon 13 duplication in the Swedish population. Familial Cancer 2005;4:191-194. https://doi.org/10.1007/s10689-004-7023-2

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Published

2024-05-31

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Research

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1.
Makhetha M, Aldous C, Chabilal N. Genetic trends and common BRCA1/2 pathogenic sequence variants in black African and Indian breast cancer patients presenting at Inkosi Albert Luthuli Central Hospital, KwaZulu-Natal, South Africa. S Afr Med J [Internet]. 2024 May 31 [cited 2024 Dec. 9];114(6):e1094. Available from: https://samajournals.co.za/index.php/samj/article/view/1094

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