BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer

Abstract

BackgroundCurrent knowledge of the aetiology of hereditary breast cancer in the four main South African population groups (black, coloured, Indian and white) is limited. Risk assessments in the black, coloured and Indian population groups are challenging because of restricted information regarding the underlying genetic contributions to inherited breast cancer in these populations. We focused this study on premenopausal patients (diagnosed with breast cancer before the age of 50; n = 78) and triple negative breast cancer (TNBC) patients (n = 30) from the four South African ethnic groups. The aim of this study was to determine the frequency and spectrum of germline mutations in BRCA1, BRCA2 and PALB2 and to evaluate the presence of the CHEK2 c.1100delC allele in these patients.MethodsIn total, 108 South African breast cancer patients underwent mutation screening using a Next-Generation Sequencing (NGS) approach in combination with Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large rearrangements in BRCA1 and BRCA2.ResultsIn 13 (12 %) patients a deleterious mutation in BRCA1/2 was detected, three of which were novel mutations in black patients. None of the study participants was found to have an unequivocal pathogenic mutation in PALB2. Two (white) patients tested positive for the CHEK2 c.1100delC mutation, however, one of these also carried a deleterious BRCA2 mutation. Additionally, six variants of unknown clinical significance were identified (4 in BRCA2, 2 in PALB2), all in black patients. Within the group of TNBC patients, a higher mutation frequency was obtained (23.3 %; 7/30) than in the group of patients diagnosed before the age of 50 (7.7 %; 6/78).ConclusionThis study highlights the importance of evaluating germline mutations in major breast cancer genes in all of the South African population groups. This NGS study shows that mutation analysis is warranted in South African patients with triple negative and/or in premenopausal breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1913-6) contains supplementary material, which is available to authorized users.

BRCA1andBRCA2pathogenic sequence variants in women of African origin or ancestry

“…Note that only 11 published studies were found that included male BRCA1/2 PSV carriers, but no additional BRCA1/2 PSVs were identified from these reports. Forty‐eight studies were included in the present report: 16 studies of Sub‐Saharan Africans (Awadelkarim et al, ; Biunno et al, ; Diez et al, ; Elimam et al, ; Fackenthal et al, ; Fackenthal et al, ; Francies et al, ; Gao et al, ; Luyeye Mvila et al, ; Stoppa‐Lyonnet et al, ; van der Merwe et al, ; Zhang et al, ; Zhang et al, ; Zhang, Fackenthal, Huo, Zheng, & Olopade, ; Zheng et al, ; Zoure et al, ), 27 of African Americas (Arena et al, ; Arena et al, ; Arena et al, ; Castilla et al, ; Churpek et al, ; Dangel et al, ; Futreal et al, ; Ganguly, Dhulipala, Godmilow, & Ganguly, ; Q. Gao, Neuhausen, Cummings, Luce, & Olopade, ; Q. Gao, Sveen, Cummings, & Olopde, ; Q. Gao et al, ; Gayol et al, ; Haffty et al, ; Hall et al, ; John et al, ; Kanaan et al, ; Kedar‐Barnes et al, ; Lynce et al, ; Martin et al, ; Miki et al, ; Nanda et al, ; Olopade et al, ; Pal et al, ; Pal et al, ; Pal, Permuth‐Wey, Holtje, & Sutphen, ; Panguluri et al, ; Shen et al, ; Sutphen & Ferlita, ; Whitfield‐Broome, Dunston, & Brody, ), and three of Afro‐Caribbean populations (Akbari et al, ; Donenberg et al, ; Donenberg et al, ) and one study reporting SRAA of unspecified geography (Hall et al, ). From these papers, we identified 414 BRCA1 and 187 BRCA2 PSVs, and 108 unique BRCA1 and 103 unique BRCA2 PSVs.…”

“…Note that only 11 published studies were found that included male BRCA1/ 2 PSV carriers, but no additional BRCA1/2 PSVs were identified from these reports. Forty-eight studies were included in the present report: 16 studies of Sub-Saharan Africans (Awadelkarim et al, 2007;Biunno et al, 2014;Diez et al, 2011;Elimam et al, 2017;Fackenthal et al, 2005;Fackenthal et al, 2012;Francies et al, 2015;Gao et al, 2000;Luyeye Mvila et al, 2014;Stoppa-Lyonnet et al, 1997;van der Merwe et al, 2012;Zhang et al, 2009;Zhang et al, 2012;Zhang, Fackenthal, Huo, Zheng, & Olopade, 2010;Zheng et al, 2018;Zoure et al, 2018), 27 of African Americas (Arena et al, 1996);Arena et al, 1997;Arena et al, 1998;Castilla et al, 1994;Churpek et al, 2015;Dangel et al, 1999;Futreal et al, 1994;Ganguly, Dhulipala, Godmilow, & Ganguly, 1998;Q. Gao, Neuhausen, Cummings, Luce, & Olopade, 1997;Q.…”

Monoallelic characteristic-bearing heterozygous L1053X in BRCA2 gene among Sudanese women with breast cancer

“…6448dupTAc. 7934delGFounder-c.5946delTC.8162delGSchoeman M, et al 2013 [58]c.5999del4c.6174delTc.582G > AFrancies FZ, et al 2015 [59]c.5771_5774delTTCAc.5213_5216delCTTAc.8754 + 1G > Ac.9097_9098insAc.4798_4800delAATc.7712A > Gc.9875C > Tc.7934delG founderfounderAfrikaner population of South Africa Seymour HJ, et al2016 [60]c.6621delASouth Africac.6761_6762delTTc.5073dupAMoroccoLAARABI FZ, et al2011 [61]c.3381delT Tazzite A, et al 2012 [62]c.7110delAc.7235insGc.517-1G > Ac.6428 C > A Guaoua S, et al2014 [63]c.745-1G > A Jouhadi H, et al2016 [64]c.5682insATunisia Troudi W, et al 2007 [65]c.1309del4c.-25G > Ac.6301 A > Cc.1595 A > Tc.7242 A > Gc.865 A > Gc.1310_1313del (1538delAAGA) Fourati A, et al 2014 [66]c.-26G > A …”

Patterns of copy number alterations in primary breast tumors of South African patients and their impact on functional cellular pathways

“…These two subtypes are known to present a clinically aggressive phenotype, including resistance to treatment and high rates of disease recurrence (7)(8)(9). Although the determinants for the high prevalence of these unfavorable tumor subtypes is unclear, several studies implicate intrinsic genetic differences, such as the presence of founder mutations in breast cancer susceptibility genes, including the BRCA1 gene (10)(11)(12) or unknown genomic variants identified by genomic wide association studies (13)(14)(15)(16).…”

“…Among the African countries, SA has the highest number of published genomic research studies (assessed between 2004-2013), however only 6.1% of these studies are associated with cancer (20). To the best of our knowledge, few breast cancer studies have characterized patient genomic profiles and/or specific molecular alterations in their populations (14,(21)(22)(23)(24)(25). As a consequence, there is limited knowledge on their tumor biology and the corresponding lack of clinically relevant biomarkers that would be particularly beneficial for the prognosis and treatment of patients with breast cancer representative of the diverse racial groups of SA.…”