Precise tracking of breast cancer trends in Sub-Saharan Africa is difficult because of a lack of population-specific data, but in KwaZulu-Natal, researchers were able to more precisely examine the epidemiology of hereditary breast cancer, using data collected between 2011 and 2021.
They found that overall, hereditary breast cancer had increased in the province in the past decade, and that black patients were diagnosed with more aggressive breast cancer at an early age, while Indian and white patients presented with extensive family history and genetic alterations.
Their study highlights the need for inclusive approaches to breast cancer care in South African populations, write M Makhetha, C Aldous, and N Chabilal in the SA Medical Journal.
Breast cancer is the world’s most commonly occurring cancer, and the second leading cause of cancer mortality among women. It is also a multi-factorial disease with genetic and environmental factors, and the risk of developing it varies with age, race, lifestyle choices, reproductive choices and genetic predisposition.
In South Africa, at least one in 30 women is said to be at risk of developing the disease by 74, although the risk differs greatly between racial groups.
Most of the country’s breast cancer patients are black, many presenting at a late stage.
Depending on the variant’s origin, the cancer can either be sporadic or hereditary. Most breast cancer cases are sporadic, developing as a result of a combination of genetics and environmental, biological or physiological triggers.
The pathogenic sequence variants identified in these cases usually accumulate during the course of life, often confined to tumours in the affected tissues. They generally develop at an advanced age, are less aggressive and have a relatively good prognosis: treatment includes surgery and taxane-based chemotherapy regimens.
In contrast, hereditary breast cancer is characterised by early occurrence, aggression, recurrence and high mortality. It is caused by the presence of germline pathogenic sequence variants in high-risk genes such as BRCA1 DNA repair associated (BRCA1) and BRCA2 DNA repair associated (BRCA2), which carry a cumulative lifetime risk of 72% and 69%, respectively.
Treatment includes prophylactic bilateral mastectomy, oophorectomy and platinum-based chemotherapy regimens.
In countries like the USA, hereditary breast cancer accounts for 5%-10% of cases while in SA, its prevalence is unknown.
According to the 2020 national cancer incidence report, breast cancer is predominant among Asian/Indian females, accounting for 41.8% of all cancer cases, and least common among white females, accounting for 21.9%.
Furthermore, the risk of varies significantly, where one in 12 white females, one in 18 Indian females, one in 22 coloured females and one in 40 black African females have a lifetime risk of developing breast cancer by 74.
Clinically, black patients are known for early-onset, high-grade tumours, high mortality and triple-negative breast cancers (TNBCs), and rates among this group have been increasing steadily over the years.
Compared with other women of African ancestry, SA black patients reportedly present with fewer cases than women from Botswana, but more cases than African-American patients.
This suggests women of African descent vary from country to country. For Asians, especially Indians from KwaZulu-Natal, patients are known for their extensive family history of breast and/or other cancers.
The white SA population is characterised by late-onset breast cancer, family history and the lowest mortality in SA.
Specifically, Afrikaner and Ashkenazi Jewish hereditary breast cancer patients are known to carry unique pathogenic sequence variants, commonly referred to as founder mutations.
This retrospective study aimed to describe common genetic variations in KwaZulu-Natal, where we reviewed the genetic data of patients who consulted at the Genetics Clinic at Inkosi Albert Luthuli Central Hospital between 2011 and 2021.
Patients and tests
SA genetic services have relied for many years on targeted tests that screen for seven SA founder mutations. For the black, Indian and coloured populations, this option has been unreliable, as patients with hereditary clinical characteristics consistently test negative. This is because six of the seven variants are exclusively common to the white population, while one variant was reported in mainly the Western Cape Province.
This indicates the risk of misdiagnosis among blacks, coloureds and Indians, which affects treatment approaches offered to patients and an oversight on preventive measures for carrier relatives.
Our study outlines variants reported over a 12-year period, which were identified using various screening methods and are potential diagnostic targets, especially for blacks, coloureds and Indians.
The cohort mainly comprised black and Indian populations, which was representative of KwaZulu-Natal’s general population.
The number of males was low compared with females. For female patients, the primary reasons for referral varied between populations, where black patients were mainly diagnosed with early-onset disease and TNBCs, while white, Indian and coloured patients presented with a positive family history of breast and related cancers.
The average age of disease onset in black patients was 37.6 years (standard deviation (SD) 11.2), which was ~10 years lower than that of Indians (mean 47.4 years, SD 13.3) and whites (mean 47.7 years, SD 10.2). In all populations, both bilateral breast cancer and recurrent breast cancers were rare, while high-risk patients were predominant among Indians. Most mutation carriers were Indian, and they carried 17 pathogenic sequence variants,
We identified 30 pathogenic sequence variants in BRCA1 and BRCA2, four large genomic rearrangements and 13 variants of unknown significance (VUS). Most importantly, we identified variants that are unique to each population group, and that could be diagnostic targets during genetic screening.
All variants were reported by a single state facility (National Health Laboratory Services (NHLS), which utilised various molecular techniques over 11 years as technology advanced. These were polymerase chain reaction, protein truncation test, single-stranded conformation polymorphism, high-resolution melting analysis, multiplex ligation-dependent probe amplification and next-generation sequencing. The target for variant screening was BRCA1 and BRCA2 genes.
We identified three BRCA1 and one BRCA2 large genomic rearrangement in five young patients. The BRCA1 exon 17 deletion, which was identified in a 36-year-old Indian breast cancer patient and her 58-year-old relative at high risk of the disease, had been described in young breast cancer patients of Dutch and Polish descent.
Similarly, we reported the deletion of BRCA1 exon 21 in a 34-year-old black woman diagnosed with TNBC. This is a common rearrangement previously reported in populations such as the Czech, the Dutch and the Pakistani.
Another deletion, a whole BRCA2 gene, was reported in a 41-year-old Indian patient presenting with bilateral breast cancer. It is a very rare deletion mostly described in non-human species.
Study limitations
The reported variants were identified using different molecular tests within different populations and over different time periods.
Some tests screened for known variants, while comprehensive tests screened the entire genes. This suggests the probability of variant underreporting, especially in targeted testing.
Numerous BRCA1 and BRCA2 pathogenic sequence variants were identified in various population groups, most variants being exclusive to specific races, which makes them ideal candidates for the diagnosis of hereditary breast cancer.
Considering the limitations of SA targeted screening, these variants can be included to optimise the tests, especially for black and Indian populations in KZN.
For novel variants identified in this study, we encourage further research and reporting to international databases to aid in the classification of each variant. We also encourage a nationwide study describing black and Asian patients, as our data represent the black African and Indian subpopulations from KZN only.
Study details
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.
M Makhetha, C Aldous, N Chabilal.
Published in the SA Medical Journal in June 2024
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.
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
M Makhetha MMedSc – Department of Clinical Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal; C Aldous PhD – Department of Genetics, Inkosi Albert Luthuli Central Hospital, Durban; N Chabilal PGDip (Health Sci Edu) – Department of Clinical Medicine, Nelson R Mandela School of Medicine, College of Health Sciences, University of KwaZulu-Natal.
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