Epidemiologic study on prostate cancer in Sudanese men across African ethnic groups

Abstract

This study sought to investigate the demographic and clinical characteristics of Sudanese men diagnosed with prostate cancer (PCa) to highlight differences in diagnosis among the three major ethnolinguistic groups. A total of 532 patients with confirmed PCa diagnosis through biopsy were enrolled from six medical centers in Sudan. The majority of patients, comprising 84.2% (448/532), were diagnosed with advanced-stage disease, with a Grade group above 3. There were no discernible differences in PCa aggressiveness among the ethnolinguistic groups. However, higher levels of prostate-specific antigen (PSA) were observed in the Niger-Congo group, where 55.2% had PSA values exceeding 50 ng/ml. Patients from this group were also diagnosed at a younger age. In contrast, 90.5% of Afro-Asiatic patients are over 60 years old. Further analysis conducted within an age-matched subgroup of patients (n = 273) revealed a higher incidence of perineural invasion in the Afro-Asiatic group. This research represents the first investigation of PCa across different African ethnic groups and associates a higher incidence of perineural invasion with a specific ethnic group. While recent efforts have been made to establish African-relevant risk models to mitigate PCa health disparities, there remains a need for further investigation into genetically distinct populations within the African continent.

Background

Prostate cancer (PCa) presents a significant global healthcare issue, constituting the predominant form of cancer found in males¹. According to the GLOBOCAN 2020 assessment, PCa emerges as the most frequently detected cancer in regions such as Africa, Europe, and the Americas, and it holds the foremost position in causing cancer-related fatalities among men in 48 nations. These include several countries situated in sub-Saharan Africa, the Caribbean, and Central and South America².

Despite its prevalent occurrence, there remains a limited understanding of its etiology. Factors that increase the risk of developing this malignancy include advancing age, a family history of the disease, and African ancestry. Numerous investigations have been conducted to gain insight into the various genetic^3,4, protein-related^5,6, microRNA⁷, and metabolic⁸ characteristics of PCa patients with African ancestry. While African ancestry is well-known to play a role in the aggressiveness of PCa, the heterogeneity of African populations is not taken deeply into consideration. The majority of studies focused on the ethnic health disparities are based on the African American population^9,10. However, African American genomes are closely related to Niger-Congo (NC)-speaking populations, including non-Bantu such as Igbo and Yoruba from Nigeria¹¹ and Bantu-speaking NC populations¹². Although, the recent efforts to establish African-relevant risk models aimed at reducing PCa health disparities^13–17, there is still the need for further investigation into other genetically distinct populations in the African continent.

The varied populations of Sudan, boasting both rich cultural traditions and diverse genetic heritage, have an extensive historical presence in northeastern Africa. This area, frequently sought as a sanctuary during extreme climatic conditions, plays a pivotal role in shaping their substantial genetic heterogeneity¹⁸. This diversity is exemplified by the prevalence of the major continental African language families in the region (Fig. 1), including the NC, Nilo-Saharan (NS), and Afro-Asiatic (AA) language families¹⁹. Populations within these groups exhibit distinct genetic backgrounds^20,21 that have evolved under specific environmental pressures^22,23, including adaptation to local pathogens^24,25 such as malaria. This strong selective pressure has led to population- and region-specific genetic variants, driving the evolution of the human immune system²⁶. Polymorphisms and different expression of immune-related genes could partially explain the different incidences and mortalities of PCa^27,28. Compared to the European American population, African American men have increased expression of immune-related genes and increased incidence of inflammation in tumor tissues^29,30.

Fig. 1.

Map of Africa showing the distribution of major African linguistic families (adapted from ref. 26). The demarcation line of Sub-Saharan Africa was drawn as indicated by the United Nations Statistics Division.

PCa ranks as the most prevalent cancer among Sudanese men, trailing only behind liver cancer in terms of mortality². Data indicates that its occurrence remains consistent across various ethnic backgrounds, typically manifesting in individuals aged 72 years or older and often at an advanced clinical stage³¹. This delayed presentation can be attributed to the limited access to crucial healthcare services³². Shockingly, over 70 percent of healthcare facilities in regions affected by conflicts in Sudan are nonfunctional or closed³³. Additionally, the concentration of healthcare centers in urban areas further hampers the ability of patients residing in remote rural areas to access diagnostic and treatment services^34,35. This dire situation in Sudan's healthcare system is mirrored by the scarcity of research studies focused on PCa.

In this study, the demographic and clinical features of Sudanese men with PCa were investigated to highlight the difference in the diagnosis among the three major ethnolinguistic groups.

Methods

Approval for this study was obtained from the National Health Research Ethics Committee of the Sudanese Federal Ministry of Health (6–9-2021). The study was performed in accordance with the Declaration of Helsinki. Patients were recruited in the Urology Departments of the Omdurman Teaching Hospital, Kuwaiti Specialized Hospital, Ibn Sina Teaching Hospital, Soba University Hospital, Military Corp, and Gezira Hospital for Renal Disease and Surgery between 2018 and 2023. All males diagnosed with PCa were included in the study. Patients younger than 40 years old were excluded from this study. The ethnicity of the patients was categorized according to the major speaking languages identified by Greenberg¹⁹: NC, NS and AA. Two dedicated genitourinary pathologists (Dr Elsadig Ahmed Adam Mohammed and Dr Nemat Mohamed Osman) undertook a systematic histopathologic review of all available hematoxylin and eosin (H&E) slides for each case, blinded to the patient ethnolinguistic group. Pathologic tumor stage (1997 American Joint Committee on Cancer TNM Classification) and perineural invasion (PNI) were reported based on standard H&E staining. PNI was defined as a tumor in close proximity to a nerve and involving any of the three layers of the nerve sheath.

Statistical analysis of the data was generated in the R (version 4.3.0) and R studio ("Ocean Storm" Release) software using functions available in the KODAMA R package³⁶. Wilcoxon rank sum test and Kruskal–Wallis rank sum test were used to compare differences in numerical covariates (e.g., age and metabolite concentration) using the function “continuous.test”. Fisher’s exact test was used to assess differences between categorical variables (e.g., ethnicity) using the function “categorical.test”. P-values less than 0.05 were considered to be significant. Matching patients were selected using the function “frequency_matching”. The geographical map of Africa showing the distribution of major African linguistic families was adapted from ref. 26 using Google Map and refined using Inkscape (version 1.32).

Results

A total of 532 patients were recruited with diagnosed PCa confirmed by biopsy from six Sudanese medical centers, including three in the capital Khartoum (i.e., Kuwaiti Specialized Hospital, Ibn Sina Teaching Hospital, and Soba University Hospital), two in the close city of Omdurman (i.e., Omdurman Teaching Hospital and Military Corp), and one in the city of Wad Madani (i.e., Gezira Hospital for Renal Disease and Surgery). Each ethnolinguistic group was represented with a similar percentage in this study, where the AA group was the largest group of patients. The demographic and clinical features are summarized in Table 1. The majority of the patients, 84.2% (448/532), were diagnosed with an advanced disease with a Grade group above 3. No differences were observed in terms of aggressiveness of PCa among the ethnolinguistic groups. However, higher values of prostate-specific antigen (PSA) were reported in the NC group compared to the NS group. Although the median value of PSA in the NC group was higher than in the AA group, no statistically significant differences were reported (Fig. 2A). AA patients were diagnosed at older age compared to NC and NS patients (Fig. 2B). Except for a small portion of patients (9.5%), AA patients were older than 60 years old.

Table 1.

Demographic and clinical features of the patients recruited in this study.

Feature	AA (n = 222)	NC (n = 181)	NS (n = 128)	p-value
Hospital				0.166
GNH, n (%)	7 (3.2)	4 (2.2)	4 (3.1)
ISH, n (%)	77 (34.7)	67 (37.0)	33 (25.8)
KSH, n (%)	17 (7.7)	11 (6.1)	4 (3.1)
MC, n (%)	5 (2.3)	10 (5.5)	4 (3.1)
OTH, n (%)	29 (13.1)	22 (12.2)	25 (19.5)
SUH, n (%)	87 (39.2)	67 (37.0)	58 (45.3)
Age (year), median [95%CI]	72 [55 89.475]	70 [50.5 87.5]	70 [55 89.65]	< 0.001
Age (≤ 60 years old)				0.009
Negative, n (%)	201 (90.5)	145 (80.1)	107 (83.6)
Positive, n (%)	21 (9.5)	36 (19.9)	21 (16.4)
Hypertension				0.844
Negative, n (%)	102 (45.9)	78 (43.1)	56 (43.8)
Positive, n (%)	120 (54.1)	103 (56.9)	72 (56.2)
T2DM				0.680
Negative, n (%)	120 (54.1)	96 (53.0)	74 (57.8)
Positive, n (%)	102 (45.9)	85 (47.0)	54 (42.2)
PSA (ng/ml), median [95%CI]	52 [10 115.825]	58 [15 131]	45.5 [10.835 100]	0.077
PSA (> 50 ng/ml)				0.036
Negative, n (%)	108 (48.6)	81 (44.8)	76 (59.4)
Positive, n (%)	114 (51.4)	100 (55.2)	52 (40.6)
Biopsy type				0.362
Needle Biopsy, n (%)	121 (54.5)	110 (60.8)	75 (58.6)
TURP, n (%)	98 (44.1)	71 (39.2)	51 (39.8)
TVP, n (%)	3 (1.4)	0 (0.0)	2 (1.6)
PNI				0.047
Negative, n (%)	178 (80.2)	147 (81.2)	115 (89.8)
Positive, n (%)	44 (19.8)	34 (18.8)	13 (10.2)
Grade group				0.288
1, n (%)	12 (5.4)	8 (4.4)	9 (7.0)
2, n (%)	17 (7.7)	6 (3.3)	5 (3.9)
3, n (%)	7 (3.2)	12 (6.6)	7 (5.5)
4, n (%)	66 (29.7)	67 (37.0)	44 (34.4)
5, n (%)	120 (54.1)	88 (48.6)	63 (49.2)

CI confidence interval, GNH Gezira Hospital for Renal Disease and Surgery, ISHIbn Sina Teaching Hospital, KSH Kuwaiti Specialized Hospital, MC Military Corp, OTH Omdurman Teaching Hospital, SUH Soba University Hospital, T2DM type-2 diabetes mellitus, PSA prostate-specific antigen, TURP transurethral resection of the prostate, TVP transurethral laser vaporization of the prostate, PNI perineural invasion.

Fig. 2.

Boxplots showing the difference of (A) PSA and (B) age among the three ethnolinguistic groups. (C) Pie charts representing the difference in percentage of ethnicity, biopsy type, and Gleason grade between tumor without and with PNI detected.

No differences were observed in the incidence of type-2 diabetes mellitus (T2DM) and hypertension among the ethnolinguistic groups.

An important determinant of tumor behavior is the ability to breach basement membranes and spread outside the confines of the organ of origin. PCa has long been recognized to show a propensity to invade and grow along prostatic nerves, which lead out of the prostate to the pelvic plexus³⁷. This phenomenon, known as PNI, has been associated with the inhibition of apoptosis, thereby allowing for increased proliferation of cancer cells³⁸.

Interestingly, a different incidence of PNI was observed among the three ethnolinguistic groups with the highest value for the AA group. This difference was also confirmed when only the reports from needle biopsy examination were taken into consideration (Table S1). No statistically significant differences in the incidence of PNI were observed in the TURP samples (Table S2).

A further analysis was performed to compare the patients positive to PNI with patients negative to PNI with a grade group higher than 2. PNI-negative patients were randomly selected to match the age of PNI-positive patients in a ratio of 2:1. The demographic and clinical features are summarized in Table 2. As expected, 70.3% of the PNI was diagnosed through needle biopsy inspection, which is primarily peripheral zone cancer. The percentage of PNI diagnosis is higher in the group with needle biopsy, 20.9% (64/306), than TURP, 12% (27/220). The analysis performed in this subgroup of patients (n = 273) confirmed a higher incidence of PNI in the AA group. The Grade group classification was reported to be higher in the PNI-positive patients. These differences are visualized in Fig. 2C. No associations were detected with other clinical features (i.e., PSA, hypertension, and T2DM).

Table 2.

Demographic and clinical features comparison between PNI-positive patients and age-matched PNI-negative patients.

Feature	PNI-negative (n = 182)	PNI-positive (n = 91)	p-value
Ethnic group			0.004
AA, n (%)	61 (33.5)	44 (48.4)
NC, n (%)	62 (34.1)	34 (37.4)
NS, n (%)	59 (32.4)	13 (14.3)
Hospital			0.225
GNH, n (%)	2 (1.1)	3 (3.3)
ISH, n (%)	62 (34.1)	39 (42.9)
KSH, n (%)	7 (3.8)	6 (6.6)
MC, n (%)	7 (3.8)	4 (4.4)
OTH, n (%)	21 (11.5)	9 (9.9)
SUH, n (%)	83 (45.6)	30 (33.0)
Age (year), median [95%CI]	70 [54.525 86.425]	70 [55 92.25]	0.735
Age (≤ 60 years old)			1.000
Negative, n (%)	156 (85.7)	78 (85.7)
Positive, n (%)	26 (14.3)	13 (14.3)
Hypertension			0.370
Negative, n (%)	89 (48.9)	39 (42.9)
Positive, n (%)	93 (51.1)	52 (57.1)
T2DM			1.000
Negative, n (%)	97 (53.3)	48 (52.7)
Positive, n (%)	85 (46.7)	43 (47.3)
PSA (ng/ml), median [95%CI]	49 [12.24 101.425]	47 [13.1 102.25]	0.954
PSA (> 50 ng/ml)			0.898
Negative, n (%)	93 (51.1)	48 (52.7)
Positive, n (%)	89 (48.9)	43 (47.3)
Biopsy type			0.018
Needle Biopsy, n (%)	98 (53.8)	64 (70.3)
TURP, n (%)	83 (45.6)	27 (29.7)
TVP, n (%)	1 (0.5)	0 (0.0)
Grade group			0.046
3, n (%)	8 (4.4)	4 (4.4)
4, n (%)	73 (40.1)	23 (25.3)
5, n (%)	101 (55.5)	64 (70.3)

CI confidence interval, GNH Gezira Hospital for Renal Disease and Surgery, ISHIbn Sina Teaching Hospital, KSH Kuwaiti Specialized Hospital, MC Military Corp, OTH Omdurman Teaching Hospital, SUH Soba University Hospital, T2DM type-2 diabetes mellitus, PSA prostate-specific antigen, TURP transurethral resection of the prostate, TVP transurethral laser vaporization of the prostate, PNI perineural invasion.

Discussion

The Republic of Sudan covers a significantly smaller geographical area than the expansive ethnic region in Africa that has been variably referred to as Kush, Nubia, and Bilad-Es-Sudan (Land of the blacks). Sudan boasts a linguistic diversity with over 140 languages spoken³⁹. These languages can be categorized into three of Greenberg's four African language families: Afro-Asiatic, Niger-Congo, and Nilo-Saharan¹⁹. There are approximately 570 tribes, which have been organized into 56 ethnic groups based on linguistic, cultural, and other ethnological traits. The capital, Khartoum, has experienced rapid population growth primarily due to migration, rather than local birthrates. Between 1984 and 1995, there was a significant influx of migrants from the western and southern regions of the country, a consequence of civil conflict and natural disasters⁴⁰.

In this study, we examined the demographic and clinical features of patients diagnosed with PCa in six health institutions in Central Sudan. For the first time, the healthy disparities of PCa were analyzed among three major ethnolinguistic groups in Africa.

Our data confirms how the higher risk of PCa associated with African ancestry could be linked as we hypothesize to the NC-speaking population. The higher PSA and the younger age at the diagnosis of NC patients corroborate the data regarding the higher PCa aggressiveness of African American patients. Our data are aligned with those recently reported on the South Africa population⁴¹ where Bantu-speaking NC population showed a significant risk for PCa diagnosis and aggressive disease presentation.

There is a lack of comparative studies between NS and AA population and others. No statistical significant difference have been reported for the PSA screening between European and Arab ancestry in US patients⁴². The major source of information on PCa relies on the national registries indicating a large disparities between North Africa dominated by AA population, such as Arabs, and sub-Saharan countries excluding those from the horn of Africa⁴³. Indeed, in Ethiopia where approximately three-quarters of its population speak AA languages, the PCa incidence and mortality are lower than in other sub-Saharan nations, with a majority of NC-speaking populations².

Our research has unveiled a novel finding, marking the first instance where the incidence of PNI in prostatic tissue is notably elevated among patients of AA population. Tumor cells interact with nerve components within the tumor microenvironment, giving rise to perineural hollows that provide a conducive environment for their survival and subsequent invasion of nerve cells⁴⁴. PNI tends to be more prevalent in advanced-stage tumors and it is often associated with unfavorable outcomes⁴⁵. Recent evidence links PNI to an approximately 50% heightened risk of biochemical recurrence⁴⁶ and the development of bone metastasis⁴⁷. Further studies are needed to exploit the possibility of a higher incidence of biochemical recurrence and bone metastasis in the AA population.

While Sudanese patients tend to be diagnosed with advanced-stage disease, it is important to consider that the biology of PCa among the three ethnic groups may be different. Given the significant genetic diversity within African populations, it becomes evident that there is a compelling need to refine the term “African ancestry” when assessing PCa risk. It is currently accepted the association of higher risk of PCa in men with African ancestry, a connection that has been consistently supported by numerous studies within the U.S. population^48,49. These studies result in several organizations have recommended adjusting screening criteria based on ethnicity to better reflect these risks. However, the terminology often used in guidelines, such as “African descent”, “Black ancestry”, or “African ancestry”, fails to accurately capture the genetic similarities and differences among populations. Our findings highlight the importance of refining ethnic terminology in screening guidelines to more precisely reflect the complex genetic diversity within African ancestry groups, thereby improving the effectiveness of PCa screening and prevention efforts.

Limitations and strengths

The recurrent conflicts in Sudan during this five-year render instability of the fragile healthcare system, less prioritizing of clinical research. The increasing number of patients with cancer has intensified the actual critical situation in terms of cancer care in Sudan³². This study is limited by the possibility to provide statistical analysis on clinical outcome measures, such as biochemical failure rates, progression free survival and overall survival. To our knowledge, we cannot exclude that different clinical features of PCa could be due to the use of cyanide in mining practices and pesticides by farmers in some areas of the country dominated by an ethnolinguistic group.

Conclusions

Given the persistent issue of health disparities in PCa, it is imperative that we adopt fresh perspectives for the study of PCa in individuals with African ancestry, focusing on a more precise genetic basis for the heightened risk rather than merely associating it with a specific geographical region.

Abbreviations

AA

Afro-asiatic

CI

Confidence interval

GNH

Gezira hospital for renal disease and surgery

ISH

Ibn sina teaching hospital

KSH

Kuwaiti specialized hospital

MC

Military corp

NC

Niger-congo

NS

Nilo-saharan

OTH

Omdurman teaching hospital

PCa

Prostate cancer

PNI

Perineural invasion

PSA

Prostate-specific antigen

SUH

Soba university hospital

T2DM

Type-2 diabetes mellitus

TURP

Transurethral resection of the prostate

TVP

Transurethral laser vaporization of the prostate

UN

United nations

Funding

The research was funded by International Centre for Genetic Engineering and Biotechnology (L.F.Z. and S.C.), and the UN Technology Bank for Least Developed Countries, TWAS and ICGEB under South-North and South-South Fellowships (D.A.).

Data availability

The authors declare the availability of the data used in the research to obtain the results reported in the manuscript upon reasonable request from the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

Specimen collection and research contents were examined and approved by the National Health Research Ethics Committee of the Sudanese Federal Ministry of Health (6–9-2021). The study was performed in accordance with the Declaration of Helsinki. Informed consent was taken from all the participants.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-024-77475-7.