Introduction: Colorectal cancer is the third most common
cancer and the second most common cause of cancer mortality worldwide. There
are disparities in the epidemiology of colorectal cancer across different
populations, most probably due to differences in exposure to lifestyle and
environmental factors related to colorectal cancer. In the next decade, East
Africa is predicted to face an unprecedented growth of cancers, including
colorectal cancer. There are indications of a significant burden of late-stage
and aggressive colorectal cancer in the Ugandan population. Survival rates in
SubSaharan Africa remain poor, with Uganda registering a low 3-year overall
survival of 33.3%. There is a paucity of data on colorectal cancer molecular
subtypes and their characteristics among patients in East Africa.
Objective: The objective is to determine the prevalence of
colorectal cancer molecular subtypes among Ugandan colorectal cancer patients.
Methodology: A descriptive cross-sectional study was
conducted in two referral hospitals and two missionary hospitals in Uganda.
Data was obtained on demographics, topography of tumour and stage. The
histopathological subtype, grade and LVI status of CRC were obtained from
H&E slides. Immunohistochemistry was carried out to determine whether PMS2
and MLH1 were MMR-deficient or proficient. CRC formalin-fixed paraffin-embedded
(FFPE) tissue blocks were used to extract DNA. The MLH-1, MSH2, MSH6, BRAF and
KRAS genes were sequenced using NGS sequencing, and the CIMP status was obtained
using targeted NextGen Bisulphite sequencing (tNGBS). The tumour molecular
subtypes were defined according to the Jass classification: Type 1: MSI
positive, CIMP-positive, BRAF-mutated (positive), K-ras mutation negative; Type
2: MSS (MSI negative), CIMP-positive, BRAF-mutated (positive), Kras-mutation
(negative); Type 3: MSS (MSI negative), CIMP-negative, BRAF-mutation negative,
Kras mutated (positive); Type 4: MSS (MSI negative), CIMP-negative,
BRAF-mutation negative, Kras-mutation negative.; Type 5: MSI positive,
CIMP-negative, BRAF mutation-negative, Kras-mutation negative (Lynch syndrome).
Other marker combinations were grouped together as “other category”.
Categorical data were summarised using proportions and frequencies
corresponding to the MSI status and each of the five molecular subtypes defined
using the Jass classification. Categorical and continuous variables were
analysed using the Chi-square and Fisher’s exact tests. For all the analyses, a
p-value ≤0.05 was considered statistically significant.
Results: Out of 127 CRC patients, the median (IQR) age was
54(43-67) years. Advanced stage III+IV was found in 109(85.8%) cases. Poorly
differentiated tumours constituted 14(11.02%), moderately differentiated
96(75.6%) and well differentiated 17(13.4%). There were 52(40.9%) MSI positive
tumours and 75(59.06%) MSS tumours. The molecular subtypes defined by the Jass
classification included 0% type I, 2.3% type 2, 3.3% type 3, 45.7% type 4, and
38.0% type 5 (Lynch syndrome). Colorectal cancer patients with Lynch syndrome
have a pathogenic germline variant in one MMR gene and a secondary gene
inactivation due to promoter hypermethylation or loss of heterozygosity.
Conclusions: Importantly, sporadic MSI-high/CIMP-high
tumours (Jass type 1) were not present (0%), and BRAF/KRAS pathogenic mutations
were infrequent, unlike tumours from the Western world. Many young CRC
participants presented with poorly differentiated and advanced-stage tumours,
with MSI-positive tumours mainly due to Lynch syndrome. Immunohistochemistry,
MSI testing and colonoscopic surveillance are cheaper than germline testing,
and in Uganda may be carried out on CRC patients with MSI-positive histology.
Author(s) Details
R. Wismayer
Department of Surgery, Masaka Regional Referral Hospital, Masaka, Uganda,
Department of Surgery, Faculty of Health Sciences, Equator University of
Science and Technology, Masaka, Uganda, Department of Surgery, Faculty of
Health Sciences, Habib Medical School, IUIU University, Kampala, Uganda and
Department of Pathology, School of Biomedical Sciences, College of Health
Sciences, Makerere University, Kampala, Uganda.
R. Matthews
Institute of Genetics and Cancer, College of Medicine and Veterinary
Medicine, University of Edinburgh, Edinburgh, UK.
C. Whalley
Institute of Cancer and Genomic Sciences, College of Medical and Dental
Sciences, University of Birmingham, Birmingham, UK.
J. Kiwanuka
Department of Epidemiology and Biostatistics, College of Health Sciences,
Makerere University, Kampala, Uganda.
F. E. Kakembo
Department of Immunology and Molecular Biology, School of Biomedical
Sciences, College of Healt
Sciences, Makerere University, Kampala, Uganda and African Centre of Excellence
in Bioinformatics and Data Intensive Sciences, Infectious, Diseases Institute,
Makerere University, Kampala, Uganda.
S. Thorn
Institute of Genetics and Cancer, College of Medicine and Veterinary
Medicine, University of Edinburgh, Edinburgh, UK and Department of Oncology,
University of Oxford, Oxford, UK.
H. Wabinga
Department of Pathology, School of Biomedical Sciences, College of Health
Sciences, Makerere University, Kampala, Uganda.
M. Odida
Department of Pathology, School of Biomedical Sciences, College of Health
Sciences, Makerere University, Kampala, Uganda and Department of Pathology,
Faculty of Medicine, Gulu University, Gulu, Uganda.
I. Tomlinson
Institute of Genetics and Cancer, College of Medicine and Veterinary
Medicine, University of Edinburgh, Edinburgh, UK and Department of Pathology,
Faculty of Medicine, Gulu University, Gulu, Uganda.
Please see the book here :- https://doi.org/10.9734/bpi/msup/v6/7150
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