Rosie Matthews's scientific contributions

Introduction: APC gene mutations are an important initiator in tumorigenesis and have been detected in many colorectal cancers (CRC). There is conflicting evidence regarding the association between clinicopathological features of CRC and PIK3CA mutations. A promising prognostic factor of CRC and an important molecule to understand the progression and tumorigenesis of CRC is the SMAD family member 4 (SMAD4). The frequency rates of APC, PIK3CA, and SMAD4 mutations in CRC differ among populations. The objective of this study was to determine the mutation frequencies and determine their association with certain clinicopathological features in Ugandan patients. Methodology: A cross-sectional study between 2008-2021 involving four hospitals in central Uganda and the Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University. The demographics, stage, grade, LVI status and histopathological subtype was obtained for each CRC participant. The CRC tumours were evaluated using next-generation sequencing (NGS). The pathological mutation rates of APC, PIK3CA and SMAD4 were recorded, along with clinicopathological features. Chi-square test and Fischer’s exact test were used to determine the association between clinocopathological features and mutation status. Results: Out of 127 CRC participants, the mutation rates were APC: 77(60.6%), PIK3CA: 37(29.1%) and SMAD4: 68(53.5%). A loss of APC was found in 70.2% female participants compared to 29.8% female participants with the presence of APC (p=0.047). There were 57% positive APC tumours that were lymphovascular invasion (LVI) positive compared to 42.9% negative APC tumours that were LVI positive (p=0.015). With increasing T-stage, more CRC participants were PIK3CA negative (p=0.018). There was no association between the stage, grade, status, and tumour topography with APC, PIK3CA and SMAD4 mutation status. Conclusions: In Uganda, the frequency of APC mutations are similar, however the frequencies of PIK3CA and SMAD4 mutations were higher than that reported in the Western world. APC mutations were associated with a positive LVI status. However, APC, PIK3CA, and SMAD4 mutations were not associated with most clinicopathological parameters.

Uganda is a developing low-income country with a low incidence of colorectal cancer, which is steadily increasing. Ugandan colorectal cancer (CRC) patients are young and present with advanced-stage disease. In our population, there is a scarcity of genetic oncological studies, therefore, we investigated the mutational status of CRC tissues, focusing in particular on the adenomatous polyposis coli (APC), phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and SMAD4 genes. Our objective was to determine whether there were any differences between other populations and Ugandan patients. We performed next-generation sequencing on the extracted DNA from formalin-fixed paraffin-embedded adenocarcinoma samples from 127 patients (mean (SD) age: 54.9 (16.0) years; male: female sex ratio: 1.2:1). Most tumours were located in the rectum 56 (44.1%), 14 (11%) tumours were high grade, and 96 (75.6%) were moderate grade CRC. Stage III+IV CRC tumours were found in 109 (85.8%) patients. We identified 48 variants of APC, including 9 novel APC mutations that were all pathogenic or deleterious. For PIK3CA, we found 19 variants, of which 9 were deleterious or pathogenic. Four PIK3CA novel pathogenic or deleterious variants were included (c.1397C>G, c.2399_2400insA, c.2621G>C, c.2632C>G). Three SMAD4 variants were reported, including two pathogenic or deleterious variants (c.1268G>T, c.556dupC) and one tolerant (c.563A>C) variant. One novel SMAD4 deleterious mutation (c.1268G>T) was reported. In conclusion, we provide clinicopathological information and new genetic variation data pertinent to CRC in Uganda.