Genetic insights: High germline variant rate in an indigenous African cohort with early-onset colorectal cancer.

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel. Materials and methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR. Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes. Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing.

The extracolonic cancer spectrum in females with the common 'South African' hMLH1 c.C1528T mutation.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, characterized by the occurrence of predominantly colon and endometrial cancer and, less frequently, cancer of the small bowel, stomach, hepatobiliary tract, ureter, renal pelvis, ovaries and brain. The phenotypic diversity may partially be explained by allelic heterogeneity. The aim of this study was to investigate the frequency of extracolonic cancers in a cohort of females sharing the same c.C1528T disease-predisposing mutation in the hMLH1 gene. Data on cancer history were obtained from 87 mutation-positive females and 121 mutation-negative sisters, as a control group. Testing for microsatellite instability (MSI) and expression of the wild-type hMLH1 allele was performed on extra-colonic tumour tissue blocks of mutation-positive individuals. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females vs. 7% (8/121) of mutation-negative females (P = 0.10). Multiple primary cancers occurred at a significantly higher incidence in the first group. Breast cancer, which was the most frequent extra-colonic cancer in mutation positive females (53%), occurred at a young age, and occurred bilaterally in two out of seven cases. Involvement of the hMLH1 gene was confirmed in five out of seven cases of breast cancer, two cases of endometrial cancer, one case of ovarian cancer and one case of renal cell carcinoma, by detecting immunohistochemical compromise of the gene product. Although the study might not have been adequately statistically powered (to provide a significant P value), the noteworthy findings in this study include the confirmation of a range of Lynch II type cancers in a cohort we previously thought was wholly predisposed to Lynch I features, and a confirmation of breast cancer as part of the spectrum of Lynch syndrome cancers affecting women.

A comparison of methods of assessment of scintigraphic colon transit.

UNLABELLED: There is no standard method of analysis of scintigraphic colonic transit investigation. This study was designed to compare 4 techniques. METHODS: Sixteen subjects (median age, 37.5 y; range, 21-61 y), who had sustained a spinal cord injury more than a year before the study, were given a pancake labeled with 10-18 MBq of (111)In bound to resin beads to eat. Anterior and posterior images were acquired with a gamma-camera 3 h after the meal and then 3 times a day for the next 4 d. Seven regions of interest, outlining the ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, rectosigmoid, and total abdominal activity at each time point, were drawn on the anterior and posterior images. The counts were decay corrected and the geometric mean (GM), for each region, at each time point calculated. The GM was used to calculate the percentage of the initial total abdominal activity in each region, at each time point. Colonic transit was assessed in 4 ways: (a) Three independent nuclear medicine physicians visually assessed transit on the analog images and classified subjects into 5 categories of colonic transit (rapid, intermediate, generalized delay, right-sided delay, or left-sided delay). (b) Parametric images were constructed from the percentage activity in each region at each time point. (c) The arrival and clearance times of the activity in the right and left colon were plotted as time-activity curves. (d) The geometric center of the distribution of the activity was calculated and plotted on a graph versus time. The results of these 4 methods were compared using an agreement matrix. RESULTS: Though simple to perform, the visual assessment was unreliable. The best agreement occurred between the parametric images and the arrival and clearance times of the activity in the right and left colon. CONCLUSION: The different methods of assessment do not produce uniform results. The best option for evaluating colonic transit appears to be a combination of the analog images, which provide a general overview of colonic transit and a quantitative method that demonstrates segmental transit.