TP53 mutations in colorectal cancer from Tunisia: relationships with site of tumor origin, microsatellite instability and KRAS mutations

Abstract

Loss of TP53 function through gene mutation is a critical event in the development and progression of colorectal cancer (CRC). Here we examined 51 primary CRC tumors from Tunisia for mutations in TP53 exons 4-9 using PCR-direct sequencing. TP53 status and mutation site/type were than correlated with nuclear protein accumulation, familial and clinicopathologic variables and data on KRAS mutations and microsatellite instability (MSI-H). The TP53 mutation analysis was possible in the tumor of 47 patients and a deleterious somatic mutation has been detected in 59.6% of the patients (28/47) including 20 (71.4%) missense mutations, 7 nonsense mutations (25%) and 1 (3.6%) frameshift mutation. 89.3% (25/28) of the detected mutations were in exons 5-8, whereas 10.7% (3/28) were in exon 4. Among the 27 non frameshift mutations, 89% (24/27) were transitions and 11% (3/27) were transversions. 64.3% (18/27) of the altered amino acids corresponded to arginine. 74% (20/27) were G>C to A>T transitions, and more than half (14/27) occur at hotspots codons with CpG sites. TP53 mutations correlated closely with TP53 accumulation (p = 0.0090) and inversely with MSI phenotype (p = 0.0658). A KRAS somatic mutation was identified in 25% (7/28) of the TP53 mutated tumors. All these mutations were G>A transitions in codon 12 and all the tumors with combined alterations but one were distally located and MSS. In conclusion, frequency and types of TP53 mutations and correlations with TP53 protein accumulation, and MSI were as reported for non-Tunisian patients. However, no significant associations have been detected between TP53 mutations and clinicopathological data in Tunisian patients as previously reported.

A Review of Cancer Genetics and Genomics Studies in Africa

“…We retrieved 56 publications on colorectal cancer genetics/genomics from Nigeria, Ghana, South Africa, Algeria, Tunisia, Morocco, and Egypt. The findings in these publications included: (1) the identification of I130K APC polymorphism in the indigenous Black population in South Africa and Tunisia to development of familial adenomatous polyposis coli ( 252 – 255 ), (2) the presence of mutations in the MUTYH , MLH1 , and MSH2 gene in patients with colorectal cancer and attenuated polyposis in Algeria, Egypt, Morocco, Tunisia, and South Africa ( 256 – 266 ), (3) the burden of KRAS and BRAF mutations in colorectal cases in Morroco, Nigeria, Ghana, Egypt and Tunisia ( 267 – 275 ) and (4) the level of microsatellite instability in South African, Nigerian, Ghanian, Tunisian, and Moroccan colorectal cancer patients ( 259 , 271 , 274 , 276 – 281 ). Other studies have also explored the contribution of epigenetic changes to colorectal cancer carcinogenesis in Africa ( 278 , 282 – 285 ).…”

POFUT1 promotes colorectal cancer development through the activation of Notch1 signaling

“…3d ). As p53 played an important role of inhibiting tumor growth and proliferation in CRC 38 , c-Myc were overexpressed in CRC and linked with CRC proliferation intimately 39 , CCND1 were closely connected with cell cycle and tumor proliferation 40 . We carried out the experiment to examine the expression levels of p53 , c-Myc , and CCND1 in cell lines.…”