P53 mutations in colorectal cancer from northern Iran: Relationships with site of tumor origin, microsatellite instability and K‐ras mutations

Abstract

CRC-associated P53 mutations have not been studied extensively in non-Western countries at relatively low CRC risk. We examined, for the first time, 196 paraffin-embedded CRC cases from Northern Iran for mutations in P53 exons 5-8 using PCR-direct sequencing. P53 status and mutation site/type were correlated with nuclear protein accumulation, clinicopathologic variables and data on K-ras mutations and high-level microsatellite instability (MSI-H). We detected 96 P53 mutations in 87 (44.4%) cases and protein accumulation in 84 cases (42.8%). P53 mutations correlated directly with stage and inversely with MSI-H. Distal CRCs were more frequently mutated at major CpG hotspot codons [248 (8/66, 12.1%), 175 (7/66, 10.6%), and 245 (7/66, 10.6%)], while in proximal tumors codon 213, emerged as most frequently mutated (5/28, 17.9% vs. 3/66, 4.5%, P = 0.048). Transitions at CpGs, the most common mutation type, were more frequent in non-mucinous (25% vs. 10.4% in mucinous, P = 0.032), and distal CRC (27% vs. 12.5% in proximal, P = 0.02), and correlated with K-ras transversions. Transitions at non-CpGs, second most common P53 mutation, were more frequent in proximal tumors (15.6% vs. 4.7% in distal, P = 0.01), and correlated with K-ras transitions and MSI-H. Overall frequency and types of mutations and correlations with P53 accumulation, stage and MSI-H were as reported for non-Iranian patients. However P53 mutation site/type and correlations between P53 and K-ras mutation types differed between proximal and distal CRC. The codon 213 P53 mutation that recurred in proximal CRC was previously reported as frequent in esophageal cancer from Northern Iran.

Prevalence of TP53 germ line mutations in young Pakistani breast cancer patients

“…These include seven variants previously classified as polymorphisms in IARC TP53 database and two novel variants. The silent c.903A[G mutation was previously found in three somatic tumors other than breast [32][33][34] and now it was detected for the first time in the germ line. It was identified in a patient of Punjabi origin, who was diagnosed with breast cancer at 27 years of age, but not in 112 healthy controls.…”

Molecular Characterization of Somatic Alterations in Dukes’ B and C Colorectal Cancers by Targeted Sequencing

“…TP53 alterations are identified as late events in CRC development, with a loss of TP53-mediated apoptotic pathways as an important factor in the progression from an adenoma to a malignant tumor (Smith et al, 2002). The frequency and spectrum of TP53 alterations were associated with the different grades, stages and locations of the tumor (Mahdavinia et al, 2008). A study by Mahdavinia et al (2008) found that the frequency of TP53 mutations significantly increased with tumor stages (36/94, 38.3%; 33/64, 51.5%, and 15/23, 65.2% in Stage B, C, and D, respectively) and this is also reflected in our finding.…”

Polymorphisms of TP53 codon 72 with prostate carcinoma risk: a meta-analysis

“…In case of its mutation, this regulation could be lost, resulting in cell proliferation without control and development of cancer. TP53 mutation has been reported to have an association with risks of several cancers such as lung cancer [12], breast cancer [13], and colorectal cancer [14]. The loss of TP53 gene could damage its DNA-binding properties and transcription factor function, thus leading to aberrant cell proliferation.…”