Prevalence and coexistence of KRAS, BRAF, PIK3CA, NRAS, TP53, and APC mutations in Indian colorectal cancer patients: Next-generation sequencing–based cohort study

Abstract

Colorectal cancer incidences are on a rise in India. In this study, we have analyzed the mutation frequencies of six potential biomarkers, their coexistence, association with clinicopathological characteristics, and tumor location in Indian colorectal cancer patients. Next-generation sequencing was performed to identify mutations in the six potential biomarker genes using formalin-fixed paraffin-embedded tissue blocks of 112 colorectal cancer patients. The mutation frequency observed in KRAS, BRAF, PIK3CA, NRAS, TP53, and APC was 35.7%, 7.1%, 16.1%, 6.3%, 39.3%, and 29.5%, respectively. The significant associations of mutations were KRAS with age less than 60 years (p = 0.041), PIK3CA with males (p = 0.032), tumor stage I-II (p = 0.013), lack of metastasis in lymph nodes (p = 0.040), NRAS with rectum (p = 0.002), and APC with T2 stage of tumor growth (p = 0.013). No single patient harbored mutations in these six genes or any five genes simultaneously. Significance was noted in coexistence of KRAS with APC (p = 0.024) and mutual exclusion of KRAS with BRAF (p = 0.029). PIK3CA exon 9 was observed to be more frequently associated with KRAS mutations than PIK3CA exon 20 (p = 0.072). NRAS mutations were mutually exclusive with BRAF and PIK3CA mutations. As per our knowledge, this is the first next-generation sequencing-based biomarker study in Indian colorectal cancer patients. Frequent coexistence of gene mutations in pairs and triplets suggests that synergistic effect of overlapping mutations might further trigger the disease. In addition, infrequent coexistence of multiple gene mutations hints toward different signaling pathways for colorectal cancer tumorigenesis.

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“…Both findings are in accordance with those of similar studies [14,19]. Right colon tumours were likelier to harbour KRAS mutations than left colon tumours; similar findings were observed in previous studies [18,19]. This could explain the relationship between right colon tumours and poor prognosis.…”

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“…Loss of TP53 function is one of the major events in the development of CRC, which is thought to occur in the later stages of colon cancer progression[ 34 ]. The TP53 mutation rate in the SMH dataset was 69%, which is consistent with the frequencies reported in various studies (45%-84%)[ 35 ].…”

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“…Additionally, as Rosenbaum, et al also noted, we observed a relationship between tumors exhibiting PD-L1 expression and BRAF V600E mutation 24 . Further, our study demonstrated a concomitant KRAS and BRAF mutation which conflicts with the theory that these two mutations occur mutually exclusive of each other 71 . This phenomenon, albeit extremely rare, had been observed by other researchers 77 , 78 .…”

“…An enormous amount of money and time has been invested in researching colon cancer, and yet the heterogeneity of the disease renders us unable to identify a biomarker to effectively diagnose and treat this insidious disease. Innumerable articles and clinical trials speak to the need for additional insight into tumor evolution and the prognostic role that the primary tumor's anatomic location plays in therapeutic response 36,42,70,71 . In this chapter, our specific aims were to 1…”