Jauhri Mayank, Bhatnagar Akanksha, Gupta Satish, Bp Manasa, Minhas Sachin, Shokeen Yogender, Aggarwal Shyam
1 Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India.
2 Amity Institute of Biotechnology, Amity University, Noida, India.
Tumour Biol. 2017 Feb;39(2):1010428317692265. doi: 10.1177/1010428317692265.
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.
印度的结直肠癌发病率呈上升趋势。在本研究中，我们分析了6种潜在生物标志物的突变频率、它们的共存情况、与临床病理特征的关联以及在印度结直肠癌患者中的肿瘤位置。使用112例结直肠癌患者的福尔马林固定石蜡包埋组织块进行下一代测序，以鉴定6种潜在生物标志物基因中的突变。在KRAS、BRAF、PIK3CA、NRAS、TP53和APC中观察到的突变频率分别为35.7%、7.1%、16.1%、6.3%、39.3%和29.5%。突变的显著关联为KRAS与年龄小于60岁相关（p = 0.041），PIK3CA与男性相关（p = 0.032）、肿瘤I-II期相关（p = 0.013）、无淋巴结转移相关（p = 0.040），NRAS与直肠相关（p = 0.002），APC与肿瘤生长的T2期相关（p = 0.013）。没有单个患者同时携带这6个基因或任何5个基因的突变。注意到KRAS与APC共存具有显著性（p = 0.024）以及KRAS与BRAF相互排斥具有显著性（p = 0.029）。观察到PIK3CA外显子9比PIK3CA外显子20更常与KRAS突变相关（p = 0.072）。NRAS突变与BRAF和PIK3CA突变相互排斥。据我们所知，这是印度结直肠癌患者中第一项基于下一代测序的生物标志物研究。成对和三联体基因突变的频繁共存表明重叠突变的协同效应可能会进一步引发该疾病。此外，多个基因突变的罕见共存提示结直肠癌发生的不同信号通路。
