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Colon Cancer: Background and Driving Mutations

CRC is the third most common cancer in the US with a ~50% projected increase by 2030.

Genomic instability and DNA mutations are hallmarks of cancer [1]. Colorectal cancer (CRC) is no different and has been shown to arise from a number of mutations in genes whose proteins regulate critical cell signaling pathways. These alterations include inactivating mutations in the tumor suppressors APC, TP53 and SMAD4, as well as activating mutations in the oncogene KRAS. The accumulation of these mutations drives the progression from healthy intestinal cell, to adenoma in the form of precancerous polyps, to sporadic CRC [2, 3]. Inactivating mutations in APC are reported in 30-70% of CRC, while activating mutations in KRAS are reported in ~40% of CRC [4-6]. KRAS mutations are also associated with a worse CRC prognosis [7]

CRC is the third most common type of cancer in the US [8]. CRC diagnosis in those younger than 50 years of age, termed early onset CRC (EOCRC), has witnessed a sharp increase in recent years, with this younger population now accounting for ~10% of diagnoses [9, 10]. This number is still on a steep upwards trajectory with an expected increase of 40% in colon and 50% in rectal cancers from 2020 to 2030 in 20 to 34-year-olds [11].

EOCRC patients are more often diagnosed at advanced cancer stages than their late onset counterparts owing in part to the minimum age set by the CRC screening guidelines in most countries, which almost entirely misses the EOCRC population [12]. Additionally, CRC screening still carries a staggering 32% miss rate – meaning that 1 in 3 early detection efforts fail to detect existing pre-malignant lesions [13]. Both of these factors are particularly concerning since the 5-year survival rate steeply declines the further the stage of cancer development is at the time of diagnosis. The 5-year survival rate is 90% for those diagnosed at the earlier stages when the cancer is still localized, drops to 71% for those at a later stage that is characterized by regional tumor spread, and stands at a shocking 14% for those diagnosed after the cancer has metastasized [9].