Cigarette smoking ups risk of colorectal cancer

Smoking cigarettes increases dose-dependently, with intensity and duration, the risk of colorectal cancer (CRC), but quitting reduces this risk, according to the results of a systematic review and meta-analysis.

“Smoking greatly increases the risk of CRC that develops through the microsatellite instability pathway, characterized by microsatellite instability-high, CpG island methylator phenotype positive, and BRAF mutation,” the researchers said.

A systematic review and meta-analysis was conducted involving epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. The researchers calculated the relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with focus on molecular subtypes of CRC.

A total of 188 original studies were included in the meta-analysis. Current smokers had a pooled RR for CRC of 1.14 (95 percent confidence interval [CI], 1.10–1.18) while former smokers had RR of 1.17 (95 percent CI, 1.15–1.20) compared with never smokers. [Am J Gastroenterol 2020;115:1940-1949]

CRC risk increased linearly with smoking intensity and duration. Notably, former smokers who had quit smoking for >25 years had markedly reduced CRC risk compared with current smokers, suggesting that the elevated risk of CRC could persist for many, many years after cessation.

“Elevated risk after quitting has been noted for other cancer types including lung and oesophageal cancer,” the researchers said.

“Surprisingly, those who had recently quit (<10 years) showed a slightly higher CRC risk compared with current smokers; this finding may reflect the tendency of people with undiagnosed cancer to quit smoking, possibly because of the initial appearance of symptoms,” they added. [Eur J Cancer Prev 2013;22:96-101]

The robust association existing between smoking and CRC risk was characterized by high CpG island methylator phenotype (CIMP; RR, 1.42, 95 percent CI, 1.20–1.67; number of studies [n]=4), BRAF mutation (RR, 1.63, 95 percent CI, 1.23–2.16; n=4), or high microsatellite instability (MSI; RR, 1.56, 95 percent CI, 1.32–1.85; n=8), but not by KRAS (RR, 1.04, 95 percent CI, 0.90–1.20; n=5) or TP53 (RR, 1.13, 95 percent CI, 0.99–1.29; n=5) mutations.

“The findings show that smoking increases the risk of CRC by 15 percent to 20 percent, both in men and in women, confirming previous estimates, and provide strong evidence that the risk increases with intensity and duration of smoking,” the researchers said. [JAMA 2008;300:2765-2778]

Analysing the association between smoking and CRC according to key molecular characteristics revealed that colorectal carcinogenesis follows two major pathways: the MSI pathway, which accounts for about 15 percent of the CRCs, and the chromosomal instability pathway, which accounts for the remaining 85 percent of the CRC. [Nat Rev Cancer 2017;17:79-92]

“The MSI pathway is characterized by a positive CIMP that induces hypermethylation and inactivation of genes including DNA mismatch repair gene MHL1,” the researchers explained. “The resulting genetic hypermutability leads to MSI and mutation of genes including the BRAF oncogene.” [Nat Genet 2006;38:787-793; Annu Rev Pathol 2011;6:479-507; Nat Rev Clin Oncol 2010;7:197-208]

Furthermore, smoking causes DNA methylation at CpG islands, which shows a possible mechanism linking smoking with the hypermethylator phenotype and accumulation of mutations in microsatellite sequences and in driver genes such as BRAF. [Clin Epigenetics 2015;7:113; Am J Hum Genet 2011;88:450-457; Nat Rev Clin Oncol 2010;7:197-208]

“Our findings support smoking cessation to reduce the risk of CRC,” the researchers said. “Further evaluations of the molecular mechanisms through which smoking affects colorectal carcinogenesis are warranted.”