Obesity raises Lynch syndrome CRC risk

By Lynda Williams, Senior medwireNews Reporter

Obesity increases the risk of colorectal cancer (CRC) in patients with Lynch syndrome (LS), research indicates, but daily aspirin use may combat this excess risk.

“These findings suggest that, in addition to recommended bowel surveillance, patients with LS are likely to benefit substantially from prevention – or effective treatment – of obesity and from regular aspirin use”, report John Mathers, from Newcastle University in the UK, and co-investigators in the Journal of Clinical Oncology.

However, Mangesh Thorat, from Queen Mary University of London, UK, commented in a statement to the press that, “although scientifically interesting, these results should be considered as hypothesis generating.”

Noting the increased risk of gastrointestinal bleeding sustained by overweight and obese individuals, and the high daily dose of aspirin used in the Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2) study, he added that “use of aspirin at this dose cannot be currently recommended for colorectal cancer prevention in the general population.”

The CAPP2 study included 937 LS patients who were randomly assigned to receive aspirin 600 mg/day or placebo, plus resistant starch 30 mg/day or placebo in a 2 x 2 factorial design for an average of 25.0 months.

After a mean follow-up of 55.7 months, 55 of the patients had developed CRC. Analysis revealed that CRC was 2.34 times more common in obese participants than those with a low or normal body mass index (BMI), with a slightly stronger association found in men than women, with adjusted hazard ratios (HRs) of 2.41 and 2.36, respectively.

And using BMI as a continuous variable, the adjusted HRs for men and women per each kg/m² increase were 1.12 and 1.06, respectively.

Further subgroup analysis revealed that the increased risk of CRC associated with obesity was limited to LS patients who carried the MLH1 mutation (HR=3.72), so that no excess risk of CRC with obesity was observed for those with the MSH2 or MSH6 mutations.

Moreover, the excess risk of CRC with obesity was found only in patients who had been given placebo, the researchers write.

There was a significant 2.75-fold increased risk of CRC diagnosis in obese placebo-treated patients compared with patients with a low or normal BMI, whereas, among aspirin-treated patients, the increased risk of CRC was 2.0-fold and did not reach statistical significance.

“The mechanism responsible for the greater cancer risk among obese patients with LS is not known”, Mathers et al admit.

“However, given the germline loss of DNA [mismatch repair] capacity in LS, it may be hypothesized that adverse sequelae of greater body fatness (eg, chronic low-level inflammation) have a promoting effect on those stem cells that have accumulated DNA damage because of this dysfunctional repair system.”

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