No actionable colorectal cancer risk increase in Dutch proven non-carriers of the predisposition for Lynch syndrome

Rein P. Stulp1, Mirjam M. de Jong1, Geertruida H. de Bock2, Sanne W. ten Broeke1, Rolf H. Sijmons1

1Department of Genetics, University Medical Center Groningen, Groningen, Netherlands. 2Department of Epidemiology, University Medical Center Groningen, Groningen, Netherlands

Abstract

Objectives

Non-carriers of the Lynch syndrome gene mutation occurring in their families are assumed to be at normal cancer risk. However, theoretically, an increased risk could exist because of shared other cancer risk factors. This study investigated colorectal cancer(CRC) risk in a cohort of proven non-carriers.

 

Methods

For all asymptomatic individuals tested negatively for their familial pathogenic MMR variant, the Dutch nationwide pathology registry was checked for CRC occurrence post-DNA testing. The  cumulative incidence and standardized incidence ratio (SIR) were estimated, including 95% CIs, where the age-matched incidence from the Dutch cancer registry was used as a reference. Kaplan-Meier analyses were performed. This study had 99% power to detect a more than 3-fold increase in CRC risk, which is the Dutch threshold for offering surveillance outside population screening.

 

Results

We included 757 individuals from 280 Dutch families (159 MLH1, 188 MSH2, 245 MSH6, 165 PMS2): 330 men and 427 women. Sixteen individuals developed CRC (10M/6F). The cumulative risk at the age of 70 was 4.4% (1.7-7.1), 5.3% (1.0-9.6) for men and 3.6% (0.1-7.1) for women, compared to 3,7% (4,7%M/2,8%F) in the population. The SIR was 0.75 (0.44-1.19). No significant difference was found in colon cancer risk between men and women (p = 0.191), nor between the non-carriers of MLH1 or MSH2 versus MSH6 or PMS2 (p = 0.0573).

 

Conclusion

There is no actionable increased CRC risk in Dutch proven non-carriers of Lynch syndrome.

Abstract references

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  2. Evans DG, Ingham SL, Buchan I, Woodward ER, Byers H, Howell A, Maher ER, Newman WG, Lalloo F., Increased rate of phenocopies in all age groups in BRCA1/BRCA2 mutation kindred, but increased prospective breast cancer risk is confined to BRCA2 mutation carriers, Cancer Epidemiol. Biomarkers Prev., 2013, 22(12):2269-2276
  3. Girardi F, Barnes DR, Barrowdale D, Frost D, Brady AF, et.al. Risks of breast or ovarian cancer in BRCA1 or BRCA2 predictive test negatives: findings from the EMBRACE study., Genet. Med., 2018, 44: E-pub ahead of print
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