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SDIRSACR Oncology Insights

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Common, low-penetrance genetic predisposition to colorectal cancer

Sergi Castellví-Bel
Genetic Predisposition to Gastrointestinal Cancer Group, August Pi i Sunyer Biomedical Research Institute / Clínic Barcelona /
CIBEREHD / University of Barcelona, Barcelona, Catalonia, Spain

Keywords: colorectal cancer, genetic predisposition, cancer risk, genetic variant, genetic association

Colorectal cancer (CRC) is recognized as one of the cancers with the highest incidence and associated mortality
worldwide [1]. It is generally acknowledged that a vast majority of CRC cases develop from non-malignant precursor
adenomas [2]. The average duration of the development of an adenoma to CRC transition is unobserved, but it
is estimated to take at least 10 years [3]. This long latent phase provides an excellent window of opportunity for
early detection. Therefore, CRC is particularly suitable for screening. Keeping in mind the magnitude of this disease,
European national health systems have started population screening programs in order to increase early detection and
improve prevention measures. Screening for CRC offers the possibility to identify the disease at an earlier stage or at
a premalignant phase. For this reason, the evidence-based European Code Against Cancer recommended that men
and women over 50 years of age should participate in CRC screening. This was given effect within the EU by the 2003
Council Recommendation on cancer screening [4].
Indeed, CRC is highly preventable by detecting and removing adenomas through colonoscopy screening, but this
procedure is very costly to be implemented as population screening and has an associated morbidity [5]. Intermediate
screens to detect occult blood in feces such as fecal immunochemical testing (FIT) are therefore often used to select
patients for colonoscopy with suboptimal sensitivity [6, 7]. This 2-step strategy for CRC screening is the most common
worldwide [8], but results in a high false positive rate due to the suboptimal specificity of the occult blood detection,
implying unnecessary colonoscopies [9]. Therefore, additional biomarkers added to the first step to the current scenario
could improve CRC screening.
As for other complex diseases, CRC is caused by both genetic and environmental factors [10]. Twin studies showed
that around 13%-30% of the variation in CRC susceptibility involves inherited genetic differences [11, 12]. Some of the
known CRC predisposition factors were already discovered in the past two decades through genome-wide association
studies [13, 14]. Right after their identification, the hope was raised for genetic pro-filing using the combination of
these common, low-penetrance genetic variants to be able to identify high-risk individuals in the population that
could benefit from preventive and therapeutic interventions [15]. Indeed, polygenic risk scores (PRS) combining the
individual, weak effects on disease risk have been developed in the past for common diseases such as CRC. Their
predicting potential was limited, most likely evidencing their usefulness but their shortcomings when used alone
without other clinical or environmental data [16, 17]. PRS models for CRC were developed by using individual genome-
wide association study (GWAS) genetic variants (from 10 to more than 100) but have recently incorporated genome-
wide data in order to improve risk prediction [18]. Certainly, genome-wide PRS have proven to identify individuals with
risk equivalent to monogenic mutations [19], which could justify its application in health care systems.
Using PRS to screen the population at medium risk for CRC is an attractive alternative to improve current results in this
setting. Frampton et al. demonstrated that personalized screening programs for CRC, in which eligibility was based
on PRS in addition to age, had the potential to greatly reduce the number of individuals screened while still detecting
nearly as many cases [20]. Some more recent studies have also tested the potential application of PRS on CRC screening
programs, showing its value to define a personalized, risk-adapted starting ages for screening [17, 21] or personalized
screening intervals after negative findings from colonoscopy [22].

References

1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; et al. Global Cancer Statistics 2020:
GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin
2021, 71, 209-249.
2. Morson, B.C. The evolution of colorectal carcinoma. Clin Radiol 1984, 35, 425-31
3. Winawer, S.J.; Fletcher, R.H.; Miller, L.; Godlee, F.; Stolar, M.H.; Mulrow, C.D.; et al. Colorectal cancer screening:
clinical guidelines and rationale. Gastroenterology 1997. 112, 594-642
4. eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:327:0034:0038:EN:PDF
5. European Colorectal Cancer Screening Guidelines Working Group; von Karsa, L.; Patnick, J.; Segnan, N.; Atkin, W.;
Halloran, S.; et al. European guidelines for quality assurance in colorectal cancer screening and diagnosis: overview
and introduction to the full supplement publication. Endoscopy 2013, 45, 51-9.

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