Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants

Abstract

A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

“…Recent studies demonstrated that the polygenic background, defined as PRS based on disease-associated SNPs, modifies the risks for several cancers of the general population including CRC considerably, both in terms of age at onset and cumulative lifetime risks [ 12 , 23 , 27 , 36 – 38 ]. In line with this, the risk alleles of those SNPs are found to also accumulate in unexplained familial and early-onset CRC cases [ 25 , 39 ]. Whereas a low polygenic burden decreases the CRC risk down to one quarter on average, individuals with a high PRS (> 80%) doubles and those with a very high PRS (99%) almost quadruplicate their risk and thus, reach a CRC risk in an order of magnitude almost comparable to carriers of hereditary CRC with low PRS [ 31 ].…”

“…As such, it is expected that the genetic background defined by the common risk variants may not only influence the occurrence of late-onset sporadic cases, but also modulate the risk of familial, early-onset, and hereditary CRC [ 25 ]. Recent studies demonstrated that high PRS values are associated with an increased risk of CRC and other common cancers in the general population up to an order of magnitude that is almost similar to hereditary tumor syndromes [ 26 , 27 ].…”

Polygenic risk score across distinct colorectal cancer screening outcomes: from premalignant polyps to colorectal cancer

“…We adjusted for family history, but participants with a history of familial CRC or one first degree relative younger than 60 would have been excluded from the CRC Screening Program and referred to the gastroenterologist. Thus, we do not have this population to study, but we have shown elsewhere that the PRS has a similar contribution in familial CRC [ 31 ]. Also, despite study participants were predominantly of European ancestry (97%), all the analyses were adjusted by five principal components obtained from the AIMS.…”

Clinically relevant combined effect of polygenic background, rare pathogenic germline variants, and family history on colorectal cancer incidence

“…Recent studies demonstrated that the polygenic background, de ned as PRS based on diseaseassociated SNPs, modi es the risks for several cancers of the general population including CRC considerably, both in terms of age at onset and cumulative lifetime risks [12,23,27,[35][36][37]. In line with this, the risk alleles of those SNPs are found to also accumulate in unexplained familial and early-onset CRC cases [25,38]. Whereas a low polygenic burden decreases the CRC risk down to one quarter on average, individuals with a high PRS (> 80%) doubles and those with a very high PRS (99%) almost quadruplicate their risk and thus, reach a CRC risk in an order of magnitude almost comparable to carriers of hereditary CRC with low PRS [31].…”

“…As such, it is expected that the genetic background de ned by the common risk variants may not only in uence the occurrence of late-onset sporadic cases, but also modulate the risk of familial, early-onset, and hereditary CRC [25]. Recent studies demonstrated that high PRS values are associated with an…”