New Pathogenic Germline Variants in Very Early Onset and Familial Colorectal Cancer Patients

Abstract

A genetic diagnosis facilitates personalized cancer treatment and clinical care of relatives at risk, however, although 25% of colorectal cancer cases are familial, around 95% of the families are genetically unresolved. In this study, we performed gene panel analysis on germline DNA of 32 established or candidate colorectal cancer predisposing genes in 149 individuals from either families with an accumulation of colorectal cancers or families with only one sporadic case of very early onset colorectal cancer (≤40 years at diagnosis). We identified pathogenic or likely pathogenic genetic variants in 10.1% of the participants in genes such as APC, POLE, MSH2 or PMS2. The MSH2 variant, c.2168C>T, p.(Ser723Phe) was previously described as a variant of unknown significance, but we have now reclassified it to be likely pathogenic. The POLE variant, c.1089C>A, p.(Asn363Lys) was identified in a patient with three metachronous colorectal cancers from age 28 and turned out to be de novo. One pathogenic PMS2 variant was novel. We also identified a number of highly interesting variants of unknown significance in APC, BUB1, TP53 and RPS20. The RPS20 variant is novel and was found in a large Amsterdam I positive family with a multi tumor phenotype including 12 cases of CRC from as early as age 24. This variant was found to segregate with cancer in the family and multiple in silico tools predict it to be pathogenic. Our data further support the shift from phenotypic-based cancer panels to large panels including all established genes involved in hereditary cancer syndromes or (targeted) whole genome sequencing. Additionally, identification of a likely disease-predisposing variant in RPS20 expands the phenotypic spectrum of RPS20-related cancers and emphasize that this gene is relevant to include in colorectal cancer gene panels.

Polygenic early‐onset colorectal cancer in pediatric patients

“…Due to limited reports of this variant, its role in clinical practice is limited and it is unclear whether this mutation led to increased carcinogenesis in our third patient's case. Based on a recent study of 149 individuals in families with accumulation of CRC or families with a sporadic case of very early‐onset CRC, genetic variants previously described as VUS were identified in patients with early‐onset CRC 19 . This study supports the need for shift from phenotypic‐based cancer panels to larger genetic panels including all established genes involved in hereditary cancer syndromes.…”

Changes in the Transcriptome Caused by Mutations in the Ribosomal Protein uS10 Associated with a Predisposition to Colorectal Cancer

“…Obviously, all these disorders can be caused by mutations in the genes of ribosomal proteins, whose occurrence in a number of such genes has been discovered in various types of cancer by recent studies using whole-exome or whole-genome sequencing techniques, as reviewed in [ 10 ]. Among these genes is RPS20 , which encodes the ribosomal protein uS10 (previously named as S20), mutations of which are associated with colorectal cancer [ 14 , 15 , 16 ]. This protein is located on the solvent-exposed surface of the head of the 40S subunit adjacent to the mRNA entry site and interacts directly with the ribosomal protein uS3 [ 17 , 18 ], which is also involved in the interaction with the translation initiation factor eIF3, as shown for yeast ribosomes [ 19 ].…”

“…A little later, a linkage of mutations in uS10 with CRC susceptibility has been confirmed for such disruptive mutations as p.V50SfsX23 and p.L61EfsX11, and for the missense one p.V54L, by the evidence reviewed in [ 15 ]. More recently, another uS10 missense mutation, p.E33V, has been shown to be associated with an inherited predisposition to several types of cancers, including CRC [ 16 ]. Finally, two mutant variants of the RPS20 gene have recently been described that correspond to substitutions I84N and I84S in the protein in patients with the genetic disorder, Diamond-Blackfan anemia (DBA), a form of ribosomopathy characterized by red cell aplasia and macrocytic anemia [ 28 ] and usually caused by mutations in genes of a number of ribosomal proteins [ 29 ].…”

Prognostic nomograms for predicting overall survival and cancer-specific survival of patients with very early onset colorectal cancer: a population‑based analysis

“…However, an opposite trend appears among younger adults [ 5 ]. It is noteworthy that the largest increase in CRC incidence occurred among subjects aged 40 years or younger, which was defined as very early-onset CRC (VEO-CRC) [ 4 , 6 ]. Hence, there is an urgent need to identify crucial prognostic factors specifically for VEO-CRC patients, thus contributing to improved prediction of survival outcome as well as further clinical decision-making.…”