Genetic Contributions

A number of genetic mutations are associated with increased risk for colorectal cancer (CRC), and genetic variants seem to play a role in young-onset disease. Overall, genetic variants drive ~20% of cases of CRC in patients <50 years of age. According to recent data, among this age group, 13% of pathogenic variants are associated with Lynch Syndrome or polyposis syndromes. It is important to note that the majority of patients with young-onset disease do not have a genetic predisposition for CRC.1

Less than 20% of cases of young-onset CRC in adults <50 years old are due to genetic predisposition1

Genetic variants only drive a small percentage of CRC2

About half of patients that have a pathogenic germline variant associated with CRC do not meet the conventional clinical diagnostic criteria for the respective hereditary disease; therefore, genetic screening is an important tool in diagnosis1

Prevalence of Pathogenic Variants by Age at CRC Diagnosis1,a

Figure of three donut charts illustrating the prevalence of pathogenic variants by age at colorectal cancer diagnosis. The three age groups shown are under 35 years, under 50 years, and over 50 years. The variants the graphic is illustrating are listed as polyposis syndromes, lynch syndrome, other variant, and none. For the under 35 group, combined pathogenic variants were seen in around 35% of cases. For the under 50 group, combined pathogenic variants were seen in around 20% of cases. In the over 50 group, combined pathogenic variants were seen in around 10% of cases.

Multigene panel tests did not identify a germline mutation in approximately 80% of these individuals with CRC.

  • Younger patients have an increased prevalence of germline variants1
  • Guidelines recommend multigene panel testing of all young patients with CRC1
 Genes That Contain Pathogenic Variants for Patients Aged <50 Years1
LYNCH SYNDROME
(10%)		 POLYPOSIS SYNDROMES
(3%)		 OTHER PATHOGENIC VARIANTS (5%)
HIGH
PENETRANCE		 MODERATE / LOW
PENETRANCE
MLH1 APC BRCA1 CHEK2
MSH2 MUTYH BRCA2 ATM
MSH6 SMAD4 TP53 NBN
PMS2 BMPR1A PALB2 BARD1
PTEN CDKN2A BRIP1
POLE

Table adapted from Stoffel, 20201

  • An increased risk for CRC is linked to germline variants in several genes1
  • Up to 10% of patients with CRC have germline variants in genes that have been linked to moderate or high cancer risk1

Pathogenesis: Genetic and Epigenetic Events2

Graphic flowchart illustrating genetic and epigenetic events involved in development of colorectal cancer. The graphic is split into three main pathways. These three pathways are the adenoma-carcinoma, also known as the conventional pathway, the serrated neoplasia pathway, and microsatellite instability.
  • Adenoma-carcinoma, or the conventional pathway, accounts for 70-90% of CRC cases, which can develop sporadically or due to familial adenomatous polyposis2
  • The serrated neoplasia pathway accounts for 10-20% of cases, while microsatellite instability is related to 2-7% of CRC cases2
  • Learn more about the pathobiology of CRC

Related Topics

Footnotes

  1. Pie charts do not consistently add to 100%.1

List of definitions

APC: adenomatous polyposis coli; ATM: ataxia telangiectasia mutated; BARD1: BRCA1-associated RING domain 1; BMPR1A: bone morphogenetic protein receptor, type IA; BRAF: B-Raf proto-oncogene serine/threonine kinase; BRCA1/2: breast cancer gene 1/2; BRIP1: BRCA1-interacting protein 1; CDKN2A: cyclin-dependent kinase inhibitor 2A; CHEK2: checkpoint kinase 2; CIMP: CpG island methylator phenotype; CRC: colorectal cancer; FAP: familial adenomatous polyposis; KRAS: Kirsten rat sarcoma viral oncogene homolog; MGMT: methyl-guanine-DNA-methyltransferase; MLH1/3: MutL homolog 1/3; MMR: mismatch repair; MSH2/6: Mut S homolog 2/6; MUTYH: mutY DNA glycosylase; NBN: Nibrin; PALB2: partner and localizer of BRCA2; PMS2/6: postmeiotic segregation increased 2/6; POLE: DNA polymerase epsilon, catalytic subunit; PTEN: phosphatase and tensin homolog; SMAD4: SMAD family member 4; TP53: tumor protein p53.


References

  1. Stoffel, EM, Murphy CC. Epidemiology and mechanisms of the increasing incidence of colon and rectal cancers in young adults. Gastroenterol. 2020;158:341-353.
  2. Dekker E, Tanis PJ, Vleugels J, et al. Colorectal cancer. Lancet. 2019;394:1467-1480.