Germline variants in POLE are associated with early onset mismatch repair deficient colorectal cancer

Colorectal cancer is usually considered a disease of the elderly. However, a small fraction of patients develops colorectal cancer earlier. The aim of our study was to define the frequency of known hereditary colorectal syndromes and to characterise genetic and epigenetic features of early nonhereditary tumors. Thirty-three patients ≤40 years with diagnosis of colorectal cancer and 41 patients with disease at >60 years of age were investigated for MSI, Mismatch Repair proteins expression,KRASandBRAFmutations, hypermethylation, and LINE-1 hypomethylation. Detection of germline mutations was performed in Mismatch Repair,APCandMUTYHgenes. Early onset colorectal cancer showed a high incidence of hereditary forms (18%).KRASmutations were detected in 36% of early nonhereditary tumors. Early onset colorectal cancer disclosed an average number of methylated genes significantly lower when compared to the controls (p=0.02). Finally both of the two groups were highly methylated inESR1,GATA5, andWT1genes and were similar for LINE-1 hypomethylation. The genetic make-up of carcinomas differs from young to elderly patients. Early onset tumors showed more frequently a constitutional defective of Mismatch Repair System and a minor number of methylated genes. Hypermethylation ofESR1,GATA5, andWT1genes suggests possible markers in the earlier diagnosis of colorectal tumorigenesis.

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The Prevalence of Pathogenic or Likely Pathogenic Germline Variants in a Nationwide Cohort of Young Colorectal Cancer Patients Using a Panel of 18 Genes Associated with Colorectal Cancer

Cancers ◽

10.3390/cancers13205094 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5094

Author(s):

Erik Frostberg ◽

Annabeth Høgh Petersen ◽

Anders Bojesen ◽

Hans Bjarke Rahr ◽

Jan Lindebjerg ◽

...

Keyword(s):

Colorectal Cancer ◽

Mismatch Repair ◽

Advanced Disease ◽

Young Patients ◽

Germline Variants ◽

Mmr Genes ◽

Disease Characteristics ◽

Colorectal Cancer Patients ◽

Repair Genes ◽

Generation Sequencing

Introduction: The prevalence of pathogenic or likely pathogenic germline variants (PGV) in colorectal cancer (CRC) in young patients is seen in approximately one in five patients, with the majority of cases having gene variants associated with Lynch syndrome (LS). The primary aim was to describe the prevalence of 18 genes, all associated with hereditary polyposis and CRC, in a nationwide population of young CRC (yCRC) patients, and outline disease characteristics in patients with or without germline variants. Methods: We screened 98 patients aged 18–40 with CRC diagnosed in 2010–2013 for variants in MSH2, MSH6, MLH1, PMS2, EPCAM, APC, MUTYH, SMAD4, BMPR1A, STK11, PTEN, POLE, POLD1, NTHL1, AXIN2, MSH3, GREM1 and RNF43 using Next Generation Sequencing. Comparisons between patients’ characteristics in patients with PGV, and patients without germline variants (NPGV) were analyzed. Results: PGV were detected in twenty-four patients (24.5%), and twenty-one patients (21.1%) had variants in the mismatch repair (MMR) genes associated with LS. Variants in the APC and MUTYH genes were detected in 1% and 4%, respectively. Patients with NPGV had more advanced disease with adverse histopathological features. Conclusion: PGV was detected in one in four yCRC patients, and one in five yCRC patients had disease causing variants in the mismatch repair genes associated with LS.

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