ADVERTISEMENT
The controversial association of CHEK2 pathogenic variants and colorectal cancer susceptibility
Background
Colorectal cancer (CRC) is the third most common cancer worldwide, with an estimated worldwide incidence of approximately 1 100 000 cases and 550 000 CCR associated deaths. Hereditary factors play an important role in CCR risk. Scientific knowledge of genetic susceptibility to gastrointestinal cancers is constantly evolving with identification of new susceptibility genes. Germ line mutations of the cell cycle checkpoint kinase 2 (CHEK2) gene have been associated with a range of cancer types including CCR. CHEK2 gene 1100 delC variant in particular has been implicated as a risk factor for CRC. Considering this association various institutional surveillance guidelines have included periodic colorectal cancer screening strategies for CHEK2 mutation carriers. At our familial cancer risk clinic, all carriers of pathogenic variants are invited to a program of prospective follow up. For the CHEK2 cohort our follow up protocols include colonoscopy surveillance starting at 40 years, or 10 years before first familiar diagnosis, repeated every 3-5 years. Familial data on CCR is critical to decide on individual surveillance programs. The aim of this study was to review CCR incidence in our cohort and to establish the increased risk for CCR in CHEK2 mutation carriers.
Methods
Review of clinical records of patients with CHEK2 pathogenic mutations followed in our familial cancer risk clinic between January 1994 and December 2021.
Results
The CHECK2 cohort includes 81 patients (16 with CHEK2 1100 delC (19.8%). Of these, 76 were females (93.8%), with a mean age of 47 years and the average follow up time was 111 months. Six patients died during follow 4 from cancer related causes and 2 from unrelated causes. In this period, the following cancers were observed: 64 breast cancers, 5 ovarian cancers, 5 papillary thyroid, and 1 each of: CRC, lung cancer, cervical cancer, prostate cancer, pancreatic cancer, chronic myeloid leukaemia and non-Hodgkin lymphoma. The patient with CRC was a 72-year old female with a c.319+2T>A missense CHEK2 variant without a previous diagnosis of cancer.
Conclusions
Although previous studies suggested an increased risk of CRC cancer in CHEK2 mutation carriers, that was not confirmed in our cohort, even after a long follow up. Reasons for this observation may be related with the mean young age of our population (less than 50) and a high prevalence of non CHEK2 gene 1100 delC variants. Prospective follow up is ongoing and a phenotype/ genotype is being explored. Familial data on CCR is critical to decide on individual surveillance programs for individuals diagnosed with a CHEK2 mutation.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
