1. Some CHEK2 alleles were shown to have a high-risk association of breast cancer compared to other alleles that were deemed low-risk or compared to wild-type CHEK2
2. CHEK2 pathological variants were shown to be statistically associated with other cancers such as kidney and thyroid
Evidence Rating Level: 2 (Good)
Study Rundown: The CHEK2 gene and its associated product, CHK2 protein kinase, has been found to be a tumor suppressor through its activity in DNA damage repair. Certain pathologic variants (PVs) of CHEK2, such as variant c.1100del which is a loss-of-function variant have been shown to be associated with breast cancer, whereas missense variants like p.I157T, p.S428F, and p.T476M have had mixed association with breast cancer. This current study looked at patients with CHEK2 PVs and compared them with those that had wild-type CHEK2. They found that CHEK2 PVs were mostly associated with women of Caucasian descent, of which a large percentage were found to have breast cancer. Certain PV such as c.444+1G>A, ex8_9del, p.R117G, and c.1100del were shown to have a high-risk association of breast cancer compared to other alleles (p.I157T, p.S428F, and p.T476M) that were deemed low-risk or compared to wild-type CHEK2. Other cancers were also implicated in their association with CHEK2 PVs. The median age of diagnosis in certain cancers were also younger in those with certain PVs compared to wild-type or other PVs. Strengths of this study included the robust genetic testing available at this single center, and the large sample size. Limitations to this study included a population that was lacking diversity, as well as its observational nature. Overall, furthering our understanding of CHEK2 PVs can help guide clinical and genetic risk assessments for patients affected by those mutations.
Click to read the study in JAMA Oncology
Relevant Reading: Structure and Activation Mechanism of the CHK2 DNA Damage Checkpoint Kinase
In-Depth [retrospective cohort]: This study compared patients with CHEK2 PVs (3,783) found on genetic testing at a single laboratory between 2012 to 2019, against patients with CHEK2 wild-type (n = 33,034) and investigated further associations with cancer panel testing. In general, 74.5% of individuals with CHEK2 PVs had cancer. 91.8% of individuals were female, out of which 63.4% of females had breast cancer. Breast cancer was most prevalent in the following PVs compared to wild-type; c.444+1G>A (OR 2.63, 95% 1.59-4.35), ex8_9del (OR 2.36, 95% 1.53-3.64), p.R117G (OR 1.65, 95% 1.12-2.44) and c.1100del (OR 1.76, 95% 1.55-2.00). CHEK2 PVs, especially the c.1100del PV, were also associated with kidney cancer (OR 2.57, 95%CI 1.75-3.68) and thyroid cancer (OR 1.63, 95%CI 1.26-2.08) compared with wild-type. It was also found that biallelic CHEK2 PV had a younger age of any cancer diagnosis (median 37 vs 47 years of age, p<0.001) compared to monoallelic PV. While the following CHEK2 PV did not have any significant difference in frequencies of any cancer compared to wild-type, they were associated with decreased levels of cancer when compared to other PVs; p.I157T (OR 0.66, 95%CI 0.56-0.78) and p.S428F (OR 0.5, 95%CI 0.39-0.65), with p.T467 showing non-significant decrease. Overall, the findings of this paper suggest that future genetic and clinical counselling may be informative for patients who are found to have CHEK2 PVs.
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