In a retrospective cohort study reported in JAMA Oncology, Brittany L. Bychkovsky, MD, MSc, and colleagues analyzed the spectrum of cancer phenotypes associated with germline CHEK2 variants. They found that CHEK2 pathogenic variants apart from p.I157T, p.S428F, and p.T476M were associated with similar phenotypes, regardless of variant type.
Study Details
The study included 3,783 participants with CHEK2 pathogenic variants and 33,034 participants with wild-type CHEK2 identified by multigene cancer panel testing between 2012 and 2019 at a single U.S. diagnostic testing laboratory (Ambry Genetics). Individuals with concurrent pathogenic variants in CHEK2 and another gene were excluded from analysis.
Brittany L. Bychkovsky, MD, MSc
Key Findings
Among the 3,783 participants with CHEK2 pathogenic variants, 92% were female, 79% were White, and 75% had cancer; among female participants, 63.4% had breast cancer. The most common monoallelic pathogenic variants were c.1100del (n = 1,252), p.I157T (n = 992), p.S428F (n = 324), and p.T476M (n = 250).
Breast cancer risk was highest among participants with c.444 + 1G>A (odds ratio [OR] = 2.63, P < .001), ex8_9del (OR = 2.36, P < .001), p.R117G (OR = 1.65, P = .01), and c.1100del variants (OR = 1.76, P < .001). Breast cancer risk was lower among those with the more frequent pathogenic variants of p.I157T (OR = 0.66, P < .001), p.S428F (OR = 0.59, P < .001), and p.T476M (OR = 0.74, P = .04) compared with other pathogenic variants. No association of these latter pathogenic variants was observed for nonbreast cancers.
In analysis excluding the frequent lower-risk variants (p.I157T, p.S428F, and p.T476M, accounting for 42% of the total CHEK2 monoallelic pathogenic variant cohort), other CHEK2 pathogenic variants were associated with cancer phenotypes similar to those associated with c.1100del. Participants with the remaining CHEK2 pathogenic variants were at a younger age at their first cancer diagnosis (P < .001), and these participants were at increased risk of breast (OR = 1.83, P < .001), thyroid (OR = 1.63, P < .001), and kidney cancers (OR = 2.57, P < .001) and reduced risk of colorectal cancer (OR = 0.62, P < .001) vs the wild-type cohort.
The investigators concluded, “CHEK2 pathogenic variants, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 pathogenic variants were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 pathogenic variants, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 pathogenic variants.”
Dr. Bychkovsky, of Dana-Farber Cancer Institute, is the corresponding author for the JAMA Oncology article.
Disclosure: For full disclosures of the study articles, visit jamanetwork.com.
