Researchers identified two germline pathogenic variants in checkpoint kinase 2 (CHEK2) that may account for a minority of men diagnosed with testicular germ cell tumors. Men with aberrations in CHEK2 have an increased risk for developing prostate, colorectal, and breast cancer, and this finding could not only help inform these men of their increased risk for later cancers, but also their family members who may harbor the aberration. The study results were recently published in JAMA Oncology.
Scott Tagawa, MD, MS, medical director of the Genitourinary Oncology Program at Weill Cornell Medicine and NewYork-Presbyterian, told Cancer Network that he was “impressed” with the study design. The researchers not only tested their hypothesis in one patient population but repeated it in two additional patient populations. He said the association between CHEK2 aberrations and testicular cancer is “much more” likely to be true because it was shown across three separate groups of patients.
The three cohorts of cases and controls included a discovery, validation, and high-risk group. In the discovery cohort, 20 of 205 cases (9.8%) with testicular germ cell tumors had at least one germline pathogenic variant; a total of 22 different variants were identified. The most common variant was CHEK2 (8 of 22 variants). Among the 8 cases with CHEK2 aberrations, 6 had variants known to lead to complete loss of function, and 2 were heterozygous for CHEK2p.Ile157Thr, a low-penetrance variant. The two variants—loss of function and low penetrance—were assessed separately in each cohort.
Among the cases in the discovery cohort, the loss-of-function CHEK2 variant accounted for 2.9% and the low-penetrance CHEK2 variant accounted for 1.0%, adding up to approximately 4% of men with testicular germ cell tumors. Cases were nearly four times more likely to have a loss-of-function CHEK2 variant than controls (odds ratio [OR], 3.87; 95% CI, 1.65–8.86; P = .006).
In the validation cohort, compared with controls, cases had an increased likelihood of harboring the loss-of-function CHEK2 variant (OR, >1.4; P = .03) and an even greater likelihood of harboring the low-penetrance CHEK2 variant (OR, 3.93; P = .002).
In the high-risk cohort, cases were more than six times more likely than controls to harbor a loss-of-function CHEK2 variant (OR, 6.30; P = .001) and twice as likely to harbor the low-penetrance CHEK2 variant (OR, 2.13; P = .19), although the latter was not statistically significant.
In regards to clinical characteristics, compared with men who had CHEK2 wild-type alleles, men with the loss-of-function CHEK2 variant tended to develop testicular germ cell tumors nearly 6 years earlier and have bilateral disease. Men with the low-penetrance CHEK2 variant also tended to develop disease earlier (1.92 years), but the difference was not statistically significant.
This study alone, Tagawa said, won’t necessarily change the frequency of germline genetic testing for patients with testicular germ cell tumors. “We don’t generally do germline screenings for testis cancer patients,” he said. “Part of that is because there is no difference in survival. We cure almost everyone.”
The study findings will, however, make him pay “even closer” attention to family history and make it part of the conversation. “If one of these men happens to also have a germline CHEK2 alteration, then he’s at higher risk for prostate and colon [cancers],” he said.
Conversely, young cancer-free men with family members who have a CHEK2 aberration may learn he also has the aberration and therefore an increased risk for testicular cancer. “The hope would be that he would be much more aware that if something feels wrong in the testicle, to seek out medical attention rather ignoring it,” Tagawa said.