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Cancer Predisposition Variants Increase Secondary Cancer Mortality Risk in Pediatric Survivors

NEW YORK – Childhood cancer survivors who carry cancer susceptibility variants are at increased risk of mortality from secondary cancers that occur five years or more after an initial pediatric cancer diagnosis, according to new research from a St. Jude Children's Research Hospital-led team.

"Cancer treatments (e.g., radiotherapy and chemotherapy) play a substantial role in the excessive risk of subsequent malignant neoplasms observed among individuals who are alive for at least five years after diagnosis of childhood cancer," senior and corresponding author Zhaoming Wang, an epidemiology and cancer control researcher at St. Jude, and his coauthors wrote in Lancet Oncology on Monday.

Using retrospective germline exome sequence or whole-genome sequence data from nearly 12,500 pediatric cancer survivors from the Childhood Cancer Survivor Study (CCSS) and the St. Jude Lifetime Cohort (SJLIFE), Wang and colleagues at St. Jude and elsewhere searched for cancer susceptibility variants spanning 60 genes linked to autosomal-dominant cancer predisposition syndromes.

When the team set these genetic profiles against prospectively collected outcome data for the participants, it saw ties between cancer predisposition variants and secondary cancer-related deaths over up to 16.6 years of follow-up. The findings expand on prior research pointing to higher-than-usual risk of secondary cancer development in childhood cancer survivors carrying cancer predisposition-related pathogenic germline variants.

"We have previously studied and reported that pathogenic germline variants confer increased risk for developing subsequent cancers (e.g., breast cancer, thyroid cancer) among survivors of childhood cancer," Wang said in an email. "With the latest findings, we demonstrated that carriers of these same pathogenic germline variants would more likely develop deadly second cancers, further highlighting the importance of genetic counseling and potential clinical genetic testing in the high-risk population."

In 8,067 individuals from the CCSS cohort followed for 2.2 to 16.6 years, the investigators tracked down cancer susceptibility variants in 347 individuals, representing just more than 4 percent of participants in that study. The secondary cancer-related mortality rate was 6.9 percent among CCSS participants carrying cancer predisposition variants, as compared to 2.1 percent in non-carrier participants from CCSS.

Similar patterns turned up in the SJLIFE cohort, in which 294 individuals, or 6.7 percent, carried known cancer risk variants. Again, secondary cancer-linked deaths in the carrier group exceeded those documented in non-carriers, coming in at 3.7 percent versus 1.5 percent, respectively, during 3.1 to 9.4 years of follow-up.

The authors noted that a larger proportion of SJLIFE participants carried cancer predisposition variants compared to the CCSS cohort, potentially due to differences in the tumor types diagnosed in participants and clinical trials performed at St. Jude Children's Research Hospital.

While the association between secondary cancer mortality and genetic predisposition to cancer was independent of participants' genetic ancestry, sex, and other factors, the sharp increase in secondary cancer mortality rates was most pronounced among individuals who received lower levels of chest radiotherapy during pediatric cancer treatment.

"It is possible that a high dose of radiotherapy might obfuscate the cancer predisposing variant effect on risk of developing subsequent malignant neoplasms and hence subsequent malignant neoplasm-related mortality," the authors suggested, "although in post hoc analyses we found that the estimated subdistribution [hazard ratio] was not significantly different between those with a high dose of radiotherapy and those with no or a low dose of radiotherapy."

Overall, the researchers documented 219 secondary cancer-related cancer deaths in the CCSS cohort and 263 secondary cancer-related deaths in individuals enrolled in SJLIFE. By contrast, there were 323 and 103 non-cancer-related deaths in the CCSS and SJLIFE cohorts, respectively.

Based on these findings, the authors said childhood cancer patients and survivors may benefit from clinical genetic testing for germline cancer susceptibility variants, coupled with genetics-informed cancer surveillance and genetic counseling to inform risk variant carriers of their increased secondary cancer risk.

"Survivors of childhood cancer can take actions by seeking genetic counseling, participating in genetic testing, and following personalized cancer screening and prevention strategies based on genetic testing results and guidance by healthcare providers," Wang added in an email. "In addition, clinicians treating childhood cancer patients may also utilize the genetic information for cancer predisposition, if available, to tailor the treatment plan to attain the goals of curing cancers while mitigating risk of second cancers."