Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors

Abstract

ediatric cancer is rare, with fewer than 10,000 solid tumors diagnosed in children annually in the United States 1. Previous studies interrogating germline predisposition broadly across pediatric cancer types have found heritable germline predisposition in 8-12% of patients. The yield of germline predisposition detected is dependent on the genes included for analysis and variant interpretation as well as the ascertainment biases found in each cohort. Iterative data are required to expand upon the understanding of susceptibility to pediatric cancer and determine the extent to which germline data may translate into clinical practice 2-7. Certain pediatric cancer diagnoses have well-established associations with germline mutations in specific genes and should automatically prompt clinical suspicion of a cancer predisposition, for example, retinoblastoma (RB1), pleuropulmonary blastoma (DICER1), optic pathway glioma (NF1), atypical teratoid/rhabdoid tumors (SMARCB1), small cell hypercalcemic ovarian tumors (SMARCA4), adrenal cortical tumors (TP53) and hypodiploid acute lymphoblastic leukemia (TP53) 8-10. Germline testing can also be critical for distinguishing between conditions like neurofibromatosis type 1 (NF1) and constitutional mismatch repair deficiency (CMMRD), which can be phenocopies of each other. For example, a child presenting with numerous café au lait spots and leukemia may have either of these conditions, but treatment and screening recommendations for the proband and family members will differ depending on the germline diagnosis 11. Besides the known associations of causal germline mutations, broad tumor-normal sequencing has revealed novel associations 9,12. While some of these findings likely represent population detection and do not play a role in the pathogenesis of the cancer in question 13 , other novel associations are likely causal. Population detection

Germline Predisposition to Pediatric Cancer, from Next Generation Sequencing to Medical Care

“…The results obtained were consistent with previously published data [4][5][6]. Recent results from the MSK-IMPACT cohort also pointed the same way [46]. New predisposition genes have been described in the last two years [12] and these genes were not included in the panel; therefore, the figure presented might be considered conservative.…”

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor

“…In our high-risk pediatric cohort, 22% of participants had at least one P/LP germline autosomal dominant or recessive variant, similar to rates seen in other cohorts. 2 , 20 - 22 Four major conclusions from our study emerged: (1) Germline variants are likely to be included in tumor-only sequencing reports, (2) some therapeutic recommendations may be made in reference to germline variants, (3) germline P/LP variants of clinical significance may be missed by tumor-only sequencing because of filtering on the basis of population frequency or masked by copy-number alterations; and (4) patients may be unnecessarily notified of a potential hereditary risk related to a finding that ultimately turns out not to be germline.…”

Companion Tumor Sequencing to Assess the Clinical Significance of Germline Sequencing in Children With Cancer

“…In contrast, only 1 of 18 (5.5%) hmGPVs in nonassociated tumors had a second hit in the tumor (difference, 85.6%; 95% CI, 62.1%-92.6%; P < .001) ( Figure ). 2 …”

“…In contrast, only 1 of 18 (5.5%) hmGPVs in nonassociated tumors had a second hit in the tumor (difference, 85.6%; 95% CI, 62.1%-92.6%; P < .001) (Figure). 2 Of 22 RB1-associated tumors with an RB1 GPV that had available zygosity information, 20 had second hit. In contrast, none of 3 cases in non-RB1-associated tumor types had second hits (although the RB1 GPVs likely played a role in the preceding bilateral retinoblastomas that were not tested).…”

“…We used tumor zygosity of hmGPVs in tumor suppressor genes (TSG) to ascertain whether hmGPVs are associated with tumorigenesis. We used germline and zygosity data from 2 recent prospectively matched tumor-normal panel-based germline testing studies: IMPACT in 751 pediatric patients with solid tumors (n = 99 hmGPVs) 2 and Mi-ONCOSEQ in 1015 adult metastatic tumors (n = 129 hmGPVs). 3 Zygosity of hmGPVs was determined using loss of heterozygosity (LOH) or a second coding sequence somatic hit.…”