<i>BRCA1/2</i> germline sequencing in children and adolescents with cancer: it is the context that matters

In this issue of the Journal, Li et al.1 employed a methodologically robust probabilistic approach that used segregation analysis from family pedigrees to provide further compelling evidence arguing against an elevated non–breast cancer risk in the first 3 decades of life in individuals with heterozygous BRCA1/2 germline pathogenic variants. Li et al. collated general cancer information and germline BRCA1/2 status (confirmed positive or negative or untested) from 47 117 individuals (3086 families) with at least 1 ascertained individual with a BRCA1/2 germline pathogenic variant. Primary cancers were reported in 274 individuals younger than 30 years of age, most of which were breast cancers specifically diagnosed in the third decade of life (relative risk of 11.4 and 5.2 for developing breast cancer in BRCA1 carriers and BRCA2 carriers aged 20-29 years, respectively). Results from the study by Li et al.1 showing no evidence of an elevated cancer risk in children and adolescents are aligned with previous epidemiological research and do not contradict the observation that adult-onset cancer-predisposing genes (especially genes involved in DNA repair) are among the most prevalent germline findings in children with cancer who undergo extensive DNA sequencing.2,3 Research incorporating molecular tumor analyses on children with cancer and germline pathogenic variants in BRCA1/2 have invariably demonstrated a lack of a classic “second hit” in BRCA1/2 (eg, loss of heterozygosity), which further argues against a primary cancer driver effect of the germline pathogenic variant.4,5 Even after 30 years, the question of haploinsufficiency and the resulting cellular phenotype in BRCA1/2 heterozygotes remains unclear, although recent data suggest that in certain tissue types, it is associated with excess accumulation of mutational events.6-8 In agreement with this finding, Villani et al.5 showed functional evidence for homologous recombination deficiency in a proportion of tumors in children with heterozygous BRCA1/2 germline pathogenic variants without classic second somatic hits in BRCA1/2, leading the researchers to consider other mechanisms driving genomic instability. In addition, epidemiological studies highlighting increased frequencies of BRCA1/2 germline pathogenic variants in pediatric cancer survivors who develop subsequent malignancies have led to generalized concern about the possibility of incremental toxicity from chemotherapy and radiation in individuals with germline pathogenic variants in DNA repair genes.9,10 Li et al.1 sum up their study results arguing against an increased cancer risk in children and adolescents with heterozygous BRCA1/2 germline pathogenic variants with 3 practical management recommendations: Cancer surveillance and risk-reducing measures should not be recommended in children and adolescents with a heterozygous BRCA1/2 germline pathogenic variants. This recommendation is largely uncontroversial.11 Presymptomatic testing in healthy pediatric (<18 years of age) offspring of a BRCA1/2 carrier is not advisable from a medical, ethical, or social standpoint.3,12 This recommendation aligns with numerous genetic screening guidelines and is rarely the subject of debate among clinicians.13 Nevertheless, there is recent advocacy for flexibility and co-decision-making with families regarding counseling and appropriate timing of predictive testing for adult-onset conditions in adolescents.14 One could also argue that, from the individual patient and collective health services perspectives, allowing for a certain level of flexibility for earlier timing of counseling or testing may help alleviate stressors related to this sense of “urgency” for genetic evaluation. The findings do not support BRCA1/2 germline testing in children or adolescents with cancer. As a pediatric oncologist involved in clinical and research precision oncology initiatives as well as in the management of individuals with cancer predisposition syndromes, I consider it important to approach Li et al.’s recommendation in a practical manner that mirrors what is happening in many oncology settings. From the point of view of cancer risk and causality, it does not seem justified to investigate for a heterozygous BRCA1/2 germline pathogenic variant in children and adolescents with cancer. When establishing priority or targeted germline sequencing strategies in children with cancer (without clinical or cancer features suggesting Fanconi anemia), BRCA1/2 should likely not be part of investigations. Nevertheless, Li et al.1 acknowledge in the final sentence of their article that BRCA1/2 are often included in larger cancer gene panels integrated in precision oncology initiatives.5,15-19 Their statement holds true when reviewing clinical and research germline cancer gene panels from recently published or active pediatric cancer sequencing initiatives.5 The apparently conflicting inclusion of BRCA1/2 reflects the complexities of pediatric oncology care as well as the practical realities of cancer genomics strategies and resources. Why are BRCA1/2 considered for inclusion in pediatric oncology gene panels in the first place? Li et al.1 highlight what is likely to be the leading reason for justifying BRCA1/2 on panels: the possibility of identifying Fanconi anemia related to biallelic germline pathogenic variants in BRCA1/2 and its recognized association with cancer in children, not to mention the therapeutic, screening, and prevention strategies in childhood.20 Once again, it comes down to a question of causality and subsequent timely interventions, 2 widely and historically acceptable reasons for considering gene inclusion. In the world of precision oncology, the process of gene selection and ongoing justification for inclusion in panels considers various perspectives of medical actionability, often translating into concerns about missing opportunities for optimal patient management. To summarize, increased cancer risk and causality between heterozygous BRCA1/2 germline pathogenic variants and pediatric-onset cancer has essentially been refuted. Predictive testing and cancer screening interventions are classically not recommended in healthy pediatric individuals, but BRCA1/2 germline pathogenic variants are identified in children and adolescents with cancer (and even more so in survivors who developed subsequent malignancies). Why? Because we are searching for them. Why are we searching for them? Because of this “fear of missing out” on (1) the rare diagnosis of Fanconi anemia, (2) the rare situation where there may be a plausible association between a heterozygous BRCA1/2 germline pathogenic variant and the oncological phenotype (eg, finding a BRCA2 germline pathogenic variant in an older adolescent with a sarcoma), (3) the opportunity for clinical trial eligibility, (4) the therapeutic option in the event of functional evidence for homologous recombination repair deficiency, and (5) the opportunity to tailor therapies and survivorship care based on the concern for incremental deleterious effects of genotoxic agents in individuals with germline pathogenic variants in BRCA1/2 and other DNA-repair genes. Combined, these elements form the ongoing rationale for BRCA1/2 gene inclusion in panels, especially when one considers the practical challenges of developing gene lists, analysis pipelines, and interpretation frameworks that are applicable to heterogeneous populations and indications. The ultimate consideration for including genes in any panel is the potential to save lives through timely diagnosis, therapeutic interventions, cancer screening, and cancer risk-reducing strategies. Most will agree that the knowledge of a heterozygous BRCA1/2 germline pathogenic variant does not save the child’s life at that particular time point and may instead create added stressors to an already-vulnerable individual. Nevertheless, such a finding may be lifesaving for a young parent identified as carrying a germline pathogenic variant in BRCA1/2 through cascade testing. This consideration alone is not enough to justify inclusion of BRCA1/2 in precision oncology gene panels, but it is a predominant factor that makes clinicians anxious to disclose such results to patients and families. The moral concern of wanting “to rescue” and the concern of being held liable for not communicating BRCA1/2 germline pathogenic variants haunts many clinicians and researchers. BRCA1/2 have historically been among the ethically problematic incidental/secondary germline findings in children and represent a growing category of genes that, in the heterozygous state, are currently understood to have no medical actionability in healthy children and do not cause pediatric cancer (eg, PALB2, ATM, BLM). In the oncologist’s mindset, the decision to justify inclusion or exclusion of such genes when investigating children with cancer is not uniquely a matter of cancer risk and causality. Rather, it is a practical matter of actionability, with the acknowledgement of the potential benefits and harms of disclosing such information. Thus, Li et al.1 have convincingly demonstrated that BRCA1/2 germline pathogenic variants do not substantially increase cancer risk in children and adolescents. Nevertheless, genetic testing of children with cancer for BRCA1/2 germline pathogenic variants could be justified: it all depends on the context. The most pressing context is that genetic testing is increasingly being ordered by clinicians who have little expertise in genetics. In the era of mainstream genetic testing in oncology, education and training of oncologists in some of the clinical, ethical, and practical aspects of genetic testing raised in this editorial are of paramount importance. I thank Lara Reichman, MSc (C)CGC, Leah Hammond, MSc CGC, and Laura Palma, MSc (C)CGC, genetic counselors at the McGill University Health Centre (MUHC), Montreal Children’s Hospital and Research Institute of the MUHC, for their helpful comments on the original draft of this manuscript. I also thank Dr William Foulkes, MBBS PhD (MUHC), for his invaluable insight into this complex topic and for his constructive comments on this manuscript. Catherine Goudie, MD, MSc (Conceptualization; Writing—original draft; Writing—review & editing). No funding was use for this editorial. C.G. has no disclosures. No new data were generated or analyzed for this editorial.

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