Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar

Abstract

Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children’s risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children’s engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

Introduction

With continued identification of genetic contributors to cancer risk, there is growing complementary interest in deciding who might benefit from receiving this information and how genetic risk information is best communicated to these individuals (McBride, Bowen, et al., 2010; Wiens, Wilson, Honeywell, & Etchegary, 2013). The pediatric population (i.e., children and youth under age 18) is one group that has been intensely debated in this arena (Clayton et al., 2014; Janvier & Farlow, 2014; Levenson, 2017). Predispositional genetic test results could provide information on whether a child is at-risk for one or more health conditions in the future. Many of the potential concerns and benefits about predispositional testing in minors have been discussed in the bioethics literature (Bush, 2014; Robertson & Savulescu, 2001). Cited concerns about providing genetic information to children and families include the potential that genetic risk information adversely affects psychological adjustment, parenting and other family interactions, and social outcomes such as stigmatization. On the other hand, potential benefits to providing pediatric genetic risk information include more informed and effective medical management that leads to improved health outcomes for children, relief from uncertainty, and increased ability for future planning (e.g., healthcare planning and decisions, family planning) (Ross, Saal, David, & Anderson, 2013). Systematic reviews of the psychosocial impact of carrier and predictive testing on children (e.g., Huntington disease, familial adenomatous polyposis) indicate that children who undergo genetic testing do not suffer significant clinical harms in terms of their sociobehavioral functioning, self-perception, and well-being (Wade, Wilfond, & McBride, 2010; Wakefield et al., 2016). However, the authors of both reviews cautioned that additional research is needed in this area (i.e., including other populations, larger samples, longitudinal study designs) before more definitive conclusions can be drawn.

Multiple guidelines, including the guideline on pediatric genetic testing created jointly by the American College of Medical Genetics and Genomics and the American Academy of Pediatrics (Ross et al., 2013), recommend that clinicians approach pediatric predispositional testing with families cautiously and with the best interest of the child in mind. The guideline notes that predispositional genetic testing for minors can be appropriate if preventive services exist that mitigate children’s risk for or severity of the health condition of focus. There are some examples of pediatric predispositional testing for early-onset cancer, such as for familial adenomatous polyposis and retinoblastoma (Leoz, Carballal, Moreira, Ocana, & Balaguer, 2015; Rao, Rothman, & Nichols, 2008). In these cases, testing can be useful because risk prevention measures, particularly medical interventions (e.g., routine screening through colonoscopies and/or preventive surgery in the case of familial adenomatous polyposis), can occur in childhood (Syngal et al., 2015)). However, there are fewer examples of the potential application of predispositional testing and associated risk communication for adult-onset disease that require implementation of self-care behaviors in childhood (Tarini, Tercyak, & Wilfond, 2011).

The goal of the current paper is to illustrate the rationale for and potential application of genetic risk communication about adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. Specifically, we apply understanding of hereditary melanoma risk communication among adults to propose strategies for predispositional testing and risk communication to children and adolescents who are at high risk for melanoma as determined through CDKN2A/p16 testing.

Melanoma and Its Relevance to Pediatric Populations

Melanoma is the most deadly form of skin cancer, and with over 1,000,000 people in the United States with a diagnosis and more than 100,000 new diagnoses in Europe each year, the increasing prevalence of melanoma is contributing significantly to morbidity and healthcare costs (Ferlay et al., 2013; Guy & Ekwueme, 2011; Howlader et al., 2015). While the incidence of many cancers is decreasing, the incidence of melanoma is increasing with much of the increase in incidence occurring in women under 44 and in young women (Little & Eide, 2012; Siegel, Miller, & Jemal, 2015; Wong, Harris, Rodriguez-Galindo, & Johnson, 2013). Modifiable environmental risk factors for melanoma, such as ultraviolet radiation (UVR) exposure and severe sunburns, date back to childhood (Dennis et al., 2008; Oliveria, Saraiya, Geller, Heneghan, & Jorgensen, 2006; Pustisek, Sikanic-Dugic, Hirsl-Hecej, & Domljan, 2010; S. Wu, Han, Laden, & Qureshi, 2014). Preventive measures which could be implemented in childhood include sun protection through the use of sunscreen and protective clothing) and limiting UVR exposure during peak hours (10 am – 4 pm). Childhood is also an ideal period in the lifespan to target such modifiable behavioral and environmental risks, owing to the influence of protective role models in children’s lives, less life experience, and malleable behavioral profiles (Balk, 2011; Florell et al., 2005; Green, Wallingford, & McBride, 2011; Yagerman & Marghoob, 2013). At the same time, childhood is an important period during which to intervene on preventive behaviors because of the challenges associated with maintaining behaviors such as sun protection as children age and experience age-specific and environmental barriers (e.g., underestimation of risk for melanoma, desire to be tan, lack of shade available) (McLoone et al., 2014; Reeder, Jopson, & Gray, 2012; Turner, Harrison, Buettner, & Nowak, 2014).

Familial Melanoma and Risk Assessment

Familial melanomas account for approximately 5–10% of melanoma cases. An unaffected individual’s risk for melanoma can range depending on their age and family history (e.g., number of affected relatives, their relation to affected family members) (Table 1). Many factors may contribute to familial melanoma risk including shared phenotypic features associated with melanoma risk (ex. fair skin, red hair, freckles, dysplastic nevi), shared UV exposure, and underlying genetic predisposition. Having a first degree relative with melanoma is associated with approximately a 2-fold increase in risk (Ford et al., 1995) while rare families with mutations in the CDKN2A/p16 gene have been estimated to have a 28–76% lifetime risk for melanoma (Begg et al., 2005; Bishop et al., 2002; van der Rhee et al., 2011). Melanoma risk assessment for unaffected family members will generally be based on their family history and phenotype. However, for families with three or more cases of melanoma on the same side of the family, genetic testing can be part of risk assessment by clarifying which family members have inherited the risk-conferring mutation (Leachman et al., 2009).

Table 1.

Risk for melanoma among unaffected individuals

Population	Risk for Melanoma or Incidence Rate
General population (overall)	Lifetime risk: 2.1% (Howlader et al., 2015)
Adolescent and young adults (15–39 years old)	Male incidence rates: 1.4 to 11.1 depending on age (Weir et al., 2011)
	Female incidence rates: 2.2 to 15.8 depending on age (Weir et al., 2011)
Any family history of melanoma	Relative risk: 1.74 (Gandini et al., 2005)
At least 1 affected first-degree relative	Relative risk: 2.24 (Ford et al., 1995)
CDKN2A/p16 carrier	Lifetime risk (by 80 years of age): 28% – 67% (Begg et al., 2005; Bishop et al., 2002)

Hereditary Melanoma Risk Communication with Adult Populations

Adults at elevated risk for melanoma demonstrate suboptimal engagement in recommended preventive behaviors (Azzarello, Dessureault, & Jacobsen, 2006; Bergenmar & Brandberg, 2001; Diao & Lee, 2013; Geller et al., 2003; Manne et al., 2011). For example, only 28%-54% of adults with a first-degree relative with melanoma practices recommended photoprotection behaviors (Azzarello et al., 2006; Geller et al., 2003). As a result, a number of interventions to improve adults’ engagement in melanoma preventive behaviors have been tested with individuals at risk for melanoma due to family history (Y. P. Wu, Aspinwall, Conn, et al., 2016). These interventions have typically included education on the individual’s elevated risk for melanoma. For example, some interventions have targeted unaffected individuals who have a first-degree relative with a history of melanoma (Geller, Emmons, et al., 2006; Manne et al., 2010). In one randomized trial, unaffected family members received information on their skin cancer risk and recommended preventive behaviors tailored to their personal risk characteristics, demographic characteristics (e.g., age, gender), and reported barriers to implementing preventive behaviors. Individuals in a comparison group received the same educational information but not tailored to their responses and risk profile. The tailored intervention led to improvements in sun protection and total body skin exam (TBSE) behaviors assessed 12 months later, but no changes in self-skin exam (SEE) frequency when compared with the untailored intervention participants (Manne et al., 2010).

Other studies examining the impact of melanoma genetic test reporting on preventive behavior adherence have found mixed effects (Aspinwall, Taber, Kohlmann, Leaf, & Leachman, 2014b; Bergenmar, Hansson, & Brandberg, 2009; Glanz et al., 2013; Kasparian, Meiser, Butow, Simpson, & Mann, 2009). For instance, in one study CDKN2A/p16 genetic testing and counseling led to increased implementation of sun protection strategies among unaffected carriers and noncarriers 2 years post-testing. Carriers also demonstrated more frequent and thorough SSE and more frequent TBSE occurrence than unaffected non-carriers (Aspinwall et al., 2014b). However, results of another CDKN2A/p16 testing study indicated that sun protection outcomes did not differ between individuals who received test results and those who declined testing, but carriers reported more frequent TBSEs than those who declined testing (Kasparian et al., 2009).

These studies did not include comparison groups who did not receive genetic counseling and the option of testing, and therefore they could not separate the impact of genetic testing from the overall effects of counseling and education. To address this issue, Aspinwall and colleagues (Taber et al., 2015) employed a unique study design in which unaffected members of families with CDKN2A/p16 mutations were compared to individuals from families with multiple cases of melanoma, but no identifiable genetic cause. Both groups received equivalent information about their melanoma risk and management recommendations, but those who also received a genetic test result were more likely to find the recommendations personally applicable and exhibited less denigration of risk information than those who were counseled only based on family history (Taber et al., 2015). These findings suggest that risk information based on genetic testing may be uniquely prioritized above other types of risk information.

In summary, the literature on adults who are at risk for melanoma suggests that genetic risk communication can impact adherence to melanoma preventive behaviors, and may have unique impacts beyond more general education or risk assessment strategies. However, families that carry mutations in CDKN2A/p16 or other highly penetrant melanoma predisposition genes are rare, and this type of information will only be available to small numbers of people. Testing for other, more common, but less penetrant genetic variants, such as those in MC1R, may not lead to the same benefit (Glanz et al., 2013). Other meta-analyses of studies evaluating the effect of genetic risk communication strategies based on lower penetrance single nucleotide polymorphisms (SNPs) and genetic variants, found limited impact on preventive behaviors such as smoking and diet (Hollands et al., 2016; McBride, Koehly, Sanderson, & Kaphingst, 2010). There may be other factors that affect the impact of genetic risk communication on health behaviors including the associated penetrance, the biological link between the genetic finding and the behavior, strength of evidence supporting the benefits of the preventive behaviors, and the approach for communicating risk and preventive health behavior information. Taken together, these findings suggest that interventions featuring genetic risk information as a motivator for engagement in preventive behaviors may require other behavior change components targeting health behaviors that go beyond provision of risk information alone.

Interventions for Children who Carry a Hereditary Risk for Melanoma

Findings from the few studies with minor children at risk for melanoma due to family history indicate poor adherence to preventive behaviors, a similar pattern to that seen in adult populations. Rates of photoprotection among at-risk children are low (42%) (Geller, Brooks, Colditz, Koh, & Frazier, 2006) and comparable to the general population (Geller et al., 2002). In addition, 39–49% of children experience sunburns (Geller, Brooks, et al., 2006; Glenn, Bastani, Chang, Khanna, & Chen, 2012; Glenn et al., 2015) a primary risk factor for melanoma (Dennis et al., 2008; Pustisek et al., 2010).

In contrast to interventions designed for adults who carry a familial risk for melanoma, there have been few interventions to promote engagement in melanoma preventive behaviors among children who are at risk for the disease due to family history (Y. P. Wu, Aspinwall, Conn, et al., 2016). In the one intervention targeting children who have a parent who had melanoma, families in the treatment group received three sets of standardized mailed materials, including print, multimedia, and interactive (activity book for children) content focused on implementation of melanoma preventive behaviors (Gritz et al., 2013). The intervention led to improvements in children’s sunscreen re-application and wearing of wide-brimmed hats, but did not significantly improve initial sunscreen application, use of long-sleeves and pants, shade-seeking, or sunburn occurrence rate.

Children from families with multiple cases of melanoma are at greatest risk, and also more likely to have a mutation in a high-risk melanoma predisposition gene such as CDKN2A/p16 (Leachman et al., 2009). These children require more intensive and customized interventions than what is typically provided through population-based interventions in order to promote rigorous and long-term adherence to melanoma preventive behaviors. Future interventions seeking to improve high-risk children’s engagement in melanoma preventive behaviors could integrate genetic risk communication (e.g., delivery of developmentally-appropriate CDKN2A/p16 genetic testing reporting and counseling) and behavior change strategies. Encouragingly, the majority (69%) of adults who received CDKN2A/p16 testing in one study expressed interest in melanoma genetic testing for their children and/or grandchildren (Taber, Aspinwall, Kohlmann, Dow, & Leachman, 2010). Participants’ reasons for supporting genetic testing for their own children included facilitating their child’s awareness of their risk for melanoma (70%) and yielding health benefits (45%) such as increased engagement in melanoma preventive behaviors.

Providing genetic risk information could target potential gaps in children’s knowledge about melanoma and preventive strategies and any misperceptions about their melanoma risk (Aspinwall, Taber, Kohlmann, Leaf, & Leachman, 2014a). Education could also describe the mechanisms through which behavioral factors increase risk for melanoma, such as how cumulative UVR exposure creates DNA damage that predisposes individuals to melanoma and that mutations in CDKN2A/p16 limit the effectiveness of DNA repair mechanisms (Y. P. Wu, Aspinwall, Nagelhout, et al., 2016). Such an educational approach is grounded in health behavior theories, such as the Protection Motivation Theory (Rogers, 1975) and theories of how genetic risk information can be presented to emphasize the genetic and environmental interactive factors that lead to disease (Marteau & Weinman, 2006). Risk communication strategies for children and families would likely benefit from employing user-friendly and age-appropriate language for children to facilitate children’s understanding. Together, the genetic risk information and complementary education could serve as foundational knowledge that cues children and their families to take action by implementing melanoma preventive behaviors. Families could then receive counseling on tailored preventive recommendations for minimizing behavioral contributors to melanoma and ways that children can collaborate and share the responsibility for implementing preventive behaviors with their families.

Future educational and other interventions for children at increased risk for melanoma could draw on existing evidence-based strategies that facilitate health behavior change in children and their families. For instance, interventions could incorporate behavioral and organizational strategies that have been successfully applied to medical regimen adherence concerns among children with chronic health conditions such as asthma and type 1 diabetes (Graves, Roberts, Rapoff, & Boyer, 2010; Kahana, Drotar, & Frazier, 2008; Pai & McGrady, 2014). In addition, interventions for children at elevated risk for melanoma could benefit from incorporating elements of prior programs targeting children at population risk for skin cancer (Nahar, 2013; Sandhu et al., 2016). Literature on prior effective health behavior change programs highlights the importance of targeting the entire family system (e.g., both parents and children) (Hilliard, Powell, & Anderson, 2016; Nahar, 2013). Incorporation of both parents and children in intervention programs is essential from a developmental perspective, given that younger children likely require close parental involvement, and as cognitive abilities mature, older children and adolescents will continue to benefit from developmentally-appropriate parental involvement and monitoring (Modi et al., 2012; Rapoff, 2010). In addition, including parents and children in health behavior change interventions can help address family factors that promote or hinder effective health behavior change, such as family functioning, communication, and problem-solving abilities (Modi et al., 2012). As genetic risk communication interventions are developed, additional work will be needed to determine the most effective ways of communicating risk information to children of different ages and cognitive abilities, and to their families.

Conclusions

The current pace of genetic discovery in cancer will yield a growing number of opportunities to provide predispositional genetic risk information to unaffected individuals, including children. In the current paper, we offered initial suggestions on how predispositional genetic risk information could be delivered to children who carry a hereditary risk for melanoma as part of a comprehensive program to improve engagement in melanoma preventive behaviors. Future efforts to determine whether such interventions are safe, effective, and acceptable to children and their families are needed, as well as studies that better understand how children of different ages or developmental levels interpret and understand genetic risk information. If such preventive interventions are effective, children and families will gain understanding of their risk for cancers such as melanoma, as well as the opportunity to implement and sustain engagement in preventive behaviors. In addition, these preventive interventions could eventually be extended to other pediatric populations at risk for hereditary cancers who are identified by new genetic tests as they become available. While melanoma is a striking example of childhood exposure affecting adult disease risk, interventions developed for this population could inform whether childhood risk assessment could be used to motivate other healthy behaviors such as diet, weight management, and tobacco avoidance, which could reduce risk later in life for heart disease, diabetes and other cancers. The ultimate outcome of such efforts is a realization of personalized and translational approaches to cancer prevention.