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Higher Early-Onset Cancer Risk Among Minorities Spurs Hunt for Genetic, Environmental Factors


NEW YORK – After discovering a higher risk of early-onset cancers among racial minority groups in California, researchers are trying to pin down the inherited genetic and environmental factors that may be contributing to this increased disease predisposition.

In a study published recently in the journal eLife Sciences, researchers at the University of Southern California and elsewhere found that the relative risk of developing cancer before age 26 for mothers and siblings of patients with early-onset cancers was significantly higher in the state among those who identified as Latino, Black, or Asian/Pacific Islander than it was among non-Latino white people.

The study's authors, including USC's Joseph Wiemels, suspect that the higher degree of familial-based clustering among minority patient populations compared to non-Latino white populations may be due to a higher prevalence of inherited cancer risk mutations and shared environmental factors. Unfortunately, because large-scale studies of genetic cancer predispositions have historically focused on patients of European ancestry, there isn't much evidence to support that hypothesis.

This has been a long-standing challenge for the field of cancer genetics. In breast cancer, for example, a dearth of diversity in genomic datasets has resulted in far less knowledge about breast cancer susceptibility genes in Black versus white patients.

"This higher risk identified in relation to the family units in US minorities has not been systematically studied," wrote Wiemels and colleagues. "Our results here beg for an analysis of comparative sources of genetic and environmental risk that contribute to the higher risk and familial clustering of certain cancers in Latinos, Blacks, and Asian/Pacific Islanders."

To conduct their study, Wiemels and colleagues used data from the California Cancer Registry and the California Birth Statistical Master File, which allowed them to capture all early-onset cancer diagnoses in California between 1989 and 2015. The dataset included 121,571 individuals, including 29,249 patients across all race and ethnicity groups diagnosed with cancer before their 26th birthday and over 62,000 healthy family members. These patients' first-degree relatives, including 112 siblings and 65 mothers diagnosed with early-onset cancers, were also included, as were 387 patients diagnosed with second primary cancers following their initial early-onset cancer diagnoses.

As expected, the researchers found that cancer risks were elevated among all mothers and siblings of patients diagnosed with cancers writ large. Analyzing the data by cancer type and by race and ethnicity, though, these relative risks were elevated in certain groups. For solid cancers, for instance, including central nervous system tumors, neuroblastomas, retinoblastomas, renal tumors, and sarcomas, among others, the standardized incidence ratio — a statistical score that the researchers used to calculate cancer risks in the subpopulations — was 4.98 for Latino mothers and siblings of patients with early-onset cancers and 7.35 for Black mothers and siblings of patients with early-onset cancers, as compared to 3.02 for non-Latino white mothers and siblings of patients with early-onset cancers.

For hematologic cancers, the standardized incidence ratio for Asian/Pacific Islander mothers or siblings of patients with early-onset cancers was 7.56 versus 2.59 among non-Latino whites. The risk of developing a second primary malignancy (as opposed to a recurrence of the same cancer) was also higher among Asian/Pacific Islander patients with early-onset cancers compared to non-Latino white patients.

While the eLife Sciences paper focused on characterizing the increased relative risks and did not delve into the specific genetic mutations that could be potentially driving this higher cancer predisposition, Wiemels and colleagues are actively working on this using exome sequencing.

"We designed the study originally to have the capability of finding the genes [that are mutated]," he said, explaining that the choice to include the entire state of California beginning with those born in the late 80s was deliberate. "The reason we used those dates is that we can get neonatal blood samples for every child born in California for research purposes."

Indeed, California's Newborn Screening Program requires that all children born in the state have blood drawn and tested for more than 80 different genetic or congenital disorders. The California Department of Public Health retains the samples, which are deidentified but linked to self-reported race and ethnicity data for use in the exact type of research Wiemels and his team are now pursuing. "We actually have the capability of sequencing every single child in every single one of these families where we have the family predisposition," he said, adding that another advantage of pursuing this research in California is that the population is incredibly diverse.

So far, using these samples, the researchers have conducted genomic analyses on about 80 families with members diagnosed with concordant hematologic malignancies, including leukemia, which, according to Wiemels, is highly prevalent among Latino children in Los Angeles County.

Using exome sequencing, he explained, his team is trying to identify genetic mutations that are shared within families and increase cancer risk for those who inherit them. "We're trying to find a smoking gun," Wiemels said. There are some cases in which the "smoking gun" is obvious from the sequencing results, but in many cases, Wiemels said, the search is more complicated.

"The problem is that there are so many genetic differences to sort through, and in some families, there might be pairs of genes shared," he said, explaining how in the ongoing study his team is taking a stepwise approach to tackling this challenge. "We start by looking at the 40 genes that are the main players in childhood cancers that we already know about. … Then, if we don't find it there, we expand it to 200 genes, and after that, there's a list of 1,200 genes. … If we're still not pulling up a smoking gun, we'll look over the whole genome."

The research team decided to start with exome sequencing and only upgrade to WGS if the search for a genetic predisposition turned up empty because exome sequencing is "much more interpretable," in Wiemels' view.

"The problem with sequencing the whole genome is that there are so many genetic variations within the vast amount of DNA, and not all the regulatory regions of the genome have been described yet," he said. "If we just look at everything at the same time, we have too many genetic differences to consider."

Within this same population of families included in the sequencing analysis — the results from which Wiemels expects to publish by year's end — the researchers are also looking for common risk alleles that may only confer a slightly higher cancer risk on their own, but when grouped together in a polygenic risk score might be significantly informative of cancer risk. Additionally, Wiemels' team hopes to expand beyond their current focus on hematologic malignancies into solid cancers, contingent on funding. They'll also take a closer look at individuals who are multiethnic or multiracial, such as Latino individuals with diverse ancestries, and pinpoint the ethnic origin of the mutation using the haplotype structure of the genome.

Ultimately, the significant increase in inherited risk of early-onset cancers among minority patient populations, according to Wiemels and colleagues, should be somewhat of a call to action for further research classifying the contributing factors. Genetics may only be part of the story, he noted; environmental factors like exposure to air pollutants, pesticides, solvents, ionizing radiation, and dietary influences might be higher among these populations and shared within families.

The ideal study that Wiemels hopes to conduct is one that looks at environmental risk and genetic risk at the same time in the same population and calculates how much of the cancer burden is attributed to each of those factors or both. Here, too, the California Newborn Screening Program will prove useful. Already, Wiemels and colleagues are starting to perform tests on the blood spots using mass spectrometry and metabolomics to assess chemicals and small molecules present in the blood.

Beyond the hope that their study will spur future research, Wiemels said he'd also like to see genetic counseling services and risk mitigation strategies expanded among minority patient populations. Ensuring access to genetic counseling services for these populations is particularly critical given recently reported racial and ethnic gaps in genetic counseling access. Toward this end, Wiemels has been working with a genetic counselor who predominantly counsels Latino families, informing her of the increased cancer risks identified in this study, so she can share them with patients.

"But genetic counselors don't talk about environmental burden much at all," Wiemels said. "What I'd like this work to do is really pin down the relative contribution of the genetic susceptibility alleles and the environmental triggers … to be able to identify who is particularly susceptible ahead of time." With this knowledge, Wiemels said, someone with a known vulnerability based on germline genetics could "pay special attention" to choosing their living environments, products, and occupations.