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Cancer Genomic Analysis Reveals Distinct Features in Tumors From Patients Under 50 Years Old

NEW YORK – Some cancers occurring in individuals under 50 years old may contain specific tumor or microenvironment features that may make them more apt to respond to specific treatment types, according to an Icahn School of Medicine at Mount Sinai team that performed a pan-cancer analysis spanning younger and older cancer patients.

"The findings highlighted key genomic and microenvironment alterations that may be targeted by kinase inhibitors and immunotherapies, presenting possible treatment options for young adult cancer patients," senior and corresponding author Kuan-lin Huang, a genetics and genomic sciences researcher at the Icahn School of Medicine at Mount Sinai, and his colleagues wrote in Cell Reports on Tuesday.

For their analyses, the researchers considered somatic mutation, copy number and chromosomal alterations, DNA methylation, and immune microenvironment features for more than 6,000 cases from 14 cancer types from the Cancer Genome Atlas Project. They also did validation testing on another 127 younger-onset and 515 older-onset cases considered by the International Cancer Genome Consortium.

By comparing features in 1,757 cases diagnosed in individuals under 50 years old with those from 3,608 individuals diagnosed later in life, they narrowed in on driver mutations that appeared to be overrepresented in 18 genes in the cases diagnosed in younger individuals.

"Young adult cancer has increased in incidence worldwide, but its molecular etiologies remain unclear," the authors explained, noting that "[w]hile young adult tumors generally show lower mutation burdens and comparable copy number variation profiles compared to later-onset cases, they are enriched for multiple driver mutations and copy number alterations in subtype-specific contexts."

In skin cutaneous melanomas from the younger group of patients, for example, the team found that the BRAF V600E driver mutation was almost twice as common as it was in the older patients — turning up in 60.5 percent of tumors from patients under 50 years old and 31.6 percent of tumors from patients over 50 — suggesting these cases may be amenable to treatment with targeted BRAF drugs.

On the other hand, BRAF mutations were far more common in colon cancers from the individuals over 50 years old than in colon cancers diagnosed earlier, the researchers reported. There, they found BRAF V600E in more than 15 percent of colon adenocarcinoma cases from the older individuals but just over 2 percent of those in the younger group.

Even so, the colon adenocarcinoma tumors found in the younger patients were more apt to contain driver mutations in the PTEN gene, as did some younger adult uterine corpus endometrial carcinoma tumors, which also appeared prone to mutations in ATRX and other genes. Somatic changes in the GATA3 gene showed significant ties to breast invasive carcinoma cases in younger individuals, while still other driver gene mutations were enriched in younger patients with other cancer types considered.

Along with suspicious copy number, expression, and methylation differences in tumors from the younger group, the team also saw tumor immune microenvironment patterns that seemed to coincide with age, including enhanced dendritic cell activity and TGF-beta signaling responses and lower lymphocyte infiltration, macrophage, and interferon-gamma responses in tumor immune microenvironments from younger patients.

The investigators also explored potential ties between the age-related tumor microenvironment features and response to immunotherapy, since tumors from older patients tended to have more single base mutations and neoantigens stemming from small insertion and deletions.

With data from more than 1,500 solid tumor cases treated with immune checkpoint inhibitors, they saw ties between cancer types showing both poor survival and lower-than-usual levels of immune cell infiltration and other negative prognostic features in the younger patients, including head and neck squamous carcinoma, breast invasive carcinoma, and colorectal adenocarcinoma cases.

"[Tumor immune microenvironment] differences in young versus older adults vary across tissues, which may be a result of the complex interplays between accumulated neoantigens and age-related immune changes that require further investigation," the authors wrote. "These differences can determine patient prognosis and suitability of immunotherapy."

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