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Pan-Cancer Analysis Reveals Unique Features in Tumors From Younger People

NEW YORK – Researchers at Weill Cornell Medicine conducted a pan-cancer analysis of tumors in The Cancer Genome Atlas (TCGA) to determine whether there are any differences in tumor molecular characteristics between younger and older patients and found that the cancers of younger individuals possessed unique features that could be used to devise new therapies.

In a study published on Tuesday in Cell Reports, the researchers noted that while older age is a strong risk factor for cancer, the etiology and biology of age-associated differences among cancers are poorly understood. To address this issue, they identified cancers with significant age-dependent outcomes in the TCGA. These included bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), colorectal adenocarcinoma (COAD), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), acute myeloid leukemia (LAML), brain lower grade glioma (LGG), lung squamous cell carcinoma (LUSC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), sarcoma (SARC), stomach adenocarcinoma (STAD), thyroid carcinoma (THCA), and uterine corpus endometrial carcinoma (UCEC).

The researchers then narrowed down this list by identifying tumors with an age-dependent molecular phenotype through an analysis of differential gene expression. Tumor types that had greater than 1 percent of genes differentially expressed between the age groups were deemed to show an age-associated molecular phenotype and were selected for all further analyses. These included BRCA, LGG, UCEC, OV, THCA, and LUSC.

The researchers analyzed these tumors to delineate differences in tumor molecular characteristics between younger and older patients and found widespread molecular differences in select tumor types between the two groups. For example, tumors in younger individuals exhibited a dysregulated molecular aging phenotype and were associated with hallmarks of premature senescence, the researchers said. Additionally, these tumors were enriched for driver gene mutations, resulting in homologous recombination defects.

The investigators also observed a trend toward decreased immune infiltration and function in older patients and found that young tumor tissue immunologically resembled aged healthy tissue.

A subsequent analysis aimed to identify patterns between healthy aging and aging in cancer, and it showed that the relationship between aging in cancer and healthy aging was tumor-type dependent, the researchers said. For example, they found that immune pathways in breast cancer were overall upregulated in older healthy donors and in young cancer patients. And although thyroid cancer showed a similar phenotype of pathway activation, other tumor types did not display this pattern.

Therefore, they concluded, patterns of pathway activation suggested that younger breast and thyroid cancer patients resembled immunological phenotypes of aged corresponding healthy tissue, suggesting dysregulation of the aging process in cancer.

The investigators were also able to show that genes that were overexpressed in younger cancer patients may be epigenetically controlled. Further, epigenetically controlled pathways associated with young breast cancer patients, but not other cancers, were enriched for senescence, suggesting dysregulated aging in the tumor.

Importantly, the researchers hypothesized that pharmaceutical compounds could reverse the aging gene signature seen in young patients. These compounds could act as senolytics and aid in therapeutic decision making. To test this theory, they used a modified connectivity mapping approach to identify ten compounds shared across three or more tumor types in the young versus old signatures. One such compound, dasatinib (Bristol Myers Squibb's Sprycel) recently demonstrated the ability to improve pharmacodynamic markers of senescence and senescence-associated inflammation when co-administered with the flavonoid quercetin in patients with diabetes and chronic kidney disease.

"Even though young patients are associated with better survival outcomes, molecular data suggest that these patients are associated with increased tumor proliferation, dysregulated aging, and immune exhaustion," the authors concluded. "Dysregulated aging and oncogenic processes associated with tumors in young adults may be leveraged for differential therapeutic strategies and biomarker discovery."

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