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Appendiceal Cancer Genomic Landscape Varies By Age At Onset

Patients diagnosed with appendiceal cancer before the age of 50 years display different gene variants to individuals who develop this cancer later in life
23 Dec 2020
Basic Principles in the Management and Treatment (of cancer);  Colon and Rectal Cancer;  Gastrointestinal Cancers;  Translational Research

Author: By Lynda Williams, Senior medwireNews Reporter 

 

medwireNews: Early-onset appendiceal cancers (ACs) frequently have somatic variations in TSC2, SMAD3 and PIK3CA, raising the possibility of targeted treatments in this patient population, suggest the results of an international consortium study. 

Writing in JAMA Network Open, the researchers report a “distinct spectrum” of genomic differences in ACs diagnosed in patients before the age of 50 years compared with those detected in older individuals. 

They believe that the study “provides novel insight into molecular differences of AC by age at disease onset and identifies potential biomarkers associated with AC diagnosed at younger ages that may help unravel distinct etiologies underlying the increasing incidence of early-onset AC.” 

Of the 385 patients with AC who were included in the GENIE consortium database between 2011 and 2019, the average age at diagnosis was 56.0 years and 28.3% of patients were diagnosed before the age of 50 years. 

Almost half (48.6%) of the patients were male and this was consistent in both early-onset and late-onset AC cases. 

The majority (79.5%) of the cohort were non-Hispanic White, but the researchers found that onset did vary by race, with non-Hispanic Black patients significantly more likely to have early-onset than late-onset AC (8.3 vs 4.0%). 

Genomic analysis identified 39 genes in AC that occurred in more than 2.0% of the cohort. This included KRAS, TP53 and GNAS alterations in 51.4%, 27.3% and 26.2% of patients, respectively. 

In addition, at least 5% of AC patients had alterations in SMAD4, APC, PIK3CA, KMT2D, SOX9 and ATM. 

Further analysis revealed that GNAS and TP53 variants were mutually exclusive in both early- and late-onset patients, while SOX9 and KRAS, and SOX9 and TP53 variants were mutually exclusive only among young patients. 

Moreover, the frequency of GNAS and PIK3CA variants significantly differed between early-onset and late-onset AC patients, report Andreana Holowatyj, from Vanderbilt University Medical Center in Nashville, Tennessee, USA, and co-workers. 

GNAS variants occurred in 19.3% of young patients versus 29.0% of older individuals, whereas PIK3CA variants were found in 11.9% and 4.7% of these groups, respectively. 

After adjusting for sex, race or ethnicity, histology and other confounding factors, early-onset AC patients were significantly more likely to have variants in TSC2, SMAD3 and PIK3CA, than late-onset cases, with odds ratios (ORs) of 12.43, 7.37 and 4.58, respectively. 

By contrast, the early-onset patients were significantly less likely to have nonsilent variants of GNAS than late-onset patients, with an OR of 0.40. 

Analysis by histology indicated that mucinous adenocarcinomas in younger patients were significantly less likely to harbour nonsilent GNAS variants than those in older individuals (OR=0.35), and a similar, albeit nonsignificant, pattern was found for those with nonmucinous adenocarcinomas (OR=0.28). 

“These findings demonstrate that ACs diagnosed among young individuals harbor a distinct molecular phenotype compared with late-onset ACs and yield clinical actionability in future studies that should aim to elucidate distinct molecular phenotypes and mechanisms of early-onset AC and to develop and test personalized therapeutic modalities tailored to young patients diagnosed with AC”, the team concludes.  

Reference

Holowatyj AN, Eng C, Wen W, Idrees K, Guo X. Spectrum of somatic cancer gene variations among adults with appendiceal cancer by age at disease onset. JAMA Netw Open;3:e2028644. Published online 9 December 2020. doi:10.1001/jamanetworkopen.2020.28644

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature group

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