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Appendiceal Cancer Sequences Suggest Distinct Mutation Patterns in Early-, Late-Onset Cases

NEW YORK – A Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center team has identified distinct mutation patterns in appendiceal cancer cases with early and late onset, pointing to the possibility of coming up with more customized treatments for the rare cancer in the future.

"[Appendiceal cancer] diagnosed among younger individuals harbored a distinct genomic landscape compared with [appendiceal cancer] diagnosed among older individuals. Development of therapeutic modalities that target these unique molecular features may yield clinical implications specifically for younger patients," co-corresponding authors Andreana Holowatyj and Xingyi Guo, both researchers at Vanderbilt University Medical Center, and their colleagues wrote in a paper published in JAMA Network Open on Wednesday.

Using data collected through the American Association for Cancer Research "Genomics Evidence Neoplasia Information Exchange" (GENIE) project, the researchers considered clinical sequencing data for almost 400 appendiceal tumors, including samples from 109 individuals with early-onset cancer in the appendix that was diagnosed before the age of 50 years old.

They uncovered recurrent mutations in a handful of genes that were particularly common in the early-onset cases, suggesting it may be possible to come up with more targeted treatments for the disease, which is currently treated surgically and with systemic treatments developed for colon cancer, if necessary.

The findings demonstrate that appendiceal cancers diagnosed among young individuals harbor a distinct molecular phenotype compared with late-onset cancers, the researchers noted, adding that future studies should aim to elucidate distinct molecular phenotypes and mechanisms of early-onset disease and to develop and test personalized therapeutic modalities tailored to young patients.

For the analysis, the team brought together clinical sequence data for 385 appendiceal cancer cases profiled for GENIE between early 2011 and late 2019. More than 28 percent of those appendiceal cancers were diagnosed in those under 50 years old, and those early-onset cases were over-represented in non-Hispanic Black participants.

In contrast to late-onset cases, which tended to be marked by recurrent, non-silent alterations in the GNAS gene, the researchers saw a significant dip in GNAS variants in tumors from individuals with early-onset disease. Instead, appendiceal cancer tumors from the younger patients tended to contain more non-silent variants in genes such as PIK3CA, SMAD3, and TSC2.

Compared to the corresponding late-onset cases, the team documented declines in GNAS mutations from early-onset appendiceal cancers from both the mucinous and non-mucinous histological subtypes of appendiceal adenocarcinoma, though the proportion of those variants differed slightly by subtype.

In the sample set considered, the investigators only detected GNAS gene mutations in early- and late-onset tumors lacking TP53 mutations, while TP53 mutations were limited to GNAS mutation-free tumors, suggesting these changes are likely mutually exclusive.

Among other potential limitations of the study, the researchers cautioned that "because all somatic variations were not systematically evaluated within GENIE, the true prevalence of somatic variations in our cohort may be even higher." 

In addition, they noted that the project used for the appendiceal cancer analysis "lacks detailed information regarding individual-level characteristics, including family history of cancer, and does not provide any data about germline genetic features, cancer treatments, or prognostic outcomes for patients with [appendiceal cancer]."