Whole exome sequencing reveals genomic landscape of appendiceal adenocarcinoma

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Published: 5 Jul 2023
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Dr Michael White - MD Anderson Cancer Center, Houston, USA

Dr Michael White speaks to ecancer about the genomic landscape of appendiceal adenocarcinoma.

In this cohort study, 855 whole exam sequences were reviewed to examine molecular subtyping.

The results revealed four distinct subtypes: KRAS-like, GNAS-like, TP53-like, and triple negative. Additionally, specific profiles were linked to copy number variation, ctDNA status, and stage, all of which were associated with the mutational status of each subtype.

Dr White concludes by discussing the ongoing studies reviewing the role of immunotherapy and checkpoint blockades in these patients.

We had the opportunity to look at the whole exome sequencing landscape of appendiceal adenocarcinoma. This is a descriptive study of over 800 patients with appendiceal adenocarcinoma of all stages who were sequenced as part of their Natera Signatera test that develops bespoke probes using whole exome sequencing. So, collaborating with Natera we were able to examine the whole exome sequences of these tumours in order to quantify the largest series to date of appendiceal adenocarcinoma whole exomes.

What was the study design?

This was simply an observational design, an observational cohort study, looking at, again, just the genetic sequencing of these tumours.

What did you find?

We were able to recapitulate previous associations that demonstrated that the tumour mutational burden and microsatellite instability status of appendiceal adenocarcinoma was distinct from matched cohorts of rectal and colon cancers and that especially the mutational burden was significantly lower in appendiceal adenocarcinoma.

Then when we looked at the molecular subtyping of these tumours we found that, as previously described, they follow subtyping categorisation as KRAS-like, GNAS-like, TP53-like and triple negative, and that there were distinct profiles associated in copy number variation as well as ctDNA status and stage that were associated with this subtyping mutational status. Again, we were able to demonstrate that the genetic landscape of appendiceal adenocarcinoma is quite distinct from both colon and rectal cancers with a much higher prevalence of GNAS mutations and a significantly lower prevalence of APC mutations as well as TP53 mutations.

What is next for the study?

That’s a great question. We are currently looking at a cohort within MD Anderson with more robust clinical data so we can better understand how to take these whole exome observations and apply them clinically for our patients. While we see that there appear to be more aggressive subtypes of appendiceal adenocarcinoma, such as the TP53 subtype, how that actually relates to patient care is yet to be further defined. So we’re in the process of applying that to our patient cohort here at MD Anderson.

Then, similarly, when we looked at the mutational signatures, while tumour mutational burden and MSI status were typically low, we found that the mutational signatures carried a mismatch repair deficient subtype in a significant proportion, up to 20%. So there are ongoing studies at MD Anderson and elsewhere looking at the role of immunotherapy and checkpoint blockade in these patients and if there could potentially be a benefit to that subset of patients with appendiceal adenocarcinoma.