Molecular Classification of Appendiceal Adenocarcinoma

Authors

Michael B. Foote

Henry Walch

Walid Chatila

Efsevia Vakiani

Chris Chandler

Felix Steinruecke

Garrett M. Nash

Zsofia Stadler

Sebastian Chung

Rona Yaeger

Maria Ignez Braghiroli

Jinru Shia

Yelena Kemel

Anna Maio

Margaret Sheehan

Benoit Rousseau

Guillem Argiles

Michael Berger

David Solit

Nikolaus Schultz

Luis A. Diaz Jr

Andrea Cercek

Doi

10.1200/JCO.22.01392

PMID: 36493333 · DOI: 10.1200/JCO.22.01392 · Journal: Journal of Clinical Oncology (2022)

TL;DR

Foote et al. performed MSK-IMPACT targeted sequencing on a retrospective MSK cohort of patients with appendiceal adenocarcinoma (AC) to ask whether co-occurring somatic mutations define clinically meaningful subtypes beyond histology. In 164 mucinous appendiceal adenocarcinomas (MAAP), they define three molecular lineages based on GNAS, RAS, and TP53 mutations: a RAS-mutant/GNAS-wt/TP53-wt indolent subtype, a chemotherapy-resistant GNAS-mut predominant subtype, and an aggressive, highly aneuploid TP53-mut predominant subtype. Subtype was associated with overall survival, peritoneal tumor burden, and first-line chemotherapy response independently of histopathologic grade PMID:36493333.

Cohort & data

  • Retrospective cohort of patients with appendiceal adenocarcinoma sequenced on MSK-IMPACT at Memorial Sloan Kettering between April 2015 and October 2020, released as the appendiceal_msk_2022 cBioPortal study PMID:36493333.
  • Molecular subtype analysis focused on 164 mucinous appendiceal adenocarcinoma (MAAP) tumors, with findings then extended to the broader AC series including goblet cell adenocarcinoma (GCA) and colonic-type appendiceal adenocarcinoma (CTAAP) PMID:36493333.
  • Matched tumor/normal hybridization-capture next-generation sequencing via MSK-IMPACT; oncogenic drivers and actionable variants annotated via OncoKB; clonality assessed with FACETS; aneuploidy scored from segment-length-weighted copy-number deviation from diploid PMID:36493333.

Key findings

  • Three MAAP molecular subtypes defined by co-occurring mutations in GNAS, KRAS/NRAS, and TP53: RAS-mut predominant (RAS-mut/GNAS-wt/TP53-wt, n=24), GNAS-mut predominant, and TP53-mut predominant PMID:36493333.
  • The RAS-mut predominant subtype had significantly fewer mutations and chromosomal alterations than GNAS-mut or TP53-mut predominant tumors; no patient with metastatic RAS-mut predominant MAAP died of cancer during follow-up PMID:36493333.
  • Overall survival was significantly better in RAS-mut predominant patients than in GNAS-mut predominant (P=.05) or TP53-mut predominant (P=.004) subtypes PMID:36493333.
  • TP53-mut predominant tumors were highly aneuploid; increased tumor aneuploidy was independently associated with poor prognosis (P=.001) in multivariable Cox models adjusting for histology, grade, age, CRS number, and first-line chemotherapy type PMID:36493333.
  • RAS-mut predominant metastases showed reduced peritoneal tumor bulk (lower peritoneal cancer index, P=.04) and reduced stromal invasion (P<.001) relative to GNAS-mut or TP53-mut predominant tumors, respectively PMID:36493333.
  • First-line chemotherapy response rate was 50% in RAS-mut predominant MAAP vs 6% in GNAS-mut predominant MAAP (P=.03) PMID:36493333.
  • Subtype-associated clinical behavior was conserved when the analysis was extended to any metastatic AC, irrespective of histopathologic subtype (MAAP, GCA, CTAAP) PMID:36493333.

Genes & alterations

  • KRAS / NRAS — RAS mutations in the absence of GNAS and TP53 alterations mark the clinically indolent MAAP subtype with the lowest mutational and chromosomal burden and the best overall survival PMID:36493333.
  • GNAS — GNAS-mut predominant MAAP is associated with chemotherapy resistance (6% first-line response) and intermediate survival PMID:36493333.
  • TP53 — TP53-mut predominant tumors are highly aneuploid, invasive, and carry the worst prognosis; aneuploidy is an independent predictor of poor OS PMID:36493333.

Clinical implications

  • The authors argue that somatic tumor profiling of appendiceal adenocarcinoma has direct clinical utility: molecular subtype may inform whether to offer cytoreductive surgery and/or systemic chemotherapy, independent of histologic grade PMID:36493333.
  • RAS-mut predominant MAAP patients may be candidates for less aggressive management given their indolent course and chemotherapy sensitivity; GNAS-mut predominant patients appear unlikely to benefit from standard colorectal-style first-line regimens combining fluorouracil, leucovorin, oxaliplatin, and/or irinotecan (FOLFOX/FOLFIRI/FOLFIRINOX), or capecitabine PMID:36493333.
  • Findings challenge the default of managing AC with colorectal cancer treatment paradigms PMID:36493333.

Limitations & open questions

  • Retrospective, single-institution MSK cohort sequenced on a targeted panel (MSK-IMPACT) rather than whole-exome/whole-genome; subtype calls depend on panel coverage PMID:36493333.
  • Sample sizes in some subtypes (e.g., 24 RAS-mut predominant MAAP) are small, and no cancer-specific deaths in that subgroup means OS estimates are imprecise PMID:36493333.
  • External validation in independent appendiceal cohorts and prospective evaluation of subtype-guided therapy selection are open questions.
  • Mechanistic basis for GNAS-mut-associated chemoresistance and TP53-mut-associated aneuploidy in appendiceal tumors remains to be determined.

Citations from this paper used in the wiki

  • “We defined distinct molecular lineages of mucinous appendiceal adenocarcinoma (MAAP) from co-occurring mutations in GNAS, RAS, and TP53.” (Abstract)
  • “No patient with RAS-mut predominant subtype metastatic MAAP died of cancer, and overall survival in this subgroup was significantly improved compared with patients with GNAS-mut (P=.05) and TP53-mut (P=.004) predominant subtypes.” (Abstract)
  • “Patients with RAS-mut predominant MAAP responded more to first-line chemotherapy (50%) compared with patients with GNAS-mut predominant tumors (6%, P=.03).” (Abstract)
  • “TP53-mut predominant subtypes were highly aneuploid; increased tumor aneuploidy was independently (P=.001) associated with poor prognosis.” (Abstract)

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