4406 - Comprehensive genomic profiling (CGP) of gall bladder adenocarcinoma (GBAC) in patients from distinct ancestral populations

Background

GBAC is an aggressive neoplasm with an abysmal 5-year survival rate and no approved targeted therapies. Incidence of GBAC varies greatly across global geographical regions, with highest reported rates in South and East Asia. We evaluated whether GBAC patients have differential genomic profiles as correlated to ancestry.

Methods

CGP was performed by an adaptor-ligation/hybrid capture-based assay of coding DNA of 315 cancer-related genes and select introns of 28 genes that are frequently involved in genomic rearrangements to detect base substitutions, insertions and deletions, copy number alterations, and rearrangements. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was assessed across 114 homopolymeric loci. Patient ancestry was determined by single nucleotide polymorphism microarray data, ancestry informative markers, and principal component analysis.

Results

The genomic profiles of tumour samples from 881 patients with GBAC were reviewed. Of these samples, 22 (2.50%) were derived from individuals of South Asian ancestry (SAS), 61 (6.92%) from East Asian (EAS) ancestry and the remainder were distributed among African, American, and European ancestry (Others). Age and gender were similar across all three groups, except for an enrichment in SAS male patients (SAS male 68.2%, EAS male 32.7%, Others male 31.2%; p = 0.001). MSI was uncommon in all three groups (0.007% overall) and TMB was low (median 2.6 mut/mb). The most commonly altered genes across all three groups were TP53, CDKN2A/B and SMAD4 (all: 64%, 53%, 17%) while alterations in ERBB2 (23% v 30% v 14%, p = 0.03) and CTNNB1 (14% v 11% v 3%, p = 0.001) were enriched in SAS and EAS populations. Amongst ERBB2 altered cases, amplifications were seen at similar frequencies across all three groups (80% v 72% v 72%), while less than half of all ERBB2 point mutations occurred at the S310 codon (18/67, 27%).

Conclusions

GBAC patients of SAS and EAS ancestry were enriched for ERBB2 and CTNBB1 relative to other ancestries. Follow-up studies are needed to understand the genomic context of this finding, as well as the influence of cancer predisposition genes in the context of ancestry specific oncogenesis.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine Inc.

Funding

Foundation Medicine Inc.

Disclosure

M. Javle: Research grant / Funding (self): QED Therapeutics; Honoraria (self): Merck & Co; Advisory / Consultancy: EDO Pharma; Advisory / Consultancy: More Health; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Seattle Genetics; Research grant / Funding (self): Meclun; Research grant / Funding (institution): Arqule; Research grant / Funding (institution): Lilly; Advisory / Consultancy: Origimed; Research grant / Funding (self): Novartis. S. Akumalla: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. R. Madison: Full / Part-time employment: Foundation Medicine; Shareholder / Stockholder / Stock options: Roche. J. Newburg: Shareholder / Stockholder / Stock options: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. B.M. Alexander: Leadership role, Full / Part-time employment, Officer / Board of Directors: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Personal Fees: AbbVie; Advisory / Consultancy, Personal Fees: Schlesinger Associates; Advisory / Consultancy, Personal Fees: Bristol-Myers Squibb; Advisory / Consultancy, Personal Fees: Precision Health Economics; Research grant / Funding (self), grants outside submitted work: Puma Biotechnology; Research grant / Funding (self), grants outside submitted work: Celgene; Research grant / Funding (self), grants outside submitted work: Eli Lily. J. Chung: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. V.A. Miller: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Revolution Medicines. J. Lee: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. J.S. Ross: Leadership role, Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Officer / Board of Directors: Celcius Therapeutics. A.B. Schrock: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. G.M. Frampton: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche. S.M. Ali: Full / Part-time employment: Foundation Medicine Inc; Shareholder / Stockholder / Stock options: Roche; Advisory / Consultancy, Scientific Advisory Board: Incysus Therapeutics, Inc.; Advisory / Consultancy: Revolution Medicines. All other authors have declared no conflicts of interest.