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. 2020 Jun;5(3):e000682.
doi: 10.1136/esmoopen-2020-000682.

Molecular profile of BRCA-mutated biliary tract cancers

Gilbert Spizzo  1 , Alberto Puccini  2 , Joanne Xiu  3 , Richard M Goldberg  4 , Axel Grothey  5 , Anthony F Shields  6 , Sukeshi Patel Arora  7 , Moh'd Khushman  8 , Mohamed E Salem  9 , Francesca Battaglin  10 , Yasmine Baca  3 , Wafik S El-Deiry  11 , Philip A Philip  12 , Madiha Nassem  10 , Michael Hall  13 , John L Marshall  14 , Florian Kocher  15 , Arno Amann  15 , Dominik Wolf  15 , W Michael Korn  3 , Heinz-Josef Lenz  10 , Andreas Seeber  16
Affiliations

Molecular profile of BRCA-mutated biliary tract cancers

Gilbert Spizzo et al. ESMO Open. 2020 Jun.

Erratum in

Abstract

Introduction: Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown.

Material and methods: Tumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry.

Results: Overall, BRCA mutations were detected in 3.6% (n=46) of samples (BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05).

Conclusions: BRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA-mutant BTC.

Keywords: BRCA; biliary tract cancer; molecular profile.

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Conflict of interest statement

Competing interests: JX, YB and WMK are employers of Caris Life Sciences. JLM and AS are consultants for Caris Life Sciences. RMG received research and travel support from Caris Life Sciences. AFS received research, travel, and speaking fees from Caris Life Sciences. MES, AG, HL and AS received travel support from Caris Life Sciences.

Figures

Figure 1
Figure 1
Mutation rates of BRCA1 and BRCA2 in biliary tract tumours. Four biliary tract tumours with uncertain specific tumour location were included in the ‘entire cohort’.
Figure 2
Figure 2
Gene mutation frequencies in BRCA-mutated (MT) and wild types (WTs) biliary tract tumours (see also online supplementary table).
Figure 3
Figure 3
Tumour mutational burden in BRCA-mutated (MT) and wild-type (WT) cohorts.
Figure 4
Figure 4
Prevalence of immune checkpoint inhibitor-associated predictive biomarkers in BRCA-mutated (MT) and wild-type (WT) biliary tract cancer (BTC). dMMR, deficient mismatch repair; MSI-H, microsatellite instability high; PD-L1, programmed death ligand 1; TMB, tumour mutational burden.
See this image and copyright information in PMC

Comment in

References

    1. de Groen PC, Gores GJ, LaRusso NF, et al. . Biliary tract cancers. N Engl J Med 1999;341:1368–78. 10.1056/NEJM199910283411807 - DOI - PubMed
    1. Charbel H, Al-Kawas FH. Cholangiocarcinoma: epidemiology, risk factors, pathogenesis, and diagnosis. Curr Gastroenterol Rep 2011;13:182–7. 10.1007/s11894-011-0178-8 - DOI - PubMed
    1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the global burden of disease study 2015. Lancet 2016;388:1545–602. 10.1016/S0140-6736(16)31678-6 - DOI - PMC - PubMed
    1. Mosconi S, Beretta GD, Labianca R, et al. . Cholangiocarcinoma. Crit Rev Oncol Hematol 2009;69:259–70. 10.1016/j.critrevonc.2008.09.008 - DOI - PubMed
    1. Bétourné A, Quiquempois Y, Bouwmans G, et al. . Design of a photonic crystal fiber for phase-matched frequency doubling or tripling. Opt Express 2008;16:14255–62. 10.1364/OE.16.014255 - DOI - PubMed