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The frequency and prognostic relevance of co-occurring TP53 mutation and NOTCH pathway activation in locally advanced, recurrent or metastatic adenoid cystic carcinoma

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The frequency and prognostic relevance of co-occurring TP53 mutation and NOTCH pathway activation in locally advanced, recurrent or metastatic adenoid cystic carcinoma

  • The frequency of co-occurrent TP53 mutation and NOTCH activation in ACC was 2.3%.
  • TP53-NOTCH co-occurrence associated with shorter overall survival verses either alone.
  • Truncating TP53 mutations may have different prognostic value than non-truncating.
  • Truncating TP53 mutation and NOTCH activation were mutually exclusive in our cohort.

    Introduction

    Adenoid cystic carcinoma (ACC) is a rare tumour primarily arising within the major and minor salivary glands or other glandular structures of the head and neck [1]. Approximately 1–2% of head and neck cancers [2], [3] and up to 10% of salivary gland cancers are classified as ACC [3]. ACC has a characteristic clinical course with metastasis [4] occurring in 50% to 70% of cases [[3], [5], [6]], this contributes to an overall survival rate at 15 years of 20% [2]. Due a lack of well-established systemic therapies, relapsed disease is often incurable [5].
    Genomic sub-classification of ACC has identified activation of the NOTCH signalling pathway, seen in 11 to 29% of patients, [7] as a biomarker predicting increased risk of metastasis, a more rapidly progressive disease course and shorter overall survival [2], [7], [8]. In our previously published study of 145 ACC patients [8], we reported that the presence TP53 mutation, present in 10% (10/121) of ACC cases, was associated with significantly shorter disease-free intervals and overall survival rates [8]. However, the relatively small number of patients limited the statistical confidence in the observations and precluded analysis of the impact of co-occurrence of TP53 mutation and NOTCH pathway activation. In the current analysis of a larger patient cohort of 351 ACC patients, we evaluate the frequency with which NOTCH activation and TP53 mutation co-occur and define the clinical outcomes in patients with NOTCH pathway-activated ACC with and without co-occurring TP53 mutation.

    Data and Patient Cohort

    351 ACC patients with clinical, genomic and survival data were identified and ethical permissions were obtained to analyze clinical and genomic data (UK cohort n = 200; cBioPortal cohort n = 151). The clinical and genomic characteristics are summarised in Table 1. Consistent with previous studies [3], [7]. ACC originated in the major salivary glands in 58.9% and 38.7% of cases respectively and the most common site of recurrent or metastatic disease was the lung (43.4% UK; 38.4% cBioPortal) followed by local recurrence (27.7% and 33.1%), liver (10.5% and 9.27%) and bone metastases (8.62% and 6.62%).
    Table 1. A complete summary of the total patient cohort characteristics including age, sex, salivary gland and site of metastases.
    Empty Cell Cohort
    UK Cohort (200) cBioPortal Cohort (151)
    Characteristic Number/Range
    Age (R/M) Median 55.5 53.7
    Range 18–81 22–90
     
    Sex Female 111 73
    Male 87 78
    Unknown 2 0
     
    Salivary Gland Major 89 47
    Other 111 64
    Unknown 0 40
     
    Site of Metastases Lung 141 58
    Liver 34 14
    Bone 28 10
    Other 32 13
    Unknown 0 6
    Local 90 50
    Of the 351 samples analysed by next generation sequencing (NGS), 13.7% (48/351) of the tumours harboured a TP53 mutation (TP53mt), whilst 14% (49/351) harboured an activating NOTCH mutation (NOTCHgof). Co-occurrent TP53mt and NOTCHgof were seen in 2.3% (8/351).

    Results

    Analysis of overall survival (OS) from the diagnosis of inoperable, locally advanced or recurrent/metastatic (LA-R/M) disease are shown in Fig. 1 and subsections 1A-D. As expected, the presence of NOTCHgof was associated with a significantly shorter overall survival (OS) from recurrence (Fig. 1A). The median OS in 49 ACC patients with NOTCHgof was 14 months compared with 59 months for 302 ACC patients without NOTCHgof (95% CI 9–19, p = 0.001).
    Fig. 1
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    2. Download: Download full-size image

    Fig. 1. Overall survival for the combined patient cohort of CBioPortal and UK Cohort organised by mutation.

    We evaluated the OS from LA-R/M disease for 48 ACC patients with TP53 mutation compared with 303 ACC patients without TP53 mutation (Fig. 1B). The presence of any TP53mt was associated with a trend towards shorter OS from recurrence compared to TP53 wild-type (TP53wt) ACC. The 12- and 24-month survival rate was lower for patients with TP53mt ( 70.8% 86.5% and 60.4%v 74.6% %) at 24 months and the median OS was 34 months for TP53mt versus 55 months for TP53wt ACC, (95% CI 48–62; p = 0.413). TP53mt and NOTCHgof co-occurred in 20% of both the TP53 mutated (8/48) and the NOTCH gain of function (8/49) cohorts. Fig. 1C shows the shortest median OS from diagnosis of LA-R/M ACC was seen is those with co-occurring TP53mt and NOTCHgof (n = 8) being 10.0 months compared with 15.0 months for those with TP53wt/NOTCHgof (n = 41) and 59.0 months for those with TP53mt/NOTCHgof (n = 40) in contrast to a median OS of 69.0 months for patients with TP53wt/NOTCHwt ACC (95.5 CI 14–124).
    Data was available for analysis of the functional classification of TP53 mutation in the 33 ACC patients in the UK cohort. For these patients, mutations in TP53 were further classed as either loss-of-function point mutations in 81.8% or truncating frameshift mutations in 18.2%. Truncating TP53 mutations were mutually exclusive with NOTCHgof. Although the smaller number in this group limits statistical power, patients with truncating TP53 mutations had a trend towards shorter OS from recurrence with a median OS from recurrent of 16 months compared to 55 months with those with other TP53 mutations (Fig. 1D).

    Discussion

    We sought to expand on the previous analysis of TP53 mutation as a prognostic biomarker in ACC, and to determine the frequency and prognostic relevance of NOTCH and TP53 co-occurrence. We also sought to further classify and clinically characterise the types of TP53 mutation based on the predicted functional impact.
    Our results were consistent with previous literature describing the prevalence of TP53mt and NOTCHgof [[3], [9]]. However, this data is the first to describe the frequency of both alterations co-occurring in the same tumour and the clinical outcomes in this group being associated with the shortest overall survival. We also describe the outcomes in patients with truncating mutations inTP53 being mutually exclusive with NOTCH gain of function and the associated with shorter survival times in these patients. This finding must be interpreted with caution given the limitation of small numbers in this sub-group. Functional consequences of the diverse TP53 mutations remain an area of future exploration.

    Conclusion

    In conclusion, the main aim of this study was to determine the frequency and prognostic impact of co-occurrence of TP53 mutation and NOTCH activation in inoperable locally advanced or recurrent/metastatic ACC. We identified that the subgroup of patients with co-occurrence of NOTCH gof and TP53mut had a significantly shorter OS that either alone. We also identified that truncating TP53 mutations may have a greater prognostic value that non truncating TP53 mutations which is an avenue for future research. This study highlights both the potential prognostic value of TP53 in ACC and this represents a patient population that should be prioritised for therapeutic trials.

    Declaration of generative AI and AI-assisted technologies in the writing process

    Generative AI and AI-assisted technologies were NOT used in the preparation of this work.

    CRediT authorship contribution statement

    Syeda Malaika Haider: Writing – original draft, Writing – review & editing, Formal analysis, Visualization. Joseph Edward Haigh: Writing – review & editing. Karan Patel: Conceptualization, Data curation, Formal analysis, Visualization, Writing – review & editing. Samuel Rack: Writing – review & editing. Sian Dobbs: Writing – review & editing. Laura Spurgeon: Writing – review & editing. Guy Betts: Investigation. Hitesh Mistry: Formal analysis, Software, Writing – review & editing. Kevin Joseph Harrington: Writing – original draft, Writing – review & editing. Robert Metcalf: Funding acquisition, Project administration, Supervision, Writing – original draft, Writing – review & editing, Data curation, Formal analysis.

    Funding

    Research Sponsor: The Christie Charity; The Infrastructure Industry Foundation; Syncona Foundation.

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    [5] Ho AS, Ochoa A, Jayakumaran G, Zehir A, Mayor CV, Tepe J, et al. Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma. The Journal of Clinical Investigation [Internet]. 2019 Oct 1 [cited 2023 Apr 13];129(10):4276–89. 

    [6] Q. Li, P. Huang, C. Zheng, J. Wang, M. Ge. Prognostic significance of p53 immunohistochemical expression in adenoid cystic carcinoma of the salivary glands: a meta-analysis. Feb 11 [cited 2023 Apr 13, Available from: Oncotarget, 8 (17) (2017), pp. 29458-29473

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