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Prognostic impact of intra-field heterogeneity in oral squamous cell carcinoma

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Abstract

Genetic heterogeneity displayed by tumour cells (intratumoural heterogeneity, ITH) represents a diagnostic challenge when assessing tumour mutational profile. In oral squamous cell carcinoma (OSCC), ITH may be found both in tumour cells and in adjacent mucosa. Genetic heterogeneity of the adjacent mucosa can be interpreted as evidence of the field cancerization (field heterogeneity, FH). The aim of the study was to investigate the impact of intratumoural and intrafield heterogeneity on locoregional control. Ten OSCC patients (5 recurrent and 5 nonrecurrent) were studied. Multiple areas were sampled from the bulk of the tumour and the adjacent nonneoplastic mucosa. A panel of 10 tumour-specific OSCC driver genes was analysed for each sample and was used to calculate heterogeneity. Values were compared among recurrent and nonrecurrent OSCC. Mutational analysis highlighted that a single tumour sample has limited accuracy in assessing the genetic profiles of tumours. High values of ITH considering shared mutations between specimens were found in both recurrent and non-recurrent OSCC (p = 0.095). On the contrary, the intrafield genetic heterogeneity was significantly less frequently in the non-recurrent OSCC group (p = 0.032). Heterogeneity within each specimen calculated with variant allele frequency confirmed that there was better discrimination between recurrent and nonrecurrent groups using nonneoplastic adjacent mucosa than tumour tissue (p value 0.0006 and 0.0048 respectively). In agreement with the theory of field cancerization, intrafield genetic heterogeneity correlates with a higher risk of developing loco-regional recurrences and second primaries. In order to reduce the ITH effects, analysis of multiple tumour areas should be encouraged.

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Abbreviations

ITH:

intratumoural heterogeneity

NGS:

next-generation sequencing

VAF:

variant allele frequency

MATH:

mutant allele tumour heterogeneity

WGS:

whole genome sequencing

FH:

field heterogeneity

OSCC:

oral squamous cell carcinoma

WT:

wild type

Mut:

mutated

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Funding

This research was supported by an academic grant (AlmaIdea 2017) from the University of Bologna.

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Authors and Affiliations

  1. Section of Oral Science, Department of Biomedical and Neuromuscular Sciences, University of Bologna, Bologna, Italy

    Andrea Gabusi, Davide Bartolomeo Gissi & Lucio Montebugnoli

  2. Department of Biomedical and Neuromotor Sciences, “M. Malpighi” Section of Anatomic Pathology, Bellaria Hospital, via Altura 3, 40139, Bologna, Italy

    Sofia Asioli, Maria P. Foschini & Luca Morandi

  3. Unit of Maxillofacial Surgery, S. Orsola Hospital, Bologna, Italy

    Achille Tarsitano & Claudio Marchetti

  4. Unit of Anatomic Pathology, S. Orsola Hospital, Bologna, Italy

    Tiziana Balbi

  5. Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK

    Timothy R. Helliwell

Authors
  1. Andrea Gabusi
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  2. Davide Bartolomeo Gissi
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  3. Lucio Montebugnoli
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  4. Sofia Asioli
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  5. Achille Tarsitano
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  6. Claudio Marchetti
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  7. Tiziana Balbi
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  8. Timothy R. Helliwell
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  9. Maria P. Foschini
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  10. Luca Morandi
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Contributions

AG, LMor, MPF, LMon, conceived and designed the study; AG, LMor, LMon, MPF, SA, AT, CM, DG, TB, TH researched and analysed the data; TH, AG, LMor, MPF, edited and reviewed the manuscript. All authors gave final approval for publication. LMor takes full responsibility for the work as a whole, including the study design, access to data and the decision to submit and publish the manuscript.

Corresponding author

Correspondence to Luca Morandi.

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The authors have declared no conflicts of interest.

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Gabusi, A., Gissi, D.B., Montebugnoli, L. et al. Prognostic impact of intra-field heterogeneity in oral squamous cell carcinoma. Virchows Arch 476, 585–595 (2020). https://doi.org/10.1007/s00428-019-02656-z

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