prognostic value of intratumour and intra field heterogeneity rate in predicting second events in oral squamous cell carcinoma
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1
University of Bologna, Department of Biomedical and Neuro-Muscular Sciences - Section of Oral Science, Italy
Aim. Improvements in sequencing technologies have revealed that genetic differences among neoplastic cells may reflect clonal expansion and thereby the coexistence of multiple subclones in a single tumour. Prognostic implications of intratumour heterogeneity are not fully understood. Aim of this project was to investigate if the degree of intratumour heterogeneity was related to tumour progression in oral squamous cell carcinoma (OSCC).
Materials and Methods. Patients operated for OSCC and attending regular follow up for disease relapse at the Unit of Oral Medicine and Maxillofacial Surgery S.Orsola Hospital, University of Bologna were recruited for the study in order to include both recurrent and non recurrent OSCC. Inclusion criteria: diagnosis of primary tumor of T2-T4 according to the p-TNM classification of tumours, absence of nodal involvement, history of non-smokers, absence of lichenoid inflammation in tumour microenvironment, surgical margin of resection free from neoplasia, Follow up ≥ 3 years after surgical resection. Multiple samples were obtained from each tumour and from related adjacent non neoplastic mucosa. Next generation sequencing for mutational analysis was applied for 10 OSCC tumour specific genes: KRAS ,NRAS, HRAS, BRAF, PIK3CA, TP53, NOTCH1, PTEN , CDKN2A, EGFR. The degree of ITH for OSCC somatic mutations was derived by calculating the heterogeneity rates (HR) of all affected genes and dividing that sum by the number of affected genes not shared by all tumor regions. These values were used to compare the ITH in the group of recurrent and non recurrent OSCCs.
Results. HR values between groups were then statistically compared using the non parametric U-Mann-Whitney test for independent samples (IBM® SPSS Software v.21). P value in primary tumours scored 0,095 and did not reach significativity indicating the absence of a statistical difference in the degree of intratumor heterogeneity among the groups of recurrent and non recurrent OSCC.By contrast, U-Mann-Whitney test performed on samples from non neoplastic adjacent mucosa disclosed that non recurrent OSCC tends to exhibit statistically lower values of HR if compared to recurrent OSCCs ( p= 0,032).
Discussion. According to our results , in primary tumours, no particular degree of heterogeneity was able to distinguish OSCC with aggressive local behaviors. Genetic instability in tumours may produce heterogeneous subclones but not all subclones may reflect aggressive behaviors. On the other hand, ITH analysis of non neoplastic adjacent mucosa disclosed that non recurrent OSCC tends to exhibit statistically lower values of HR if compared to recurrent OSCCs ( p= 0,032). Fields of less aggressive OSCCs are thus more homogeneous. A prognostic implication of genetic heterogeneity of pre neoplastic field is here documented for the first time.
References
1. Cao W, Wu W, Yan M, Tian F, Ma C, Zhang Q, et al. Multiple region whole-exome sequencing reveals dramatically evolving intratumor genomic heterogeneity in esophageal squamous cell carcinoma. Oncogenesis. 2015 Nov 30;4:e175.
Keywords:
Oral squamous cell carcinoma (OSCC),
Intratumor heterogeneity (ITH),
Field cancerization,
Prognostic value,
second primary cancer
Conference:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.
Presentation Type:
Poster Presentation
Topic:
Oral Diseases
Citation:
Gabusi
A,
Gissi
D,
Rossi
R and
Morandi
L
(2019). prognostic value of intratumour and intra field heterogeneity rate in predicting second events in oral squamous cell carcinoma.
Front. Physiol.
Conference Abstract:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine..
doi: 10.3389/conf.fphys.2019.27.00050
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Received:
02 Nov 2018;
Published Online:
09 Dec 2019.
*
Correspondence:
Dr. Andrea Gabusi, University of Bologna, Department of Biomedical and Neuro-Muscular Sciences - Section of Oral Science, Bologna, Emilia-Romagna, 40126, Italy, andrea.gabusi3@unibo.it