Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma

Schubert, Adrian D.; Broner, Esther Channah; Agrawal, Nishant; London, Nyall R.; Pearson, Alexander; Gupta, Anuj; Wali, Neha; Seiwert, Tanguy Y.; Wheelan, Sarah J.; Lingen, Mark W.; Macleod, Kay F.; Allen, Hailey; Chatterjee, Aditi; Saloura, Vassiliki; Gaykalova, Daria A.; Hoque, Mohammad Obaidul; Sidransky, David; Suresh, Karthik; Izumchenko, Evgeny

doi:10.1016/j.canlet.2019.12.006

Cited by 12 publications

(11 citation statements)

References 76 publications

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“…Moreover, the ratio of non-synonymous to synonymous mutations in cancer tissue was higher than in matched blood samples, showing a positive selection of non-synonymous mutations in OSCC tumors, similar to what we also observed in our samples. Surprisingly, another study recently published [ 24 ] detected 166 somatic point mutations in half of the cancer samples (14 out of 28) and none in the other half of the samples. However, in line with our results, the majority of the identified mutations were located in the protein-coding region.…”

Section: Discussionmentioning

confidence: 94%

“…Only a few studies used next-generation sequencing techniques and investigated heteroplasmic variants in the whole mtDNA [ 18 , 23 , 24 ]. Recently, Palodhi et al [ 23 ] investigated tumor tissue and matched blood samples from 89 OSCC patients.…”

Section: Discussionmentioning

confidence: 99%

“…The majority, however, suffered from limitations such as low sensitivity Sanger sequencing on a very small part of the mtDNA genome, like the D-Loop that undermined the original claims. Only a few studies presented data from deep next-generation sequencing of the whole mtDNA [ 18 , 23 , 24 ]. In addition to this, the literature displays sequence artifacts [ 25 ] misinterpreted as pathogenic mtDNA mutation emphasizing the necessity for the establishment of a reliable sequencing strategy.…”

Section: Introductionmentioning

confidence: 99%

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Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Fendt

Fazzini

Weißensteiner

et al. 2020

Cancers

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While a shift in energy metabolism is essential to cancers, the knowledge about the involvement of the mitochondrial genome in tumorigenesis and progression in oral squamous cell carcinoma (OSCC) is still very limited. In this study, we evaluated 37 OSCC tumors and the corresponding benign mucosa tissue pairs by deep sequencing of the complete mitochondrial DNA (mtDNA). After extensive quality control, we identified 287 variants, 137 in tumor and 150 in benign samples exceeding the 1% threshold. Variant heteroplasmy levels were significantly increased in cancer compared to benign tissues (p = 0.0002). Furthermore, pairwise high heteroplasmy frequency difference variants (∆HF% > 20) with potential functional impact were increased in the cancer tissues (p = 0.024). Fourteen mutations were identified in the protein-coding region, out of which thirteen were detected in cancer and only one in benign tissue. After eight years of follow-up, the risk of mortality was higher for patients who harbored at least one ∆HF% > 20 variant in mtDNA protein-coding regions relative to those with no mutations (HR = 4.6, (95%CI = 1.3–17); p = 0.019 in primary tumor carriers). Haplogroup affiliation showed an impact on survival time, which however needs confirmation in a larger study. In conclusion, we observed a significantly higher accumulation of somatic mutations in the cancer tissues associated with a worse prognosis.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Fendt

Fazzini

Weißensteiner

et al. 2020

Cancers

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“…Therefore, diseases where the progression can be correlated with or compensated for mitochondrial function are collectively referred as mitochondrial diseases. At present, in addition to neurodegenerative disorders ( Baldassarro et al, 2019 ), there are numerous diseases related to abnormal mitochondrial structure and function, including mental diseases ( Ashwini et al, 2015 ), tumor ( Schubert et al, 2020 ), aging ( Bornstein et al, 2020 ), cardiovascular disease ( Veloso et al, 2019 ), diabetes ( Szendroedi et al, 2012 ), etc. Therapeutics which target mitochondria also result in positive responses in some cases ( Jeena et al, 2019 ).…”

Section: The Structure Function and Related Diseases Of Mitochondriamentioning

confidence: 99%

Recent Advances in Chemical Biology of Mitochondria Targeting

et al. 2021

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Mitochondria are vital subcellular organelles that generate most cellular chemical energy, regulate cell metabolism and maintain cell function. Mitochondrial dysfunction is directly linked to numerous diseases including neurodegenerative disorders, diabetes, thyroid squamous disease, cancer and septicemia. Thus, the design of specific mitochondria-targeting molecules and the realization of real-time acquisition of mitochondrial activity are powerful tools in the study and treatment of mitochondria dysfunction in related diseases. Recent advances in mitochondria-targeting agents have led to several important mitochondria chemical probes that offer the opportunity for selective targeting molecules, novel biological applications and therapeutic strategies. This review details the structural and physiological functional characteristics of mitochondria, and comprehensively summarizes and classifies mitochondria-targeting agents. In addition, their pros and cons and their related chemical biological applications are discussed. Finally, the potential biomedical applications of these agents are briefly prospected.

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“…It is known that, as tumor grows, it sheds tumor cells and DNA into various body fluids, including saliva. [28][29][30][31][32] The presence of tumor cells and tumor-derived DNA (tDNA) in saliva from patients with head and neck cancer is well documented. [33][34][35] Several studies have indicated that mutations in tDNA exactly correspond to mutations in the primary tumor 31,[36][37][38] and thus could be used as a surrogate for a biopsy.…”

Section: Introductionmentioning

confidence: 99%

Ultrasensitive detection of tumor‐specific mutations in saliva of patients with oral cavity squamous cell carcinoma

Shanmugam

Hariharan

Hasina

et al. 2021

Cancer

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BACKGROUND: Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck malignancy. Although the survival rate of patients with advanced-stage disease remains approximately 20% to 60%, when detected at an early stage, the survival rate approaches 80%, posing a pressing need for a well validated profiling method to assess patients who have a high risk of developing OCSCC. Tumor DNA detection in saliva may provide a robust biomarker platform that overcomes the limitations of current diagnostic tests. However, there is no routine saliva-based screening method for patients with OCSCC. METHODS: The authors designed a custom nextgeneration sequencing panel with unique molecular identifiers that covers coding regions of 7 frequently mutated genes in OCSCC and applied it on DNA extracted from 121 treatment-naive OCSCC tumors and matched preoperative saliva specimens. RESULTS: By using stringent variant-calling criteria, mutations were detected in 106 tumors, consistent with a predicted detection rate ≥88%. Moreover, mutations identified in primary malignancies were also detected in 93% of saliva samples. To ensure that variants are not errors resulting in false-positive calls, a multistep analytical validation of this approach was performed: 1) re-sequencing of 46 saliva samples confirmed 88% of somatic variants; 2) no functionally relevant mutations were detected in saliva samples from 11 healthy individuals without a history of tobacco or alcohol; and 3) using a panel of 7 synthetic loci across 8 sequencing runs, it was confirmed that the platform developed is reproducible and provides sensitivity on par with droplet digital polymerase chain reaction. CONCLUSIONS: The current data highlight the feasibility of somatic mutation identification in driver genes in saliva collected at the time of OCSCC diagnosis.

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Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma

Cited by 12 publications

References 76 publications

Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Profiling of Mitochondrial DNA Heteroplasmy in a Prospective Oral Squamous Cell Carcinoma Study

Recent Advances in Chemical Biology of Mitochondria Targeting

Ultrasensitive detection of tumor‐specific mutations in saliva of patients with oral cavity squamous cell carcinoma

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