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Simple Summary: Patients with Fanconi anemia (FA) have a very high risk of developing oral lesions and squamous carcinomas at early ages. As treatment strategies in this setting are very limited, new early diagnosis methods are urgently needed. We performed a pilot, prospective clinical study in which saliva and plasma samples were analyzed with the deep sequencing of cancer genes. The patients included had apparently normal oral mucosa when recruited. Mutations were detected in the liquid biopsies with allele frequencies of down to 0.07%. We found that patients with mutations displayed a higher risk of developing lesions/carcinomas after mutation detection. We propose that this non-invasive, highly sensitive technology could allow for the better management of these pathologies in FA individuals. Fanconi anemia (FA) patients display an exacerbated risk of oral squamous cell carcinoma (OSCC) and oral potentially malignant lesions (OPMLs) at early ages. As patients have defects in their DNA repair mechanisms, standard-of-care treatments for OSCC such as radiotherapy and chemotherapy, give rise to severe toxicities. New methods for early diagnosis are urgently needed to allow for treatment in early disease stages and achieve better clinical outcomes. We conducted a prospective, longitudinal study wherein liquid biopsies from sixteen patients with no clinical diagnoses of OPML and/or OSCC were analyzed for the presence of mutations in cancer genes. The DNA from saliva and plasma were sequentially collected and deep-sequenced, and the clinical evaluation followed over a median time of approximately 2 years. In 9/16 FA patients, we detected mutations in cancer genes (mainly TP53) with minor allele frequencies (MAF) of down to 0.07%. Importantly, all patients that had mutations and clinical follow-up data after mutation detection (n = 6) developed oral precursor lesions or OSCC. The lead-time between mutation detection and tumor diagnosis ranged from 23 to 630 days. Strikingly, FA patients without mutations displayed a significantly lower risk of developing precursor lesions or OSCCs. Therefore, our diagnostic approach could help to stratify FA patients into risk groups, which would allow for closer surveillance for OSCCs or precursor lesions. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of specific biomarkers to monitor response to the several available cancer drugs is a major challenge for modern clinical oncology. A reasonable solution for this problem could be to use circulating biomarkers linked to the tumor cell death induced by therapeutic treatment, instead of biomarkers linked to the molecular action of each drug. To test our hypothesis, we selected SOD2, an abundant mitochondrial protein extremely stable. During our studies, we proved that drug-induced tumor cell death increases the plasma levels of SOD2 correlating with the response to neoadjuvant therapy in breast cancer patients. We believe that measuring the circulating levels of SOD2 during therapeutic treatment of advanced cancer patients could offer a simple, non-invasive diagnostic tool complementing standard imaging techniques. There is a great need for non-invasive tools that inform of an early molecular response to cancer therapeutic treatment. Here, we tested the hypothesis that proteolytically resistant proteins could be candidate circulating tumor biomarkers for cancer therapy. Proteins resistant to proteolysis are drastically under-sampled by current proteomic workflows. These proteins could be reliable sensors for the response to therapy since they are likely to stay longer in circulation. We selected manganese superoxide dismutase (SOD2), a mitochondrial redox enzyme, from a screening of proteolytic resistant proteins in breast cancer (BC). First, we confirmed the robustness of SOD2 and determined that its proteolytic resistance is mediated by its quaternary protein structure. We also proved that the release of SOD2 upon chemotherapy treatment correlates with cell death in BC cells. Then, after confirming that SOD2 is very stable in human serum, we sought to measure its circulating levels in a cohort of BC patients undergoing neoadjuvant therapy. The results showed that circulating levels of SOD2 increased when patients responded to the treatment according to the tumor shrinkage during neoadjuvant chemotherapy. Therefore, the measurement of SOD2 levels in plasma could improve the non-invasive monitoring of the therapeutic treatment in breast cancer patients. The identification of circulating biomarkers linked to the tumor cell death induced by treatment could be useful for monitoring the action of the large number of cancer drugs currently used in clinics. We envision that our approach could help uncover candidate tumor biomarkers to measure a tumor's response to cancer therapy in real time by sampling the tumor throughout the course of treatment. [ABSTRACT FROM AUTHOR]