Field Carcinogenesis Research Articles

Multi-regional genomic and transcriptomic characterization of a melanoma-associated oral cavity cancer provide evidence for CASP8 alteration-mediated field cancerization

BackgroundPrecancerous and malignant tumours arise within the oral cavity from a predisposed “field” of epithelial cells upon exposure to carcinogenic stimulus. This phenomenon is known as “Field Cancerization”. The molecular genomic and transcriptomic alterations that lead to field cancerization and tumour progression is unknown in Indian Oral squamous cell carcinoma (OSCC) patients.MethodsWe have performed whole exome sequencing, copy-number variation array and whole transcriptome sequencing from five tumours and dysplastic lesions (sampled from distinct anatomical subsites - one each from buccal anterior and posterior alveolus, dorsum of tongue–mucosal melanoma, lip and left buccal mucosa) and blood from a rare OSCC patient with field cancerization.ResultsA missense CASP8 gene mutation (p.S375F) was observed to be the initiating event in oral tumour field development. APOBEC mutation signatures, arm-level copy number alterations, depletion of CD8 + T cells and activated NK cells and enrichment of pro-inflammatory mast cells were features of early-originating tumours. Pharmacological inhibition of CASP8 protein in a CASP8-wild type OSCC cell line showed enhanced levels of cellular migration and viability.ConclusionCASP8 alterations are the earliest driving events in oral field carcinogenesis, whereas additional somatic mutational, copy number and transcriptomic alterations ultimately lead to OSCC tumour formation and progression.

Early screening of colorectal cancer using feature engineering with artificial intelligence-enhanced analysis of nanoscale chromatin modifications

Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7 to 8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5 to 20 nm, ~1 kbp) fold into chromatin packing domains (~ 100 to 200 nm, ~ 100 to 1000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity of cancer cells. We deployed an optical spectroscopic nanosensing technique, chromatin-sensitive partial wave spectroscopic microscopy (csPWS), to evaluate the packing density scaling D of the chromatin chain conformation within packing domains from rectal mucosa in 256 patients with varying degrees of progression to colorectal cancer. We found average packing scaling D of chromatin domains was elevated in tumor cells, histologically normal-appearing cells 4 cm proximal to the tumor, and histologically normal-appearing rectal mucosa compared to cells from control patients (p < 0.001). Nuclear D had a robust correlation with the model of 5-year risk of CRC with r2 = 0.94. Furthermore, rectal D was evaluated as a screening biomarker for patients with advanced adenomas presenting an AUC of 0.85 and 85% sensitivity and specificity. artificial intelligence-enhanced csPWS improved diagnostic performance with AUC = 0.90. Considering the low sensitivity of existing CRC tests, including liquid biopsies, to early-stage cancers our work highlights the potential of chromatin biomarkers of field carcinogenesis in detecting early, significant precancerous colon lesions.

Mapping cutaneous field carcinogenesis of nonmelanoma skin cancer using mesoscopic imaging of pro-inflammation cues.

Nonmelanoma skin cancers remain the most widely diagnosed types of cancers globally. Thus, for optimal patient management, it has become imperative that we focus our efforts on the detection and monitoring of cutaneous field carcinogenesis. The concept of field cancerization (or field carcinogenesis), introduced by Slaughter in 1953 in the context of oral cancer, suggests that invasive cancer may emerge from a molecularly and genetically altered field affecting a substantial area of underlying tissue including the skin. A carcinogenic field alteration, present in precancerous tissue over a relatively large area, is not easily detected by routine visualization. Conventional dermoscopy and microscopy imaging are often limited in assessing the entire carcinogenic landscape. Recent efforts have suggested the use of noninvasive mesoscopic (between microscopic and macroscopic) optical imaging methods that can detect chronic inflammatory features to identify pre-cancerous and cancerous angiogenic changes in tissue microenvironments. This concise review covers major types of mesoscopic optical imaging modalities capable of assessing pro-inflammatory cues by quantifying blood haemoglobin parameters and hemodynamics. Importantly, these imaging modalities demonstrate the ability to detect angiogenesis and inflammation associated with actinically damaged skin. Representative experimental preclinical and human clinical studies using these imaging methods provide biological and clinical relevance to cutaneous field carcinogenesis in altered tissue microenvironments in the apparently normal epidermis and dermis. Overall, mesoscopic optical imaging modalities assessing chronic inflammatory hyperemia can enhance the understanding of cutaneous field carcinogenesis, offer a window of intervention and monitoring for actinic keratoses and nonmelanoma skin cancers and maximise currently available treatment options.

Abstract IA011: Understanding field carcinogenesis in obesity-related endometrial cancer

Abstract Over the last decade, endometrial cancer (EC) incidence has increased at an average rate of 0.8% each year. Although cancer death rates decreased during this time, EC showed the greatest increase in cancer death among women. Public awareness of EC remains low, and EC research remains underfunded relative to its societal burden. While most women with EC are post-menopausal, up to 30% of cases occur in pre-menopausal women under 50 years of age, with obesity being a major risk factor. More than half of all EC is associated with obesity. Obesity is also a leading risk factor for benign endometrial hyperplasia, which is considered the precursor lesion to EC. Like other cancers, the causes of EC are multifactorial, with obesity and somatic mutations playing causal roles. By 2030, half of all adult women in the U.S. are expected to be classified as obese. Therefore, EC incidence is expected to increase. If detected early, EC can be cured with surgical hysterectomy, but this solution is not ideal for all women. Intentional weight loss can lower endometrial cancer risk in obese women, but certain barriers prevent obese, at-risk women from losing weight or maintaining healthy lifestyles while living in obesogenic environments. There is a critical need to understand the biological mechanisms underlying EC pathogenesis in at-risk obese women. Although EC is thought to arise from a hyperplastic endometrial epithelium, our previous findings suggest that high-fat diet induced obesity affects other cell types within the endometrial microenvironment, including endometrial stroma and immune cells, in the absence of histopathological change. Common EC somatic mutations can also arise in the absence of histopathological change or occur in cases of benign disease. Our overarching hypothesis is that a normal appearing endometrium may accrue cell-context dependent alterations in response to obesity and somatic mutations across a pre-malignant tissue field that are predictive of malignant transformation. This presentation will highlight our recent work on the combined molecular and phenotypic effects of obesity and common EC driver mutations on the endometrial tissue field. The identification of high-value molecular targets across the endometrial pre-malignant field may inform new early detection and prevention strategies for EC. Citation Format: Ronald Chandler. Understanding field carcinogenesis in obesity-related endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA011.

Early detection of lung cancer using artificial intelligence-enhanced optical nanosensing of chromatin alterations in field carcinogenesis

Supranucleosomal chromatin structure, including chromatin domain conformation, is involved in the regulation of gene expression and its dysregulation has been associated with carcinogenesis. Prior studies have shown that cells in the buccal mucosa carry a molecular signature of lung cancer among the cigarette-smoking population, the phenomenon known as field carcinogenesis or field of injury. Thus, we hypothesized that chromatin structural changes in buccal mucosa can be predictive of lung cancer. However, the small size of the chromatin chain (approximately 20 nm) folded into chromatin packing domains, themselves typically below 300 nm in diameter, preclude the detection of alterations in intradomain chromatin conformation using diffraction-limited optical microscopy. In this study, we developed an optical spectroscopic statistical nanosensing technique to detect chromatin packing domain changes in buccal mucosa as a lung cancer biomarker: chromatin-sensitive partial wave spectroscopic microscopy (csPWS). Artificial intelligence (AI) was applied to csPWS measurements of chromatin alterations to enhance diagnostic performance. Our AI-enhanced buccal csPWS nanocytology of 179 patients at two clinical sites distinguished Stage-I lung cancer versus cancer-free controls with an area under the ROC curve (AUC) of 0.92 ± 0.06 for Site 1 (in-state location) and 0.82 ± 0.11 for Site 2 (out-of-state location).

Initial development and testing of an exhaled microRNA detection strategy for lung cancer case–control discrimination

For detecting field carcinogenesis non-invasively, early technical development and case–control testing of exhaled breath condensate microRNAs was performed. In design, human lung tissue microRNA-seq discovery was reconciled with TCGA and published tumor-discriminant microRNAs, yielding a panel of 24 upregulated microRNAs. The airway origin of exhaled microRNAs was topographically “fingerprinted”, using paired EBC, upper and lower airway donor sample sets. A clinic-based case–control study (166 NSCLC cases, 185 controls) was interrogated with the microRNA panel by qualitative RT-PCR. Data were analyzed by logistic regression (LR), and by random-forest (RF) models. Feasibility testing of exhaled microRNA detection, including optimized whole EBC extraction, and RT and qualitative PCR method evaluation, was performed. For sensitivity in this low template setting, intercalating dye-based URT-PCR was superior to fluorescent probe-based PCR (TaqMan). In application, adjusted logistic regression models identified exhaled miR-21, 33b, 212 as overall case–control discriminant. RF analysis of combined clinical + microRNA models showed modest added discrimination capacity (1.1–2.5%) beyond clinical models alone: all subjects 1.1% (p = 8.7e−04)); former smokers 2.5% (p = 3.6e−05); early stage 1.2% (p = 9.0e−03), yielding combined ROC AUC ranging from 0.74 to 0.83. We conclude that exhaled microRNAs are qualitatively measureable, reflect in part lower airway signatures; and when further refined/quantitated, can potentially help to improve lung cancer risk assessment.

Field carcinogenesis and biological significance of the potential of the bystander effect: carcinogenesis, therapeutic response, and tissue regeneration.

The "bystander effect" is a transmission phenomenon mediating communication from target to non-target cells, as well as cell-to-cell interactions between neighboring and distantly located cells. In this narrative review, we describe the fundamental and clinical significance of the bystander effect with respect to cell-to-cell interactions in carcinogenesis, therapeutic response, and tissue regeneration. In carcinogenesis, the bystander effect mediates communications between tumor microenvironments and non-malignant epithelial cells and has been suggested to impact heterogeneous tumorigenic cells in tumors and cancerized fields. In therapeutic response, the bystander effect mediates communications between drug-sensitive and drug-resistant cells and may transmit both drug efficacy and resistance. Therefore, control of therapeutic response transmission via the bystander effect might offer a promising future cancer treatment. Finally, in tissue regeneration, circulating cells and stromal cells may differentiate into various cells for the purpose of tissue regeneration under direction of the bystander effect arising from surrounding cells in a defective space. We hope that the findings we present will promote the development of innovative cancer therapies and tissue regeneration methodologies from the viewpoint of cell-to-cell interactions through the bystander effect.

A Review of Existing Therapies for Actinic Keratosis: Current Status and Future Directions.

Actinic keratosis (AK) is a chronic skin disease in which clinical and subclinical cutaneous lesions coexist on sun-exposed areas such as the head and neck region and the extremities. The high prevalence of AK means the disease burden is substantial, especially in middle-aged and elderly populations. Evidence indicates that AK may progress into invasive cutaneous squamous cell carcinoma, so the European guidelines recommend treatment of any AK regardless of clinical severity. Given the aging population and therefore the increasing incidence of AK and cutaneous field carcinogenesis, further updates on the long-term efficacy of current therapies and new investigational agents are critical to guide treatment choice. Patients often have difficulty adequately applying topical treatments and coping with adverse local skin reactions, leading to less than optimum treatment adherence. The development of associated local skin symptoms and cosmetic outcomes for the area of interest are also relevant to the choice of an appropriate therapeutic strategy. Treatment is always individually tailored according to the characteristics of both patients and lesions. This review focuses on the therapeutic approaches to AK and illustrates the currently available home-based and physician-managed treatments.

Field carcinogenesis for risk stratification of colorectal cancer.

Colorectal cancer (CRC) is characterized by genetic-environmental interplay leading to diffuse changes in the entire colonic mucosa (field carcinogenesis or field of injury) and to a pro-neoplastic genetic/epigenetic/physiological milieu. The clinical consequences are increased risk of synchronous and metachronous neoplasia. Factors such as genetics, race, ethnicity, age, and socioeconomic status are thought to influence neoplasia development. Here, we explore the potential improvement to CRC screening through exploiting field carcinogenesis, with particular focus on racial disparities and chemoprevention strategies. Also, we discuss future directions for field carcinogenesis/risk stratification using molecular and novel biophotonic techniques for personalized CRC screening.

Field Carcinogenesis in Cancer Evolution: What the Cell Is Going On?

Field carcinogenesis describes the prevalence of tumor-related alterations in normal appearing tissues. Here, we summarize recent efforts in profiling molecular field dynamics for resolving early events in cancer evolution. We also highlight gaps in our knowledge of the molecular and cellular heterogeneity of field carcinogenesis and propose directions to tackle these voids using single-cell-based approaches and unique tissue sampling models. By interrogating both the mutagenized epithelium and its microenvironment, we surmise that single-cell-guided studies will help chart the spatiotemporal molecular and cellular "atlas" of field carcinogenesis, will further delineate preneoplastic initiation and progression, and will help identify cancer prevention and early intervention targets.

Abstract 1518: A single-cell transcriptomic atlas of lung adenocarcinoma and adjacent normal-appearing tissue

Abstract Lung adenocarcinoma (LUAD) is the most frequently diagnosed histological subtype of lung cancer and accounts for most smoking-related cancer deaths, warranting strategies for early intervention. Earlier work revealed genome-wide aberrations in LUADs and the adjacent premalignant field, known as “field carcinogenesis”, that are pertinent to LUAD pathogenesis. Yet, we still poorly understand the cellular and molecular architecture of LUAD and its nearby “field”. To fill this void, we performed, using the 10X Genomics system and NovaSeq 6000 platform, single-cell RNA sequencing (scRNA-seq) analysis of 4 early-stage resected LUADs as well as 11 matched normal lung tissues with differing spatial proximity from the tumors. We first analyzed 15,739 cells from a LUAD and matched tumor-adjacent and -distant normal tissues from patient 1. The resulting fraction of EPCAM+ cells from this analysis was approximately 4%. For deeper single-cell resolution of LUAD, we thus performed scRNA-seq of separately sorted/enriched epithelial cells (EPCAM+; n = 50,883) and non-epithelial cells (EPCAM-; n= 91,093) from patients 2, 3 and 4, each with an early-stage LUAD and three matched spatially-distributed normal-appearing tissues. Overall, we achieved on average approximately 150,000 reads and 1,956 genes detected per cell. Divergent populations of malignant and non-malignant cells and multiple epithelial and immune subsets clustered in an overall spatially modulated pattern according to proximity to the tumor. Hierarchical clustering revealed multiple distinct populations of airway lineage cells, including alveolar type 1 (AT1), alveolar type 2 (AT2), AT1/AT2 bipotential cells, club, goblet, basal and ciliated cells, with cells from the resected LUAD present in some but not all clusters. By analysis of epithelial-enriched fractions, we were also able to identify and interrogate rare cell subpopulations including CFTR-expressing ionocytes. By inference of copy number variation along with analysis of key oncogene expression patterns, we also identified epithelial cells that represent potential tumor cells-of-origin. Spatial reprogramming of field carcinogenesis encompassed immune cell populations including tumor-exclusive FOXP3+ regulatory T cells with marked over-expression of the major immune checkpoints CTLA4 and TIGIT. In contrast, for at least some of the cases, tumors were nearly devoid of natural killer cells, and abundance of CD8+ T cells dampened with increasing proximity to the tumor. Our single-cell surveys offer insights into novel cues in LUAD pathogenesis. Efforts are underway to interrogate the single-cell epithelial and immune landscape of additional LUADs and matched nearby normal-appearing lung, including those from non-smokers, to better understand the evolution of the disease and, thus, identify a low-hanging fruit of targets for early management of this fatal malignancy. Citation Format: Ansam Sinjab, Guangchun Han, Warapen Treekitkarnmongkol, Patrick Brennan, Kieko Hara, Kyle Chang, Elena Bogatenkova, Beatriz Sanchez-Espiridion, Carmen Behrens, Jianjun Zhang, Boris Sepesi, Tina Cascone, Don L. Gibbons, Jichao Chen, George Eapen, Edwin J. Ostrin, Junya Fujimoto, Avrum E. Spira, Paul A. Scheet, Ignacio I. Wistuba, Linghua Wang, Humam Kadara. A single-cell transcriptomic atlas of lung adenocarcinoma and adjacent normal-appearing tissue [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1518.

The actinic dysplasia syndrome - diagnostic approaches defining a new concept in field carcinogenesis with multiple cSCC.

Usually, SCC lesions are surrounded by a number of clinically visible and non-visible (subclinical) areas of actinically damaged skin containing cells with dysplasia, and thus may be designated actinic dysplasia syndrome. The epithelial damage is caused mainly by UV radiation, inducing mutations in keratinocytes that may confer growth advantages resulting in preneoplastic fields. The development of visible dysplastic lesions (actinic keratosis - AK) and subsequent progression to invasive SCC requires further mutations in cancer-associated genes, like tumour suppressor genes and cell cycle regulators. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) represent a considerable advantage for the investigation of field cancerization. In addition, imaging allows the non-invasive monitoring of topical treatments for AKs. RCM provides invivo horizontal skin sections with a high, 1-μm lateral resolution (similar to histopathology) but with a limited penetration (about 200μm), which can hamper the visualization of important areas such as the dermal-epidermal junction. Conventional OCT has better penetration (1-2mm) at the expense of a more limited resolution (much lower than histopathology). Line-field confocal OCT (LC-OCT) combines the high precision of RCM and the good penetration of OCT in a single device and therefore appears to be very useful in diagnosing/managing AKs.

Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer.

Rationale: Uninvolved normal-appearing airway epithelium has been shown to exhibit specific mutations characteristic of nearby non-small cell lung cancers (NSCLCs). Yet, its somatic mutational landscape in patients with early-stage NSCLC is unknown.Objectives: To comprehensively survey the somatic mutational architecture of the normal airway epithelium in patients with early-stage NSCLC.Methods: Multiregion normal airways, comprising tumor-adjacent small airways, tumor-distant large airways, nasal epithelium and uninvolved normal lung (collectively airway field), matched NSCLCs, and blood cells (n = 498) from 48 patients were interrogated for somatic single-nucleotide variants by deep-targeted DNA sequencing and for chromosomal allelic imbalance events by genome-wide genotype array profiling. Spatiotemporal relationships between the airway field and NSCLCs were assessed by phylogenetic analysis.Measurements and Main Results: Genomic airway field carcinogenesis was observed in 25 cases (52%). The airway field epithelium exhibited a total of 269 somatic mutations in most patients (n = 36) including key drivers that were shared with the NSCLCs. Allele frequencies of these acquired variants were overall higher in NSCLCs. Integrative analysis of single-nucleotide variants and allelic imbalance events revealed driver genes with shared "two-hit" alterations in the airway field (e.g., TP53, KRAS, KEAP1, STK11, and CDKN2A) and those with single hits progressing to two in the NSCLCs (e.g., PIK3CA and NOTCH1).Conclusions: Tumor-adjacent and tumor-distant normal-appearing airway epithelia exhibit somatic driver alterations that undergo selection-driven clonal expansion in NSCLC. These events offer spatiotemporal insights into the development of NSCLC and, thus, potential targets for early treatment.

Correction: Biophotonic detection of high order chromatin alterations in field carcinogenesis predicts risk of future hepatocellular carcinoma: A pilot study.

[This corrects the article DOI: 10.1371/journal.pone.0197427.].

PO-503 The cohesin stromal antigen 1 (SA-1) modulates colonic and colorectal cancer (CRC) stem cells: mechanism for racial disparities

IntroductionCRC disproportionately impacts African-Americans (incidence and mortality increased by ~25% and~50%, respectively). While mechanisms remain unclear, Vogelstein posited that the number of stem cell divisions determine CRC risk Science 2015. CRC stem cells may impact mortality via chemoresistance. LGR5, aldehyde dehydrogenase (ALDH1a3) and DCAMKL1 are markers of both intestinal and CRC stem cells. We have noted loss of SA-1 (a chromatin remodeler) occurred during colonic field carcinogenesis was markedly accentuated in Blacks (Cancer Prev Res 2016) via specific SNPs (Neoplasia 2018). SA-1 loss was also associated with poorer CRC prognosis. We hypothesised that SA-1 loss leads to stem cell induction and hence CRC disparities.Material and methodsRectal biopsies were obtained from endoscopically normal mucosa from ~200 patients undergoing screening colonoscopy with an IRB approved protocol. SA-1 was assessed by RT-PCR normalised to β-actin. We modulated SA-1 in human CRC cell line HT29 and tested efficacy of chemotherapy 5 fluorouracil (5-FU) and oxaliplatin via annexin V apoptosis assay.Results and discussionsAdenoma-harbouring subjects had ~50% increase in LGR5, ALD1a3 and DCAMKL1 (p<0.05) with concomitant suppression of SA-1. Causality was indicated by demonstrating that SiRNA SA-1 knockdowns (KD) in HT29 cells caused stem cell marker induction (LGR5=380%, ALD1a3=30% and DCAMKL1=85%, p<0.05). SA-1 overexpression resulted in reciprocal effects downregulation of all 3 stem cell markers. Functionally, SA-1 KD suppressed 5-FU and oxaliplatin induced apoptosis by 56% and 72% respectively versus scramble vector (p<0.0001). Underscoring racial disparities relevance was the observation that Blacks have a 31% greater SA1 loss vs. Whites (p<0.0004) which mirrored a 35% higher upregulation in LGR5 and ALDH1a3 (p<0.05). CRISPR editing of RKO cells to have the SNP rs34149860 (found only in Blacks) resulted in SA1 loss (41% loss, p<0.005) and concomitant ~45% LGR5 and ALDH1a3 upregulation (p<0.05).ConclusionThis novel finding that the proneoplastic effects of SA-1 loss may be transduced through intestinal/colonic stem cell (CRC incidence) and also augmenting CRC stem cells resulting in chemotherapy resistance (CRC mortality). Future studies may mitigate CRC disparities in Blacks through development of effective biomarkers and therapeutic.

Biophotonic detection of high order chromatin alterations in field carcinogenesis predicts risk of future hepatocellular carcinoma: A pilot study.

PurposeHepatocellular carcinoma (HCC) results from chronic inflammation/cirrhosis. Unfortunately, despite use of radiological/serological screening techniques, HCC ranks as a leading cause of cancer deaths. Our group has used alterations in high order chromatin as a marker for field carcinogenesis and hence risk for a variety of cancers (including colon, lung, prostate, ovarian, esophageal). In this study we wanted to address whether these chromatin alterations occur in HCC and if it could be used for risk stratification.Experimental designA case control study was performed in patients with cirrhosis who went on to develop HCC and patients with cirrhosis who did not develop cancer. We performed partial wave spectroscopic microscopy (PWS) which measures nanoscale alterations on formalin fixed deparaffinized liver biopsy specimens, 17 progressors and 26 non-progressors. Follow up was 2089 and 2892 days, respectively.ResultsPWS parameter disorder strength Ld were notably higher for the progressors (Ld = 1.47 ± 0.76) than the non-progressors (Ld = 1.00 ± 0.27) (p = 0.024). Overall, the Cohen’s d effect size was 0.907 (90.7%). AUROC analysis yielded an area of 0.70. There was no evidence of confounding by gender, age, BMI, smoking status and race.ConclusionsHigh order chromatin alterations, as detected by PWS, is altered in pre-malignant hepatocytes with cirrhosis and may predict future risk of HCC.

Correlating colorectal cancer risk with field carcinogenesis progression using partial wave spectroscopic microscopy.

Prior to the development of a localized cancerous tumor, diffuse molecular, and structural alterations occur throughout an organ due to genetic, environmental, and lifestyle factors. This process is known as field carcinogenesis. In this study, we used partial wave spectroscopic (PWS) microscopy to explore the progression of field carcinogenesis by measuring samples collected from 190 patients with a range of colonic history (no history, low‐risk history, and high‐risk history) and current colon health (healthy, nondiminutive adenomas (NDA; ≥5 mm and <10 mm), and advanced adenoma [AA; ≥10 mm, HGD, or >25% villous features]). The low‐risk history groups include patients with a history of NDA. The high‐risk history groups include patients with either a history of AA or colorectal cancer (CRC). PWS is a nanoscale‐sensitive imaging technique which measures the organization of intracellular structure. Previous studies have shown that PWS is sensitive to changes in the higher‐order (20–200 nm) chromatin topology that occur due to field carcinogenesis within histologically normal cells. The results of this study show that these nanoscale structural alterations are correlated with a patient's colonic history, which suggests that PWS can detect altered field carcinogenic signatures even in patients with negative colonoscopies. Furthermore, we developed a model to calculate the 5‐year risk of developing CRC for each patient group. We found that our data fit this model remarkably well (R 2 = 0.946). This correlation suggests that PWS could potentially be used to monitor CRC progression less invasively and in patients without adenomas, which opens PWS to many potential cancer care applications.

The transformation of the nuclear nanoarchitecture in human field carcinogenesis.

Morphological alterations of the nuclear texture are a hallmark of carcinogenesis. At later stages of disease, these changes are well characterized and detectable by light microscopy. Evidence suggests that similar albeit nanoscopic alterations develop at the predysplastic stages of carcinogenesis. Using the novel optical technique partial wave spectroscopic microscopy, we identified profound changes in the nanoscale chromatin topology in microscopically normal tissue as a common event in the field carcinogenesis of many cancers. In particular, higher-order chromatin structure at supranucleosomal length scales (20–200 nm) becomes exceedingly heterogeneous, a measure we quantify using the disorder strength (Ld) of the spatial arrangement of chromatin density. Here, we review partial wave spectroscopic nanocytology clinical studies and the technology's promise as an early cancer screening technology.

77 - PRDM16-Mediated Metabolic Reprogramming in Colonic Field Carcinogenesis: Potential Role of Sonic Hedgehog Signaling

77 - PRDM16-Mediated Metabolic Reprogramming in Colonic Field Carcinogenesis: Potential Role of Sonic Hedgehog Signaling

PP - ORAL SQUAMOUS CELL CARCINOMA AND FIELD CANCERIZATION IN A PATIENT WITH FANCONI ANEMIA

Fanconi anemia is a chromosomal instability disorder characterized by bone marrow failure and a high risk of cancer. Hematopoietic stem cell transplant (HSCT), chronic graft versus host disease (GVHD) and age can increase the risk for oral squamous cell carcinoma (OSCC). This report details a case of a 19-year-old male patient with FA who had developed OSCC after an allogeneic HSCT. Four years after transplant, the patient was being closely monitored because of scattered white patches on the right buccal mucosa, anterior, and posterior vestibule bilaterally as well as the tongue. The patient also exhibited chronic GVHD in the liver and the eyes. All the oral lesions were analyzed with smear cytometry, but no aneuploid cells were found. The follow-up was scheduled biannually. Four years after HSCT, the patient presented an exophytic and ulcerated lesion on the left commissural mucosa that was submitted for incisional biopsy. The histopathology exam showed a well differentiated OSCC. The surveillance of the oral mucosa in patients with FA is a challenge to the transplant team. The patients with FA should be stimulated to participate in a strict program of oral surveillance for field carcinogenesis because they tend to decrease the follow-up frequency after hematological recovery.