Dietary habits, lifestyles, and overall adherence to 2018 WCRF/AICR cancer prevention recommendations among adult women in the EPIC-Florence cohort: Changes from adulthood to older age and differences across birth cohorts.

OBJECTIVES, SETTING AND PARTICIPANTS: We aimed to examine changes in dietary habits, lifestyles (e.g., smoking, physical activity levels, and alcohol intake), anthropometry, other individual health-relevant characteristics, and overall adherence to 2018 WCRF/AICR cancer prevention recommendations, among women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Florence cohort. DESIGN AND MEASUREMENTS: We fitted age- and energy intake-adjusted generalized linear models to describe (a) changes occurring over a person's lifetime in the transition from adulthood to older age, and (b) differences between women aged 56-60 years belonging to two birth cohorts spaced apart by around 25 years (born in 1933-1941 vs. 1958-1964). RESULTS: Dietary habits and overall adherence to cancer prevention recommendations improved among women (n = 3,309) followed from adulthood to older age (mean age 47.4 and 71.8 years, respectively), despite increases in the prevalence of adiposity and sedentary lifestyle. Women in the younger birth cohort (n = 163) showed significantly greater overall adherence to cancer prevention recommendations than in the older birth cohort (n = 355), but had more often a positive smoking history and an average larger waist circumference. CONCLUSION: A trend toward better adherence to cancer prevention recommendations emerged when analyzing adult-to-older-age trajectories and differences across birth cohort, yet some critical issues were also identified. Continuous monitoring is essential to detect changing prevention needs and adapt public health policies and practices.

Cigarette smoking and mammographic breast density in post-menopausal women from the EPIC Florence cohort.

Introduction: Cigarette smoking has been recognized as a risk factor for breast cancer (BC) also if the biological mechanism remains poorly understood. High mammographic breast density (MBD) is associated with BC risk and many BC risk factors, such as genetic, anthropometric, reproductive and lifestyle factors and age, are also able to modulate MBD. The aim of the present study was to prospectively explore, in post-menopausal women, the association between smoking habits and MBD, assessed using an automated software, considering duration and intensity of smoking. Methods: The analysis was carried out in 3,774 women enrolled in the European Prospective Investigation into Cancer and Nutrition (EPIC) Florence cohort in 1993-98, participating in the 2004-06 follow up (FU) and with at least one full-field digital mammography (FFDM) performed after FU. For each woman, detailed information on smoking habits, anthropometry, lifestyle and reproductive history was collected at enrollment and at FU. Smoking information at baseline and at FU was integrated. The fully automated Volpara™ software was used to obtain total breast volume (cm3), absolute breast dense volume (DV, cm3) and volumetric percent density (VPD, %) from the first available FFDM (average 5.3 years from FU). Multivariable linear regression models were applied to evaluate the associations between smoking habits and VPD or DV. Results: An inverse association between smoking exposure and VPD emerged (Diff% -7.96%, p <0.0001 for current smokers and -3.92%, p 0.01 for former smokers, compared with non-smokers). An inverse dose-response relationship with number of cigarettes/day, years of smoking duration and lifetime smoking exposure (pack-years) and a direct association with time since smoking cessation among former smokers emerged. Similar associations, with an attenuated effect, emerged when DV was considered as the outcome variable. Discussion: This longitudinal study confirms the inverse association between active smoking, a known risk factor for BC, and MBD among post-menopausal women. The inclusion of smoking habits in the existing BC risk prediction models could be evaluated in future studies.

Use and misuse of the emergency room by patients with eating disorders in a matched-cohort analysis: What can we learn from it?

We examined the pattern of access to hospital emergency room (hER) in 2018-2021 among patients with eating disorders (ED) from Florence, Italy, diagnosed during 1994-2018, using a matched cohort design. We included 902 ED patients and an equal number of sex-, age-, and residence-matched individuals. We fitted conditional Poisson regression models with robust variance estimator to estimate incidence rate ratios (IRR) and 95% confidence intervals. ED patients accessed hER more than twice as often as matched individuals: the IRR was 2.11 (1.21-3.70), 2.02 (1.36-3.00), and 2.49 (1.71-3.61) among AN, BN, and BED patients. Factors associated with increased hER use were older age (≥40 years; for AN patients, also younger age, <20 years), BMI ≤ 16 kg/m2 (for AN), and psychopathological severity. The rise in access to hER was particularly marked during the early phases of the COVID-19 pandemic and declined only partially thereafter. Acute psychiatric symptoms and non-specific medical conditions represented the main causes of increased access to hER. Use of hER was more often inappropriate among ED patients than matched individuals. Integration of primary and mental health care may be necessary to counteract the high and often inappropriate use of hER by patients with ED.

Lifetime changes in body fatness and breast density in postmenopausal women: the FEDRA study.

BACKGROUND: High mammographic breast density (MBD) is an established risk factor for breast cancer (BC). Body fatness conveys an increased BC risk in postmenopause but is associated with less dense breasts. Here, we studied the relationship between body fatness and breast composition within the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) longitudinal study. METHODS: Repeated anthropometric data and MBD parameters (obtained through an automated software on BC screening digital mammograms) were available for all participants, as well as information on other BC risk factors. Multivariate linear regression and functional data analysis were used to longitudinally evaluate the association of body fatness, and changes thereof over time, with dense (DV) and non-dense (NDV) breast volumes and volumetric percent density (VPD). RESULTS: A total of 5,262 women were included, with anthropometric data available at 20 and 40 years of age, at EPIC baseline (mean 49.0 years), and an average of 9.4 years thereafter. The mean number of mammograms per woman was 3.3 (SD 1.6). Body fatness (and increases thereof) at any age was positively associated with DV and NDV (the association being consistently stronger for the latter), and inversely associated with VPD. For instance, an increase by 1 kg/year between the age of 40 years and EPIC baseline was significantly associated with 1.97% higher DV, 8.85% higher NDV, and 5.82% lower VPD. CONCLUSION: Body fatness and its increase from young adulthood until midlife are inversely associated with volumetric percent density, but positively associated with dense and non-dense breast volumes in postmenopausal women.

The FEDRA Longitudinal Study: Repeated Volumetric Breast Density Measures and Breast Cancer Risk.

Mammographic breast density (MBD) is a strong independent risk factor for breast cancer (BC). We investigated the association between volumetric MBD measures, their changes over time, and BC risk in a cohort of women participating in the FEDRA (Florence-EPIC Digital mammographic density and breast cancer Risk Assessment) study. The study was carried out among 6148 women with repeated MBD measures from full-field digital mammograms and repeated information on lifestyle habits, reproductive history, and anthropometry. The association between MBD measures (modeled as time-dependent covariates), their relative annual changes, and BC risk were evaluated by adjusted Cox models. During an average of 7.8 years of follow-up, 262 BC cases were identified. BC risk was directly associated with standard deviation increments of volumetric percent density (VPD, HR 1.37, 95%CI 1.22-1.54) and dense volume (DV, HR 1.29, 95%CI 1.18-1.41). An inverse association emerged with non-dense volume (NDV, HR 0.82, 95%CI 0.69-0.98). No significant associations emerged between annual changes in VPD, DV, NDV, and BC risk. Higher values of MBD measures, modeled as time-dependent covariates, were positively associated with increased BC risk, while an inverse association was evident for increasing NDV. No effect of annual changes in MBD emerged.

Association between Alcohol Intake and Prostate Cancer Mortality and Survival.

We conducted a systematic review and meta-analysis to investigate the role of alcohol consumption with the prognosis of prostate cancer (PCa). Published reports were gathered on 15 October 2022, from PUBMED/MEDLINE and EMBASE. We found 19 independent eligible studies on the association between consumption of alcoholic beverages and the risk of fatal PCa (n = 5), PCa mortality (n = 5) in healthy subjects, and PCa patients' survival (n = 7) or surrogates thereof (n = 2). We used random effects meta-analysis to obtain a summary risk estimate (SRE) and 95% confidence intervals (95%CI) for incidence of fatal PCa and PCa mortality. The meta-analysis revealed no association between alcohol consumption and fatal prostate cancer incidence risk in healthy subjects with an indication for publication bias, but omitting the study that mainly increased the between-study heterogeneity, the SRE becomes significant (SRE 1.33, 95%CI 1.12-1.58), and the heterogeneity disappeared (I2 = 0%) with no indication of publication bias. No association of alcohol consumption was found with mortality risk in PCa patients (SRE 0.97, 95%CI 0.92-1.03) and PCa mortality risk in healthy subjects (SRE 1.03, 95%CI 0.82-1.30). In conclusion, this study suggests that there is some evidence of an association between high alcohol consumption and an increased risk of incidence of fatal prostate cancer in healthy subjects. Given the inconsistencies this result warrants further confirmation.

The clinical impact of continued smoking in patients with breast and other hormone-dependent cancer: A systematic literature review.

We conducted a systematic review of studies that investigated whether quitting smoking at or around diagnosis improves survival of patients with hormone-dependent cancers (HDC). Nine studies published in 2013-2022 were included. Studies were very diverse in terms of design, definition of quitters and continued smokers, and prevalence of prognostic factors other than smoking cessation (e.g. patients' demographics, tumour characteristic, and treatments). For breast, ovarian, and endometrial cancer, all included studies found that quitters had better overall, disease specific, and disease-free survival than continued smokers. For prostate cancer, there was no evidence of an association of smoking cessation with improved survival. This literature review provided suggestive evidence that female smokers diagnosed with cancer of the breast, ovary, or endometrium may improve their chances of surviving by stopping smoking. Smoking cessation counselling should become part of standard oncological care for these patients and integrated into breast cancer screening programs.

Dietary Patterns, Dietary Interventions, and Mammographic Breast Density: A Systematic Literature Review.

BACKGROUND: Breast cancer (BC) is the most common and deadliest malignancy among women. High mammographic breast density (MBD) is an established modifiable risk marker for BC, and it is of interest, for prevention purposes, to consider lifestyle factors that may modulate both MBD and BC risk. Here, we conducted a systematic review of the most up-to-date evidence on the association between diet as a whole and MBD. METHODS: We considered as eligible for inclusion in our review (PROSPERO registration code CRD42022335289) the studies published until 31 December 2021, that reported on the association between a priori or a posteriori dietary patterns (in observational studies) or dietary interventions (in randomized controlled trials) and MBD. RESULTS: In total, twelve studies were included. MBD tended to be inversely associated with adherence to dietary patterns characterized by high consumption of plant-based foods and low in meat, animal fats, and alcohol, defined both a priori (e.g., Mediterranean diet and WCRF/AICR guidelines) or a posteriori (e.g., "fruit-vegetable-cereal" and "salad-sauce-pasta/grains" patterns). Findings from intervention studies were in fair agreement with those from observational studies. CONCLUSIONS: While further studies are needed, we found suggestive evidence that the adoption of a healthy diet is associated with lower MBD.

A Priori Dietary Patterns, Physical Activity Level, and Body Composition in Postmenopausal Women: A Cross-Sectional Study.

Midlife weight gain and fat distribution changes increase the risk of age-related pathologies. We aimed to explore, in a series of 388 healthy postmenopausal women living in Tuscany, Central Italy, the relationship between three a priori dietary patterns, the level of physical activity (PA), and four body composition measures: body mass index (BMI), percent fat mass (%FM), percent muscle mass (%MM), and waist circumference (WC). Detailed information on lifestyle, including the amount of recreational and household PA, sitting time, and dietary habits were collected through detailed questionnaires, and adherence scores to Greek Modified Mediterranean Diet, Italian Mediterranean Diet (IMD), and Dietary Approaches to Stop Hypertension diet were calculated. The %FM and %MM were estimated via TANITA MC-780MA analyzer. WC and BMI were measured according to standard international protocols. Cross-sectional adjusted regression models showed that increasing adherence to IMD was inversely associated with BMI, %FM, and WC, and directly associated with %MM. Higher levels of recreational PA were associated with lower %FM, BMI, and WC and with higher %MM values. Higher levels of sitting time were associated with higher %FM, BMI, and WC, and lower %MM. Dietary habits and moderate PA confirm their central role in maintaining good health even in menopausal women.

Fish Consumption and Colorectal Cancer Risk: Meta-Analysis of Prospective Epidemiological Studies and Review of Evidence from Animal Studies.

Background: Epidemiological studies on the association between fish consumption and colorectal cancer (CRC) risk have yielded inconsistent results, despite evidence from preclinical studies that long-chain ω-3 polyunsaturated fatty acids inhibit colorectal carcinogenesis. We conducted a meta-analysis of prospective epidemiological studies investigating the association between fish consumption and CRC risk among humans and reviewed studies examining the link between fish components and colorectal carcinogenesis in animal models. Methods: We included studies published until November 2020. We calculated the summary risk ratio (SRR) and 95% confidence intervals (CI) through random effects meta-analysis models in order to summarize evidence from studies among humans. Results: Twenty-five prospective epidemiological studies encompassing 25,777 CRC cases were included. Individuals in the highest (vs. lowest) category of fish consumption had a significantly reduced risk of CRC (SRR 0.94, 95%CI 0.89-0.99). In dose-response meta-analysis, a 50-g increment in the daily consumption of fish was associated with a statistically significant 4% reduction in CRC risk (SRR 0.96, 95%CI 0.92-0.99). Preclinical studies (n = 25) identified multiple mechanisms of action of fish and fish components on colorectal carcinogenesis. Conclusions: Dietary recommendations for cancer prevention should take into account the evidence from epidemiological and preclinical studies that increasing fish consumption may be effective in preventing CRC.

Polymorphisms of Metabolizing Enzymes and Susceptibility to Ethmoid Intestinal-type Adenocarcinoma in Professionally Exposed Patients.

Intestinal-type adenocarcinoma (ITAC) of ethmoid is a rare tumor associated with occupational exposure to wood and leather dusts. Polymorphisms in xenobiotic metabolizing enzymes play an important role in gene-environment interactions and may contribute to a high degree of variance in individual susceptibility to cancer risk. The aim of this study was to investigate by polymerase chain reaction the role of polymorphisms at CYP1A1 and GSTM1 genes in 30 ethmoid ITAC patients and 79 healthy donors. The distribution of Thr/Asn genotype at CYP1A1 codon 461 was significantly overrepresented among the patients (23.3%; P = .0422), whereas the Ile/Val genotype at CYP1A1 codon 462 was not significantly different between cases and controls (P = .76). The GSTM1 null genotype was not significantly different between cases and control (P = 1), but we observed that the combined codon 461 Thr/Asn and GSTM1 null genotype was overrepresented in the patient group (P = .0019). The results reveal that patients with CYP1A1 codon 461 polymorphism may be at high genetic risk of ITAC and that the risk increases in the presence of combined polymorphism of CYP1A1 and GSTM1 null genotype. This strongly suggests that CYP1A1 codon 461 and GSTM1 null genotype may be useful in selecting exposed individuals at risk for ethmoid ITAC.

PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor.

We investigated the activation of platelet-derived growth factor (PDGF) receptor A (PDGFRA), PDGF receptor B (PDGFRB), epidermal growth factor receptor (EGFR), and their downstream pathways in malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA, PDGFRB, and EGFR were immunohistochemically, biochemically, cytogenetically, and mutationally analyzed along with the detection of their cognate ligands in 16 neurofibromatosis type 1 (NF1)-related and 11 sporadic MPNSTs. The activation of the downstream receptor pathways was also studied by means of v-akt murine thymoma viral oncogene homolog (AKT), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) Western blotting experiments, as well as rat sarcoma viral oncogene homolog (RAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA), and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutational analysis and fluorescence in situ hybridization. PDGFRA, PDGFRB, and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation paralleling increasing EGFR gene copy numbers in the NF1-related cases (71%). Autocrine loop activation of these receptors along with their coactivation were suggested by the expression of the cognate ligands in the absence of mutations and the presence of receptor tyrosine kinase (RTK) heterodimers, respectively. Both MPNST groups showed AKT, ERK, and mTOR expression/phosphorylation. No BRAF, PI3KCA, or PTEN mutations were found in either group of MPNSTs, but 18% of the sporadic MPNSTs showed RAS mutations. PTEN monosomy segregated with the NF1-related cases (50%, p = 0.018), but PTEN protein was expressed in all but two cases. In conclusion, PDGFRA, PDGFRB, and EGFR seem to be promising molecular targets for tailored treatments in MPNST. In particular, the ligand- and heterodimerization-dependent RTK activation/expression coupled with a downstream signaling phosphorylation, mediated by the upstream receptors or RAS activation, may provide a rationale to apply combined RTK and mTOR inhibitor treatments both to sporadic and NF1-related cases.

Cyclooxygenase-2 and platelet-derived growth factor receptors as potential targets in treating aggressive fibromatosis.

PURPOSE: To explore the molecular bases of potential new pharmacologic targets in aggressive fibromatosis (desmoid tumor). EXPERIMENTAL DESIGN: Tumor specimens from 14 patients surgically treated for aggressive fibromatosis (6 familial adenomatous polyposis and 8 sporadic cases), analyzed for adenomatous polyposis coli (APC) and CTNNB1 (beta-catenin) mutations, were further investigated for beta-catenin, cyclooxygenase-2 (COX-2), platelet-derived growth factor (PDGF) receptor alpha (PDGFRA)/PDGF receptor beta (PDGFRB), their cognate ligands (PDGFA and PDGFB), and KIT using a comprehensive immunohistochemical, biochemical, molecular, and cytogenetic approach. RESULTS: No CTNNB1 (beta-catenin) mutations were found in the familial adenomatous polyposis patients, but previously reported activating mutations were found in six of the eight sporadic patients. All of the cases carrying an altered WNT pathway showed nuclear and cytoplasmic immunoreactivity for beta-catenin, whereas beta-catenin expression was restricted to the cytoplasm in the sporadic patients lacking CTNNB1 mutations. COX-2 protein and mRNA overexpression was detected in all 14 cases, together with the expression and phosphorylation of PDGFRA and PDGFRB, which in turn paralleled the presence of their cognate ligands. No PDGFRB mutations were found. The results are consistent with PDGFRA and PDGFRB activation sustained by an autocrine/paracrine loop. CONCLUSIONS: Aggressive fibromatosis is characterized by WNT/oncogene pathway alterations triggering COX-2-mediated constitutive coactivation of PDGFRA and PDGFRB, and may therefore benefit from combined nonsteroidal anti-inflammatory drug + tyrosine kinase inhibitor treatment.

p53 codon 72 polymorphisms in human papillomavirus-negative and human papillomavirus-positive squamous cell carcinomas of the oropharynx.

BACKGROUND: Tobacco smoking, alcohol abuse, and high-risk human papillomavirus (HPV) are risk factors in the etiology of oropharyngeal squamous cell carcinomas (SCCs). The TP53 polymorphism, in which an arginine (R) is changed to proline (P) at codon 72, is functionally significant and could therefore be a predisposing genetic defect. METHODS: The aim of the study was to investigate the role of codon 72 polymorphism by means of double gradient-denaturing gel electrophoresis in 77 oropharyngeal SCC patients including 33 TP53 mutated and 16 HPV-16-positive cases. The controls consisted of 141 consecutive healthy blood donors. RESULTS: The cases and controls showed significantly different genotype distribution (P = .0005): the frequencies of the RR, RP, and PP genotypes among the cases were, respectively, 81.8%, 10.4%, and 7.8%, as opposed to 59.6%, 33.3%, and 7.1% among the controls, in agreement with the Hardy-Weinberg equilibrium (P = .35). The PP genotype was significantly overrepresented among females (22.2% vs 3.4%; P = .0243) and in HPV-16-positive cases (25.0% vs 3.3%; P = .0152). No segregation was found between either of the codon 72 genotypes and age or TP53 mutations. CONCLUSIONS: The significantly lower frequency of the RP genotype in the patients as a whole suggests that it has a protective effect on oropharyngeal SCCs. Moreover, the PP genotype may be a risk factor for the development of oropharyngeal SCC by females and the development of HPV-16-related SCC, although the findings need to be validated in a larger number of tumors.

Evidence for activation of KIT, PDGFRalpha, and PDGFRbeta receptors in the Ewing sarcoma family of tumors.

BACKGROUND: The Ewing sarcoma family of tumors (ESFT) is one of the most common malignant neoplasms of children and adolescents, characterized by nonrandom translocations involving the Ewing sarcoma (EWS) gene. Over the years the adoption of intensive multimodality treatment approaches has led to a gradual improvement in the survival of patients with ESFT. The prognosis is still unsatisfactory for high-risk patients, however, and novel therapeutic approaches are desirable. The aim of the study was to investigate the expression/activation of KIT, PDGFRalpha, and PDGFRbeta receptor tyrosine kinases (RTKs) as potential therapeutic targets in ESFT. METHODS: RNA and proteins were extracted from 20 frozen ESFT specimens to ascertain the state activation of KIT, PDGFRalpha, and PDGFRbeta. RESULTS: No mutations were found, whereas the cognate ligands were detected in all cases by polymerase chain reaction (PCR). The expression and activation of KIT, PDGFRalpha, and PDGFRbeta were confirmed by quantitative PCR, immunohistochemistry, and immunoprecipitation and/or Western blot analysis. In particular, when compared with a protein pool obtained from normal adult tissues, PDGFRbeta showed a greater protein expression and/or a stronger phosphorylation signal. CONCLUSIONS: The results are consistent with an autocrine/paracrine loop activation of the KIT, PDGFRalpha, and PDGFRbeta receptors and suggest a rationale for the use of RTK inhibitors, either alone or in combination with chemotherapy.

Molecular and biochemical analyses of platelet-derived growth factor receptor (PDGFR) B, PDGFRA, and KIT receptors in chordomas.

PURPOSE: We have previously shown the presence of an activated platelet-derived growth factor (PDGF) receptor (PDGFR) B and its ligand PDGFB in a limited number of patients with clinical and radiological responses to imatinib mesylate treatment. This article describes the results of comprehensive molecular/biochemical analyses of the three receptors targeted by the drug (PDGFRB, PDGFRA, and KIT) in a series of 31 chordoma patients. EXPERIMENTAL DESIGN: The presence and activation status of PDGFRB, PDGFRA, and KIT receptors were investigated by means of immunoprecipitation and Western blot analyses complemented by immunohistochemistry, their expression level was analyzed by means of real-time PCR, and the occurrence of activating point mutations was investigated by means of cDNA sequencing. The PDGFB, PDGFA, and stem cell factor cognate ligands were investigated by reverse transcription-PCR, and gene status was assessed by fluorescence in situ hybridization. RESULTS: The results show that PDGFRB was highly expressed and phosphorylated, whereas PDGFRA and KIT were less expressed but phosphorylated and thus activated. These findings, together with the absence of gain-of-function mutations and the presence of the cognate ligands, strongly support the hypothesis that the activation mechanism is the autocrine/paracrine loop. No role seems to be played by gene amplification. CONCLUSIONS: In the light of our findings, the clinical benefit observed in chordoma patients treated with imatinib seems to be attributable to the switching off of all three receptors.

Molecular and cytogenetic subgroups of oropharyngeal squamous cell carcinoma.

PURPOSE: The aim of this study was to acquire further insights into the pathogenetic pathways of head and neck squamous cell carcinomas (HNSCC) that may be useful for identifying new biomarkers instrumental in developing more specific treatment approaches. EXPERIMENTAL DESIGN: Cell cycle regulators and epidermal growth factor receptor (EGFR) and BRAF genes were analyzed in a series of 90 oropharyngeal SCCs of a cohort of surgically treated patients from a single institution, and the results were matched with the presence of high-risk human papillomavirus (HR-HPV) DNA and the TP53 status. RESULTS: At least four distinct groups of tumors were identified sharing a common histology but displaying different molecular/cytogenetic patterns: (a) 19% were HPV-positive SCCs whose lack of alterations of the investigated genes could explain their particular natural history, which requires less aggressive treatment; (b) 37% were HPV-negative SCCs carrying TP53 mutations, which may be more effectively treated by drugs acting through p53-independent apoptosis; (c) 34% were HPV-negative SCCs carrying wild-type TP53 and loss of 9p21 (p16INK4a and p15INK4b) and/or cyclin D1 overexpression that justify treatment with DNA-damaging drugs followed by cell cycle inhibitors; and (d) 10% were HPV-negative lacking tumor suppressor genes and cell cycle alterations. The second, third, and fourth groups also showed an increased copy number of EGFR and chromosome 7 (43%) that might justify the additional or alternative use of EGFR inhibitors. CONCLUSIONS: Our findings suggest that assessing HPV, TP53, 9p21, and EGFR status may be crucial to finding more tailored and beneficial treatments for oropharyngeal SCCs.

Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y).

In human tumors, p53 is often disabled by mutations in its DNA-binding domain and is thus inactive as a transcription factor. Alternatively, MDM2 gene amplification or up-regulation represents a mechanism of p53 wild-type inactivation, mainly reported in soft tissue sarcomas. In a previous TP53 analysis carried out on sporadic and NF1-related malignant peripheral nerve sheath tumors, in two cases, we observed the occurrence of C238Y missense mutation, leading to p53 stabilization unexpectedly coupled with immunophenotypic MDM2 overexpression. To investigate this TP53 missense mutation not yet functionally characterized in mammalian cell, we did MDM2 Southern blot and p53(C238Y)/MDM2 biochemical and functional analyses followed by molecular modeling. The results showed a lack of MDM2 gene amplification, evidence of p53-MDM2 protein complexes, and presence of a p53 that retains the ability to become phosphorylated on Ser15 and to induce the transcription of p21(waf1). Additional molecular modeling data highlighted the structural similarities between p53(C238Y) and wild-type p53, further supporting that the p53(C238Y) mutant still retains functional wild-type p53 properties.