Associations of clock genes polymorphisms with soft tissue sarcoma susceptibility and prognosis

BACKGROUND: Dysfunction of the circadian clock and polymorphisms of some circadian genes have been linked to cancer development and progression. We investigated the relationship between circadian genes germline variation and susceptibility or prognosis of patients with soft tissue sarcoma. PATIENTS AND METHODS: We considered the 14 single nucleotide polymorphisms (SNPs) of 6 core circadian genes that have a minor allele frequency >\u20095% and that are known to be associated with cancer risk or prognosis. Genotyping was performed by q-PCR. Peripheral blood and clinic-pathological data were available for 162 patients with liposarcoma or leiomyosarcoma and 610 healthy donors. Associations between the selected clock genes polymorphisms and sarcoma susceptibility or prognosis were tested assuming 3 models of inheritance: additive, recessive and dominant. Subgroup analysis based on sarcoma histotype was performed under the additive genetic model. Multivariate logistic regression and multivariate Cox proportional hazard regression analyses were utilized to assess the association between SNPs with patient susceptibility and survival, respectively. Pathway variation analysis was conducted employing the Adaptive Rank Truncated Product method. RESULTS: Six out of the 14 analyzed SNPs were statistically significantly associated with susceptibility or prognosis of soft tissue sarcoma (P <\u20090.05). The present analysis suggested that carriers of the minor allele of the CLOCK polymorphism rs1801260 (C) or of PER2 rs934945 (T) had a reduced predisposition to sarcoma (26% and 35% respectively with the additive model) and liposarcoma (33% and 41% respectively). The minor allele (A) of NPAS2 rs895520 was associated with an increased predisposition to sarcoma of 33% and leiomyosarcoma of 44%. RORA rs339972 C allele was associated with a decreased predisposition to develop sarcoma assuming an additive model (29%) and leiomyosarcoma (36%). PER1 rs3027178 was associated with a reduced predisposition only in liposarcoma subgroup (32%). rs7602358 located upstream PER2 was significantly associated with liposarcoma survival (HR: 1.98; 95% CI 1.02-3.85; P\u2009=\u20090.04). Germline genetic variation in the circadian pathway was associated with the risk of developing soft tissue sarcoma (P\u2009=\u20090.035). CONCLUSIONS: Genetic variation of circadian genes appears to play a role in the determinism of patient susceptibility and prognosis. These findings prompt further studies to fully dissect the molecular mechanisms

Circadian pathway genetic variation and cancer risk: Evidence from genome-wide association studies

Background: Dysfunction of the circadian clock and single polymorphisms of some circadian genes have been linked to cancer susceptibility, although data are scarce and findings inconsistent. We aimed to investigate the association between circadian pathway genetic variation and risk of developing common cancers based on the findings of genome-wide association studies (GWASs). Methods: Single nucleotide polymorphisms (SNPs) of 17 circadian genes reported by three GWAS meta-analyses dedicated to breast (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Consortium; cases, n = 15,748; controls, n = 18,084), prostate (Elucidating Loci Involved in Prostate Cancer Susceptibility (ELLIPSE) Consortium; cases, n = 14,160; controls, n = 12,724) and lung carcinoma (Transdisciplinary Research In Cancer of the Lung (TRICL) Consortium; cases, n = 12,160; controls, n = 16,838) in patients of European ancestry were utilized to perform pathway analysis by means of the adaptive rank truncated product (ARTP) method. Data were also available for the following subgroups: estrogen receptor negative breast cancer, aggressive prostate cancer, squamous lung carcinoma and lung adenocarcinoma. Results: We found a highly significant statistical association between circadian pathway genetic variation and the risk of breast (pathway P value = 1.9 x 10(-6); top gene RORA, gene P value = 0.0003), prostate (pathway P value= 4.1x10(-6); top gene ARNTL, gene P value = 0.0002) and lung cancer (pathway P value = 6.9 x 10(-7); top gene RORA, gene P value= 2.0 x 10(-6)), as well as all their subgroups. Out of 17 genes investigated, 15 were found to be significantly associated with the risk of cancer: four genes were shared by all three malignancies (ARNTL, CLOCK, RORA and RORB), two by breast and lung cancer (CRY1 and CRY2) and three by prostate and lung cancer (NPAS2, NR1D1 and PER3), whereas four genes were specific for lung cancer (ARNTL2, CSNK1E, NR1D2 and PER2) and two for breast cancer (PER1, RORC). Conclusions: Our findings, based on the largest series ever utilized for ARTP-based gene and pathway analysis, support the hypothesis that circadian pathway genetic variation is involved in cancer predisposition

Cytoreductive surgery alone or combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for pseudomyxoma peritonei

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The aim of this work is to evaluate the efficacy of cytoreductive surgery alone versus cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy (HIPEC), on patient benefits, complications and short-term outcomes in patients with pseudomyxoma peritonei (PMP). \ua9 2018 The Cochrane Collaboration

Solitary biceps muscle metastasis from neuroendocrine breast tumor.

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Prognostic factors in merkel cell carcinoma: A retrospective single-center study in 90 patients

Abstract Merkel Cell Carcinoma (MCC) is a rare but highly aggressive neuroendocrine neoplasm of the skin. This study aimed at describing characteristics, treatment, and prognosis of a series of consecutive cases of MCC patients, in order to contribute to the investigation of this rare malignancy and provide better patient care. This is a retrospective cohort study including all 90 patients diagnosed and/or treated for MCC between 1991 and 2018 at the Veneto Institute of Oncology in Padua (Italy). Patient and tumor characteristics, treatment, and immunohistochemical data were extracted from a prospectively collected local database. There were 68 primary (76%) and 22 non-primary (15 occult primary, three metastatic, four recurrence) tumors (24%). CK20 expression was associated with reduced overall (HR 2.92, 95% CI 1.04-8.16) and disease-specific (HR 4.62, 95% CI 1.31-16.28) survival. Immunomodulatory regimens for treatment of other comorbidities were associated with reduced disease-specific ((HR 2.15, 95% CI 1.06-4.36) and recurrence-free (HR 3.08, 95% CI 1.44-6.57) survival. latrogenic immunomodulation resulted as the main factor associated with impaired prognosis. Lack of CK20 expression was associated with better survival

A Therapeutic and Diagnostic Multidisciplinary Pathway for Merkel Cell Carcinoma Patients

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin. Due to its rarity, the management of MCC is not standardized across centers. In this article, we present the experience of the Veneto region in the North-East of Italy, where a committee of skin cancer experts has proposed a clinical pathway for the diagnosis and treatment of MCC. Putting together the evidence available in the international literature, we outlined the best approach to the management of patients affected with this malignancy step- by- step for each possible clinical situation. Crucial in this pathway is the role of the multidisciplinary team to deal with the lack of robust information on each aspect of the management of this disease

GERMLINE POLYMORPHISMS OF CANDIDATE GENES AS PREDICTORS OF RISK AND PROGNOSIS IN PATIENTS WITH SOFT TISSUE SARCOMAS

Background. Le varianti genetiche nei geni dell\u2019orologio biologico e nei geni correlati al telomero sono un potenziale fattore di rischio per l\u2019insorgenza e la progressione tumorale e si ritiene che abbiano un ruolo anche nei sarcomi dei tessuti molli. Attualmente non vi sono abbastanza evidenze. Questo studio ha l\u2019obbiettivo di esplorare tale associazione. Materiali e metodi. Abbiamo analizzato 19 polimorfismi a singolo nucleotide (SNPs) nei seguenti geni candidati: A) Geni dell\u2019orologio biologico: CLOCK (clock circadian regulator), PER1 (period circadian clock 1), PER2 (period circadian clock 2), NPAS2 (neuronal PAS domain protein 2), TIMELESS (timeless circadian clock), RORA (RAR related orphan receptorA) B) Geni correlati al telomero: TERT (Telomerase Reverse Transcriptase). Abbiamo raccolto campioni di sangue periferico e dati clino-patologici di 162 pazienti con diagnosi di liposarcoma e leiomiosarcoma e da 610 controlli sani. E\u2019 stata testata l\u2019associazione tra gli SNPs selezionati, la suscettibilit\ue0 a sviluppare sarcoma e la prognosi dei pazienti, valutando i 3 modelli genetici: additivo, recessivo e dominante. Abbiamo eseguito anche l\u2019analisi statistica per istotipo. Con l\u2019analisi di regressione logistica multivariata abbiamo valutato l\u2019associazione tra gli SNPs e la suscettibilit\ue0, con il modello dei rischi proporzionali di Cox abbiamo valutato l\u2019associazione tra gli SNPs e la prognosi. La \u201cPathway Variation Analysis\u201d \ue8 stata eseguita con l\u2019 \u201cAdaptive Rank Truncated Product Model\u201d. Risultati: Abbiamo riscontrato che 4 SNPs risultavano associati ad un rischio inferiore di sviluppare sarcoma dei tessuti molli e 2 SNPs ad un rischio maggiore. In dettaglio: CLOCK rs1801260 era associato ad una ridotta suscettibilit\ue0 allo sviluppo di sarcoma, considerando un modello additivo (OR 0.74; 95% CI 0.55-1; P= 0.05) e recessivo (OR 0.40; 95% CI 0.18-0.88; P= 0.02) e alla predisposizione all\u2019insorgenza di liposarcoma; PER2 rs934945 risultava associato ad una ridotta predisposizione allo sviluppo di sarcoma , considerando un modello additivo (OR 0.65; 95% CI 0.45-0.94; P= 0.02) e dominante (OR 0.63; 95% CI 0.42-0,95; P= 0.03) e all\u2019insorgenza di liposarcoma; PER1 rs3027178 era associato ad una ridotta predisposizione allo sviluppo di liposarcoma; RORA rs339972 risultava associato ad un rischio ridotto di insorgenza di sarcoma considerando un modello additivo (OR 0.71; 95% CI 0.53-0.96; P=0.02) e dominante (OR 0.64; 95% CI 0.44-0.93, P=0.02) e al leiomiosarcoma; NPAS rs895520 era associato ad un aumentato rischio di sviluppo di sarcoma sotto un modello additivo (OR 1.33; 95% CI 1.02-1.73; P= 0.03) e recessivo (OR 1.70; 95% CI 1.08-2.68; P=0.02) e al leiomiosarcoma; PER2 rs2304674 \ue8 risultato essere associato ad un\u2019aumentata predisposizione sotto un modello recessivo (OR 2.51; 95% CI 1.26-5.00; P=0.009). Per quanto concerne la prognosi, abbiamo riscontrato che: PER2 rs7602358 rappresentava un fattore prognostico negativo nei pazienti con liposarcoma, considerando un modello additivo (HR 1.98; 95% CI 1.02-3.58, p =0.04); NPAS2 rs2305160 \ue8 risultato essere un fattore prognostico negativo nei pazienti affetti da liposarcoma sotto un modello recessivo (HR 2.78; 95% CI 1.12-6.91, P=0.02); TERT rs 2736100 \ue8 risultato essere un fattore prognostico negativo, considerando un modello additivo (HR 1.46, 95% CI 1.03-2.07, p =0.03) e recessivo (HR 2.31, 95% CI 1.35-3.94, p= 0.00) e nei pazienti con leiomiosarcoma sotto un modello recessivo. La variabilit\ue0 genetica in tutto il pathway dei geni dell\u2019orologio biologico \ue8 risultata essere associata al rischio di sviluppare sarcoma dei tessuti molli (P =0.035). Conclusioni: Le varianti genetiche nei geni dell\u2019orologio biologico e nei geni correlati al telomero sembrano essere dei predittori di rischio e prognosi nei pazienti affetti da sarcoma dei tessuti molli. I nostri risultati rappresentano il punto di partenza per ulteriori studi

Melanoma: epidemiology, risk factors, pathogenesis, diagnosis and classification

This article reviews epidemiology, risk factors, pathogenesis and diagnosis of melanoma. Data on melanoma from the majority of countries show a rapid increase of the incidence of this cancer, with a slowing of the rate of incidence in the period 1990-2000. Males are approximately 1.5-times more likely to develop melanoma than females, while according to other studies, the different prevalence in both sexes must be analyzed in relation with age: the incidence rate of melanoma is grater in women than men until they reach the age of 40 years, however, by 75 years of age, the incidence is almost 3-times as high in men versus women. The most important and potentially modifiable environmental risk factor for developing malignant melanoma is the exposure to ultraviolet (UV) rays because of their genotoxic effect. Artificial UV exposure may play a role in the development of melanoma. The most important host risk factors are the number of melanocytic nevi, familiar history and genetic susceptibility. A patient with a personal history of melanoma must be considered at greater risk for subsequent melanoma. Indeed approximately 1-8% of patients with prior history of melanoma will develop multiple primary melanomas. We herein review the dermatological diagnosis and classification of melanoma

Additional file 2: Table S2. of Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies

Adaptive rank truncated product (ARTP)-based analysis of single circadian genes: primary analysis (all cases included) by tumour type. (DOCX 15 kb

Additional file 3: Table S3. of Circadian pathway genetic variation and cancer risk: evidence from genome-wide association studies

Adaptive rank truncated product (ARTP)-based analysis of single circadian genes: subgroup analysis (by histological subtype) by tumour type. (DOCX 15 kb