| 1. |
- Castro Wersäll, Ofra, et al.
(författare)
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Dietary Habits and Daily Routines as Prognostic Factors in Endometrial Cancer : A Machine Learning Approach
- 2023
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Ingår i: Nutrition and Cancer. - : Routledge. - 0163-5581 .- 1532-7914. ; 75:1, s. 310-319
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer (EC) is becoming more common worldwide, primarily due to an increase in life expectancy and obesity. As several modifiable factors may affect EC incidence and progression, we aimed to elucidate how dietary habits and daily routines influence recurrence and survival among women with EC, using a Random Survival Forest (RSF) approach. 481 women who previously underwent hysterectomy due to EC completed two extensive questionnaires on dietary habits and daily routines, and we used RSF to identify risky or protective variables. Among the 186 variables considered, consumption of sugar-sweetened beverages and fried potatoes increased the risk of EC recurrence and death, while physical activity decreased the risk of death. We conclude that RSF is a suitable approach to study survival in multivariable datasets.
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| 2. |
- Wersäll, Ofra Castro
(författare)
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Hereditary, molecular and prognostic factors in endometrial cancer
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: The overall aim of this thesis is to describe and evaluate hereditary uterine cancer syndrome both independent of and in relation to hereditary patterns of Lynch and/or Cowden syndrome for the purpose of recognizing and defining a unique pattern of familial uterine cancer. The thesis also aims to determine whether the TERT-CLPTM1L region is a novel risk locus for endometrial cancer. Finally, we aim to assess expression of two mitochondrial proteins, PGC1 and VDAC1, within the same population, as well as to consider the impact of different dietary and lifestyle factors on prognosis for endometrial cancer (EC). Materials and methods: All studies are retrospective and based on a cohort population of women who were diagnosed with endometrial cancer and underwent surgery at Karolinska Hospital, Stockholm, Sweden, between January 1, 2008 and March 31, 2012. All women who agreed to participate completed questionnaires, one concerning family history of cancer and the other regarding personal health history including comorbidity, parity, medications, lifestyle and dietary habits. Data on clinicopathological variables were obtained from the Take Care medical records system. In study I we constructed pedigrees based on the questionnaires with verification by telephone interview, assessed the relative frequencies of various cancers among family members and compared those with the general Swedish population in 1970 and 2010. Study II entails a collaborative effort, known as the Endometrial Cancer Association Consortium (ECAC), in which 5591 women of European ancestry with a history of histologically verified diagnosis of endometrial cancer were enrolled into 11 separate studies conducted in Western Europe, North America, and Australia. The Swedish contribution to this multicenter study derives from the Registry of Endometrial Cancer in Sweden (RENDOCAS), which is a hospital-based registry of consecutively occurring EC cases. The study included 262 cases of EC taken from the same group as Study I and enrollment continued until 2011. In addition to the above information, DNA samples for each patient were obtained from peripheral blood. In Study III, both tumor and adjacent benign tissue were analyzed using immunohistochemistry and subsequently scored to assess PGC1 and VDAC1 expression in both types of tissue and to correlate these findings with clinical data. In Study IV a smart machine learning model, Random Survival Forest, was used to analyze the extensive data and correlate them with prognosis for endometrial cancer. Results: In Study I we found an increased prevalence of EC among our study population compared with the general population in Sweden in 1970 and 2010. Lynch syndrome, as defined according to the Amsterdam II criteria, was found in 7 families. In all, 13% of index patients had at least one relative with EC and these families showed a tendency for more cases of early onset cancer among family members. In study II, data concerning single nucleotide polymorphisms (SNPs) taken from the 5p15 region were available from 4401 cases and 28 758 controls. Using logistic regression, we found three imputed SNPs (rs7705526 (in SNP set 1), rs13174814 (SNP set 2) and rs62329728 (SNP set 3)) that each showed evidence of being independently associated with disease for which the respective ORs were 1.11, 0.87 and 1.27 by unconditional analysis. The linkage disequilibrium (LD) between these three SNPs is weak, which further suggests that they represent independent risk factors for endometrial cancer. When comparing with data taken from the cancer genome atlas (TCGA), we were able to identify higher expression of TERT-CLPTM1L RNA in EC tissue than found in normal tissue. Study III found that both PGC1 and VDAC1 showed significantly lower expression in tumor tissue compared with benign tissue. We also observed a correlation trend indicating an association between low PGC1a expression and shorter time to death among patients in the FIGO I group. The study IV analysis revealed that consumption of fried potatoes and carbonated soft drinks is higher among women with recurrent endometrial cancer and death. Conclusions: Our study found an overrepresentation of EC among first- and second-degree relatives, as well as first cousins of endometrial cancer patients, when compared with the general population. Young age of onset and occurrence of multiple cancers in families with EC suggest the presence of additional factors relating to hereditary EC syndrome. We emphasize the importance of accurate diagnosis, with referral for genetic counseling, and improved surveillance of individuals at high risk for EC. In study II we succeeded in uncovering a novel risk locus for EC and implicated three novel independent genetic variants within the 5p15 locus (already associated with several cancers) that increase risk of developing EC. Overexpression of TERT in cases of EC when compared with normal tissue suggests a potentially important role for this gene in tumorigenesis. Our findings may account for about 0.5% of the relative risk for familial EC. Study III found downregulation of both PGC1 and VDAC1 in malignant tissue, as well as a correlation between low PGC1a expression and shorter time to death among patients in the FIGO I group. This correlation has important clinical implications since these patients are treated exclusively by surgery. Should lower expression of PGC1a correlate with increased risk of recurrence, new therapeutic strategies may be required. In study IV we observed that consumption of fried potatoes and sweetened carbonated beverages is associated with higher risk of recurrence and death from EC. Dietary modification may therefore be advisable for women with endometrial cancer.
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| 3. |
- Wersäll, Ofra Castro, et al.
(författare)
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PGC1α and VDAC1 expression in endometrial cancer
- 2021
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Ingår i: Molecular and clinical oncology. - : Spandidos Publications. - 2049-9450 .- 2049-9469. ; 14:2
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial cancer (EC) is one of the ten most common gynecological cancers. As in most cancers, EC tumour progression involves alterations in cellular metabolism and can be associated with, for instance, altered levels of glycolytic enzymes. Mitochondrial functions and proteins are known to serve key roles in tumour metabolism and progression. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1α) is a major regulator of mitochondrial biogenesis and function, albeit of varying prognostic value in different cancers. The voltage-dependent anion channel type 1 (VDAC1) regulates apoptosis as well as metabolite import and export over the mitochondrial outer membrane, and is often used for comparative quantification of mitochondrial content. Using immunohistochemistry, the present study examined protein expression levels of PGC1α and VDAC1 in tumour and paired benign tissue samples from 148 patients with EC, in order to examine associations with clinical data, such as stage and grade, Ki-67, p53 status, clinical resistance and overall survival. The expression levels of both PGC1α and VDAC1, as well as a PGC1α downstream effector, were significantly lower in tumor tissues than in benign tissues, suggesting altered mitochondrial function in EC. However, Kaplan-Meier, log rank and Spearman's rank correlation tests revealed that their expression was not correlated with survival and clinical data. Therefore, PGC1α and VDAC1 are not of major prognostic value in EC.
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| 4. |
- Wersäll, Ofra Castro, et al.
(författare)
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Which dietary and everyday life habits affect endometrial cancer recurrence? The machine gives the answer
- 2020
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 30:Suppl. 4, s. A32-A33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Background: The increased life expectancy and westernization of the lifestyle are considered the major contributors to a sustainable rise in endometrial cancer (EC) rates. The factors predicting EC recurrence include patient age and tumour characteristics, such as type, differentiation, and depth of invasion. At the same time, recent studies testify the impact of meal and exercises on the course of various diseases. What are the food preferences and activities that could influence the ultimate risk of EC relapse and death?Methodology: The study included 481 women who previously underwent a hysterectomy due to EC at Karolinska University Hospital. The participants filled an extensive questionnaire on their dietary habits and everyday routines. Related clinical data was obtained through the National e-health system. It resulted in a large dataset with more than 180 variables, which was processed using the Random Survival Forest (RSF) approach. The latter is applied to a right-censored data and uses a collection of decision trees to rank the variables by their importance for the occurrence of an event. The top-ranked variables were further investigated with the Cox proportional hazards model. Analyzes were performed using the RandomForestSRC package for Python.Results: The consumption of the fried potatoes significantly increased the risk of EC relapse and death [HR=8.62 (2.22–33.56), p=0.002; HR=6.00 (1.06–34.01), p=0.043, respectively), the latter persisted after adjustment for body mass index, age and smoking status. Besides, each additional serving of sweetened soda drinks increased the risk of death [3.262 (1.834–5.800), p=0.0001]. In contrast, physical activity was beneficial with each additional Metabolic Equivalent per day decreasing the risk of death by 7.3% [HR=0.927 (0.892–0.964), p< 0.0001).Conclusion: We hypothesise that the fried potatoes’ detrimental effect may be related to the acrylamide, which is formed in starch-rich foods under high-temperature conditions. It acts as a carcinogen and endocrine disruptor, causing the endometrial hyperplasia and EC in animal studies. Sweetened beverages cause a rise in insulin, which in turn inhibits sex-hormone binding protein. This results in higher levels of circulating free oestrogens. Also, insulin has mitogenic and anti-apoptotic properties, further inducing the endometrium proliferation. The favorable influence of regular physical activity on EC relapse and death is in accordance with previous studies, including recent meta-analysis.Therefore, we encourage women treated for EC to consider reducing sweetened beverages and fried potatoes consumption and increasing physical activity.
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