Nutrigenetics and Omega-3 and Gamma-Linolenic Acid Intake and Status in Patients with Cancer: A PRISMA Scoping Review of Research Trends and Challenges

Academic Editor: Ana Cristina Gonçalves Received: 11 April 2025 Revised: 16 May 2025 Accepted: 17 May 2025 Published: 19 May 2025 Citation: Zikic, V.; Paunovic, M.; Milovic-Kovacevic, M.; Vucic, V.; Ristic-Medic, D. Nutrigenetics and Omega-3 and Gamma-Linolenic Acid Intake and Status in Patients with Cancer: A PRISMA Scoping Review of Research Trends and Challenges. Int. J. Mol. Sci. 2025,26, 4867. https:// doi.org/10.3390/ijms26104867 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/ licenses/by/4.0/). Review Nutrigenetics and Omega-3 and Gamma-Linolenic Acid Intake and Status in Patients with Cancer: A PRISMA Scoping Review of Research Trends and Challenges Vladica Zikic 1,2,†, Marija Paunovic 3,† , Marijana Milovic-Kovacevic 4,5 , Vesna Vucic 3,* and Danijela Ristic-Medic 3 1Cognitive Neuroscience Department, Research and Development Institute “Life Activities Advancement Institute”, 11000 Belgrade, Serbia; [email protected] 2Department of Speech, Language and Hearing Sciences, Institute for Experimental Phonetics and Speech Pathology, 11000 Belgrade, Serbia 3Group for Nutritional Biochemistry and Dietology, Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia; [email protected] (M.P.); [email protected] (D.R.-M.) 4Department of Medical Oncology, Institute of Oncology and Radiology Serbia, 11000 Belgrade, Serbia; [email protected] 5Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia *Correspondence: [email protected] †These authors contributed equally. Abstract: Epidemiological studies report inconsistent findings regarding the association between dietary polyunsaturated fatty acid (PUFA) intake and cancer risk. Genetic variations— particularly single-nucleotide polymorphisms (SNPs) in the FADS1 and FADS2 genes— affect PUFA metabolism, linking circulating PUFA levels to the risk of several cancers, including breast, colorectal, prostate, and pancreatic cancers. This review aimed to investigate the relationship between FADS1 and FADS2 gene variants and dietary intake, supplementation, or intervention with omega-3 fatty acids, gamma-linolenic acid (GLA), or their combination in cancer patients. A secondary objective was to examine genetically determined fatty acid profiles—shaped by FADS1 and FADS2 polymorphisms—in cancer patients without intervention and their potential association with PUFA-related cancer risk. A systematic search of the Scopus, PubMed, and Web of Science databases (up to 2024) identified 11 eligible studies out of 298 initial records. Analysis of the available literature suggests that specific FADS genotypes influence long-chain PUFA (LC-PUFA) concentrations in blood and tissues and that altered LC-PUFA levels may contribute to cancer development. The most consistent association identified is between the rs174537 variant and altered PUFA metabolism in prostate and breast cancer. However, conclusive evidence is lacking on the impact of dietary patterns on FADS desaturase activity or expression. Only one study has examined omega-3 supplementation in relation to FADS gene variants in prostate cancer patients, while the effects of GLA supplementation remain unexplored. Given the relative novelty of this research area and the limited number of studies, future investigations should integrate dietary PUFA intake, genetic variation in PUFA-metabolizing enzymes, and potential gene–nutrient interactions involving FADS gene polymorphisms and PUFAs to clarify their role in cancer risk. Keywords: fatty acid desaturase; FADS1;FADS2; omega-3 fatty acids; gamma-linolenic acid; single-nucleotide polymorphisms; cancer; cancer risk Int. J. Mol. Sci. 2025,26, 4867 https://doi.org/10.3390/ijms26104867 Int. J. Mol. Sci. 2025,26, 4867 2 of 21 1. Introduction Cancer represents the second leading cause of death globally [1]. Projections suggest that by the end of the century it will become the leading cause of premature death and the primary factor limiting lifespan [ 2 ]. A diet rich in vegetables, whole grains, and healthy fats, enriched with antioxidants, may reduce cancer risk [ 3 , 4 ]. Nutrigenetics explores how genetic variations influence the body’s response to diet, shaping nutrient metabolism, dietary effects, and the risk of diet-related illnesses [ 5 , 6 ]. By considering an individual’s genetic makeup, nutrigenetics aims to develop personalized nutrition, enabling more effective and targeted dietary recommendations [ 7 ]. Dietary fats play essential roles in different physiological processes, impacting plasma fatty acid profiles. Their metabolism involves the delta-5 and delta-6 desaturase enzymes encoded by the fatty acid desaturase 1 (FADS1) and desaturase 2 (FADS2) genes, located on human chromosome 11 (11q12-13.1). These enzymes are involved in the endogenous conversion process of 18-carbon polyunsaturated fatty acids (PUFAs) into long-chain PUFAs (LC-PUFAs) such as arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) [8–11] (Figure 1). Figure 1. Pathways of long-chain omega-6 and omega-3 fatty acid synthesis from dietary intake and their further metabolism to the production of inflammation mediators: involvement of FADS1 and FADS2 genes. Int. J. Mol. Sci. 2025,26, 4867 3 of 21 Variations in single-nucleotide polymorphisms (SNPs) within the FADS genes significantly influence an individual’s ability to synthesize EPA and DHA [ 9 ], thereby affecting LC-PUFA levels. This modulation of lipid metabolism may play a crucial role in the onset of different diet-related disorders. LC-PUFAs also serve as precursors for eicosanoids, bioactive molecules that regulate inflammation through either pro-inflammatory or antiinflammatory pathways [ 12 ]. Chronic inflammation is a well-established risk factor for numerous diseases, including neurodegenerative diseases, type 2 diabetes, cardiovascular disease, and various cancers [ 13 ]. Despite being an omega-6 PUFA, gamma-linolenic acid (GLA) exerts anti-inflammatory effects via its conversion to dihomo-gamma-linolenic acid (DGLA) and subsequently to prostaglandin PGE1. Among LC-PUFAs, AA is primarily a precursor for pro-inflammatory eicosanoids, and its plasma phospholipid concentration may contribute to the development of certain cancers [ 14 ]. In contrast, omega-3 LC-PUFAs, such as EPA and DHA, exhibit anti-inflammatory properties and have been associated with a protective effect against the development of breast [ 15 ], colorectal [ 16 ], and pancreatic cancers [17]. Cancer tissue also alters lipid metabolism compared to healthy tissue, notably by increasing AA levels [ 18 ], a process that may be influenced by genetic variation within the FADS locus [ 19 ]. It was shown that the efficiency of LC-PUFA synthesis was highly dependent on the rs174537 genotype. Individuals with the GG genotype had higher concentrations of LC-PUFAs (both omega-6 and omega-3) compared to those with the TT genotype [ 20 ]. On the other hand, studies have confirmed that the increased activity of PUFA desaturases, associated with the rs174546 genetic variant, correlates with a higher risk of developing lung cancer, different subtypes of colorectal cancer, esophageal squamous cell carcinoma, respiratory and intrathoracic cancers, basal cell carcinoma, and non-melanoma and overall skin cancer [ 21 ]. Similar data have been collected for rs174548 variants, where their presence has been linked to an increased risk of lung cancer [ 22 ]. Beyond the blood, expression of FADS1 and FADS2 genes has been documented in at least 44 different tissues, with the highest level of expression in the adrenal gland and brain tissue [19]. Even though FADS polymorphisms can influence fatty acid profiles [ 23 ], data on the relationship between nutrition enriched with LC-PUFAs and changes in their expression remain inconclusive. While a study on personalized omega-3 dosages showed an increase in their blood levels, there is insufficient evidence to determine whether these variations result from FADS1/2 gene variants or personalized supplementation [ 24 ]. Additionally, the prevalence of the TT polymorphism in the rs174583 variant of the FADS2 gene has been associated with a higher risk of obesity and increased body mass index in carriers. However, research has not demonstrated a clear correlation between these outcomes and different dietary patterns [ 25 ]. FADS1 expression has been linked to cancer progression. It is overexpressed in bladder tumors, correlating with higher tumor grade and enhanced proliferation [ 26 ], whereas its downregulation in non-small-cell lung cancer and bladder cancer is associated with tumor characteristics (location, size, and histological grade) and poor prognosis [ 27 ]. FADS enzymes also influence inflammation, DNA repair, and apoptosis, and they have been associated with distinct molecular subtypes of tumors in breast cancer. These findings suggest a strong correlation between FADS2 expression and clinicopathological characteristics, highlighting its potential as a diagnostic biomarker for breast cancer [ 28 ]. Moreover, according to available data, FADS1 is causally involved in cancer cell proliferation and, together with FADS2, has emerged as a promising pharmacological target for anti-cancer therapy [ 26 , 29 – 31 ]. Elevated FADS1 expression is associated with poor prognosis, tumor progression, and an altered tumor microenvironment. Patients with high FADS1 expression may benefit from FADS1-targeted therapies, as inhibition has been shown to suppress cancer cell growth. Similarly, FADS2 is highly expressed in breast cancer, Int. J. Mol. Sci. 2025,26, 4867 4 of 21 and its knockout reduces cell invasion, migration, and colony formation. These findings suggest that targeting FADS1/2, particularly when combined with genome-tailored nutritional strategies, could offer a novel and effective approach for precision oncology in selected patient groups. Since the data on PUFA metabolism and FADS polymorphisms remain inconclusive, this review aimed to examine the influence of FADS1 and FADS2 gene variants on metabolism and biological effects of omega-3 fatty acids and gamma-linolenic acid, both individually and in combination, in cancer patients. This included evaluating the impact of dietary intake, supplementation, and intervention, as well as assessing the genetically determined status of PUFAs in relation to cancer risk, disease progression, and treatment outcomes, across different cancer types. To the best of our knowledge, no previous review has focused on this specific combined assessment. 2. Results A total of n= 298 articles were retrieved in the initial search from all three databases, covering the period up to the end of April 2024. After removing duplicates (n= 56), a total of n= 242 articles were screened based on the title and abstract. Of those, n= 227 were excluded (abstracts, reviews, editorials, book chapters, and publications not in English or on irrelevant topics). The remaining 15 articles underwent a full review, of which 4 were excluded (irrelevant topic or endpoints). Two more were added from the reference lists. Finally, n= 11 articles met the eligibility criteria and were evaluated in this review. To update the search, we conducted secondary research of databases, covering the period from the beginning of May until the end of 2024. Out of 17 new articles, none fit the criteria; hence, the final number of studies remained 11. Figure 2presents the PRISMA flowchart of the study selection process. Notably, most of the included studies were published between 2017 and 2024, with only two articles from 2012 and 2013. The relative novelty of this research area explains the limited number of available studies. The selected articles were divided into three groups: 1. dietary intervention with omega-3 PUFAs, along with genetic variants of FADS1/FADS2 genes, in cancer patients (only one study, Table 1); 2. PUFA status in plasma/tissues and its association with FADS1/FADS2 polymorphism in cancer patients (three studies, Table 2); and 3. PUFA status in relation to FADS1/FADS2 genotypes as risk factors for cancer development (7 studies, Table 3). Most studies were conducted in the USA (five studies), followed by China (two studies), while Poland, India, and Korea each contributed one study. Additionally, one study covered both the USA and Ghana (Tables 1–3). Among the selected studies, only one [ 32 ] investigated a dietary intervention in prostate cancer patients using a flaxseed-enriched diet. Three studies focused on PUFA status and genetic variation in FADS1/FADS2 genes, two on prostate cancer [ 33 , 34 ] and one on glioblastoma multiforme [ 35 ]. The remaining seven studies examined the relationship between PUFA status, SPNs in FADS genes, and cancer risk factors [36–42]. Regarding PUFA measurement methods, three studies analyzed PUFA status from whole blood [ 33 , 38 , 41 ], while four studies measured PUFAs in malignant tissue [ 32 , 34 , 36 , 39 ] and in both tumor tissues and blood components (red blood cells/serum) [ 37 , 40 ]. Among the studies that did not directly assess PUFA levels, one estimated PUFA intake using a Food Frequency Questionnaire (FFQ) [ 42 ], while the other focused on mRNA expression levels of desaturase enzymes [35]. Int. J. Mol. Sci. 2025,26, 4867 5 of 21 Table 1. Dietary supplementation of omega-3 fatty acids, along with genetic variants in the FADS1/FADS2 gene clusters, in cancer patients. Reference Country Cancer Area Study Design Sample Size, (n) Age (Years) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment Intervention/ Supplementation Duration PUFA Status Study-Related Conclusions Azrad et al., 2012 [32]USA Prostate cancer RCT n= 161 I-control (n= 41), II-flaxseed (FS) (n= 40) C-59 (36-71) FS-60 (44-73) rs99780, rs174537, rs174545, rs174572, rs498793, rs3834458, rs968567 NCI DHQ ALA intake: 1.23 vs. 7.57 g/day C vs. FS Flaxseed (30 g/day) 30 days follow-up Prostatic tissue −Dietary intake: ↑ALA; ↑ ω-3:ω-6 ratio in FS −Prostate levels: ALA similar, ↑EPA in FS −rs498793 and ALA: significant interaction and influence on aggressive prostatecancer biomarkers independent of the amount of ALA consumed Abbreviations: RCT, Randomized Control Trial; NCI DHQ, National Cancer Institute Diet History Questionnaire; ALA, Alpha-Linolenic Acid; EPA, Eicosapentaenoic Acid, n= mean number. Table 2. PUFA status in plasma/tissues and its association with FADS1/FADS2 polymorphism in cancer patients. Reference Country Cancer Area Study Design Sample Size, n, Sex (%) Age (Mean ±SD or Range) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment PUFA Status: Blood/ Tissues Associations Between FADS1 and FADS2 Genotypes Study-Related Conclusions Minas et al., 2023 [33] Ghana, USA Prostate Cancer Case– control n= 976; male -n= 489 African American n= 487 European American; 1033 controls, 485 African American and 548 European American 50–74 years rs174556 Nutritional questionnaire Whole blood SNP significant associations with ω-6 FA (AA, DGLA, ADA, GLA) in European American men; exception: rs174556 SNP in FADS1 gene; SNPs did not influence ω-6 levels in African American or Ghanaian men DHA, DPA, and EPA: inversely associated with prostate cancer among Ghanaian men −ω-6 FAs associated with prostate cancer among European American men −trans FAs positively associated with prostate cancer in all study population Palmitoleic acid: positive dose-dependent relationship with higher NCCN risk scores Int. J. Mol. Sci. 2025,26, 4867 6 of 21 Table 2. Cont. Reference Country Cancer Area Study Design Sample Size, n, Sex (%) Age (Mean ±SD or Range) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment PUFA Status: Blood/ Tissues Associations Between FADS1 and FADS2 Genotypes Study-Related Conclusions Korbecki et al., 2020 [35]Poland Glioblastoma multiforme Case– control n= 28 (16 males, 12 females) 60 ±12 years Quantitative determination of total FADS, FADS2 expression No mRNA expression levels of desaturase enzymes SCD and FADS2 FADS1 and FADS2 expression ↓ in growing tumor area and necrotic core vs. peritumoral area FADS2 expression in the peritumoral area: 2 times higher than in the necrotic core Expression of desaturases in GBM tumors does not differ between the sexes Biosynthesis of MUFAs and PUFAs in GBM tumors is less intense than in the peritumoral area Nutritional deficiency increases the biosynthesis of MUFAs and PUFAs in GBM cells Cui et al., 2016 [34]USA Prostate cancer C-S n= 60 55 European American, 4 African American, and 1 Asian No data rs174537 No Prostate tissue G allele at rs174537: ↑ levels of AA and ADA ↑ω -3 LC-PUFAs (DHA, DPA) and more efficient n-6 PUFA biosynthesis (higher AA/LA and AA/DGLA ratios) FADS1 activity: higher in G allele carriers AA: 15.8% of total FAs; ω-6 PUFA pathway in specimens from homozygous G individuals exhibited increasingly higher values vs. heterozygous and homozygous T individuals Efficient ω-6 PUFA biosynthesis: promotes tumor growth via lipid signaling Higher AA levels in homozygous GG may influence PCA FADS, Fatty Acid Desaturase; SNP, Single-Nucleotide Polymorphism; AA, Arachidonic Acid; DGLA, Dihomoγ -Linolenic Acid; ADA, Adrenic Acid; GLA, Gamma-Linolenic Acid; DHA, Docosahexaenoic Acid; DPA, Docosapentaenoic Acid; EPA, Eicosapentaenoic Acid; C-S, Cross-Sectional Study; NCCN, National Comprehensive Cancer Network; LA, Linoleic Acid; SCD, Stearoyl-CoA Desaturase; GBM, Glioblastoma Multiforme; MUFAs, Monounsaturated Fatty Acids; PUFAs, Polyunsaturated Fatty Acids. Int. J. Mol. Sci. 2025,26, 4867 7 of 21 Table 3. PUFA status and FADS1/FADS2 genotypes as potential risk factors for cancer development. Reference Country Cancer Type Study Design Sample Size, n, Sex (%) Age (Mean + SD/Range) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment or Intervention PUFA Status: Blood/ Tissues Gene–PUFA Interaction and Cancer Risk White et al., 2019 [40] Tennessee, USA Colorectal cancer RCT n= 141 40 to 80 years FADS1 rs174535 No 3 fish oil capsules (1395 mg EPA +1125 mg DHA) 3 olive oil capsules oil (total 3g) Red blood cells RBC membrane: −AA lower in homozygous individuals (T allele of the FADS gene) −LA was greater in individuals who had the T allele −No interaction between fish oil supplementation and urinary PGE-M based on FADS genotype −No effect modification between ω-3 LC-PUFA supplementation and urinary PGE-M based on ↑NSAID use −No interaction between fish oil supplementation and rectal eicosanoids based on FADS genotype Porenta et al., 2013 [37] California, USA Colon cancer RCT n= 108 51.1–54.9 rs3834458, rs174556, rs174561, rs174537 Mediterranean diet group/ healthy eating group baseline and after 6 months 2-day food records and two 24 h recalls Serum, colon tissue −AA at 6 months—significantly different between diet arms in persons with no minor alleles in FADS1/2 gene cluster −Colon AA at 6 months in no minor allele carriers ↑HE ↑MD MD may reduce colon cancer risk in individuals with no minor alleles Int. J. Mol. Sci. 2025,26, 4867 8 of 21 Table 3. Cont. Reference Country Cancer Type Study Design Sample Size, n, Sex (%) Age (Mean + SD/Range) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment or Intervention PUFA Status: Blood/ Tissues Gene–PUFA Interaction and Cancer Risk Wang et al., 2017 [39]China Lung cancer OCS/GWAS (observational, crosssectional genomewide association study) n= 253 FADS1 rs174548 No Liver Tissue rs174548 Stronger effect on lung cancer risk in females Only mQTL variant of PUFAs reported by previous GWASs and explained a large proportion of heritability Plasma PUFAs causally associated with lung cancer based on the idea of Mendelian randomization Murff et al., 2021 [36] Tennessee, USA Colorectal cancer RCT n= 141 40-80 years rs174535 No dietary data Intervention: capsules fish oil (1395 mg EPA + 1125 mg DHA) RBCs Rectal epithelial cells FADS genotype: No influence on RBC membrane ω-3 LCPUFA percentages in response to supplementation −Impact on RBC membrane AA content decreased −Regardless of the FADS genotype, no evidence of a proliferative or pro-apoptotic effect on ω-3 LC-PUFA supplementation on rectal mucosae Chen et al., 2017 [41]China Oral cancer Case– control n= 305 oral cancer patients; n= 579 healthy controls 20 to 80 years rs174549 Fish intake Whole blood −Significant gene–diet multiplicative interaction between FADS1 rs174549 polymorphism and fish intake for oral cancer FADS1—a variant allele associated with a significantly decreased risk of oral cancer AA genotype associated with a decreased risk of oral cancer compared to the GG genotype Int. J. Mol. Sci. 2025,26, 4867 9 of 21 Table 3. Cont. Reference Country Cancer Type Study Design Sample Size, n, Sex (%) Age (Mean + SD/Range) Genetic Variation in the FADS1/FADS2 Gene Cluster Dietary Assessment or Intervention PUFA Status: Blood/ Tissues Gene–PUFA Interaction and Cancer Risk Preethika et al., 2022 [38]India Breast cancer OCS 102 25-60 age range rs 174537 No Whole blood −DNA variation: does not lead to cancer; it modifies molecular traits that go on to affect breast cancer risk − High levels of AA and low levels of ω-3 LC-PUFAs −Individuals who exhibit lower FADS1 activity (T allele) benefit from ω-3 LC-PUFAs by reduction in risk of breast cancer Lee et al., 2018 [42]Korea Gastric cancer Case– control 402 cases 1.062 controls Cases: 55.27 ±10.91 Controls: 52.03 ±8.60 FADS1 rs174546 FADS2 rs174583 Semiquantitative FFQ composed of 106 food items No −Inverse association between dietary DHA and the risk of gastric cancer −FADS1 rs174546 and FADS2 rs174583: did not change association between ω-3 or ω-6 PUFAs and gastric cancer risk RCT, Randomized Controlled Trial; FADS, Fatty Acid Desaturase; EPA, Eicosapentaenoic Acid; DHA, Docosahexaenoic Acid; AA, Arachidonic Acid; LA, Linoleic Acid; PGEM, Prostaglandin E Metabolite; NSAID, Nonsteroidal Anti-Inflammatory Drug; mOTL, Modified Oligonucleotide Therapy; GWAS, Genome-Wide Association Study; PUFAs, Polyunsaturated Fatty Acids; RBCs, Red Blood Cells; LCPUFAs, Long-Chain Polyunsaturated Fatty Acids; FFQ, Food Frequency Questionnaire. Int. J. Mol. Sci. 2025,26, 4867 16 of 21 3.5. Strengths and Limitations This study provides a systematic and up-to-date review of the relationship between PUFA metabolism, genetic variations in FADS genes, and cancer. It highlights the importance of gene–diet interactions in cancer research and identifies key areas for future investigation. Furthermore, the inclusion of multiple reputable databases ensures a thorough and comprehensive literature search. This review is limited by the small number of included studies (n= 11), which may not offer a comprehensive overview of the topic. Additionally, the heterogeneity in study designs, sample sizes, and methodology makes it difficult to draw definitive conclusions. The lack of intervention studies further limits the ability to establish causal relationships between dietary PUFA intake, genetic variations, and cancer risk. 4. Materials and Methods 4.1. Scoping Review Approach A scoping review approach was employed to explore a complex issue that has not been comprehensively reviewed to date and to highlight the existing knowledge gaps in the field. 4.2. Search Strategy The PICOTSS framework—Population, Intervention (or Exposure), Comparator(s), Outcome(s), Timing, Setting(s), and Study Design—was used in this study. Target population: Adults with different types of cancer. Exposure: Omega-3 fatty acids, gamma-linolenic acid, fish oil, and foods rich in omega-3 fatty acids. Comparators: Studies with comparable controls and polymorphism. Outcome variables: FADS1/FADS2 polymorphism in relation to fatty acid status or intake in cancer patients or in individuals with higher risk for cancer. Timing: From inception to the end of 2024. Settings: All settings included where cancer patients spent time (home, hospital, nursing home, etc.). Study design: Observational, including cross-sectional and prospective studies and intervention studies The search in the PubMed, Scopus, and Web of Science databases was conducted to examine relevant articles published from inception to the end of 2024. The first search examined articles published from inception to April 2024, and the updated search examined articles from May to December 2024. In the search strategies (strings adapted when necessary to fit the specific search requirements of each database), the following keywords and terms were used: (Nutrigenetic OR Nutrigenomic OR FADS1 OR FADS2 OR Fatty Acid Desaturase 1 OR Fatty Acid Desaturase 2 AND (omega-3 OR n-3 OR eicosapentaenoic acid OR EPA OR docosahexaenoic acid OR DHA OR fish oil OR fatty fish OR sea foods OR gamma-linolenic acid OR GLA OR evening primrose oil OR borage oil OR black currant oil OR spirulina OR purslane OR chia seeds OR flaxseed OR walnuts OR hemp seed oil) combined with cancer as the outcome term. 4.3. Eligibility Criteria A comprehensive selection process was applied to identify relevant studies. Only research conducted on human participants over the age of 18 and published in English was considered, with no restrictions on publication date, concluding at the end of 2024. Two of the co-authors (V.Z., and M.P.) screened titles and abstracts according to these criteria, selecting eligible studies for further review. Full-text articles were reviewed by three co- Int. J. Mol. Sci. 2025,26, 4867 17 of 21 authors (V.Z., M.P., and D.R.), and 20% were double-checked for accuracy. Reviews, book chapters, conference abstracts, letters, articles lacking usable data, and studies focused on children, adolescents, pregnant women, animal models, or cell cultures were excluded. Studies involving participants with chronic conditions (e.g., kidney or liver disease, HIV, thyroid disorders, or glucocorticoid use) were also excluded. Additionally, in order not to miss relevant articles, the reference lists of the related articles and reviews were examined. The final selection of articles was based on the following criteria: (1) observational or epidemiological studies, (2) clinical trials focused on interventions related to omega-3 fatty acid intake and/or gamma linolenic acid intake, and (3) studies on genetic and epigenetic variations in the FADS gene cluster revealing complex gene–diet supplementation interactions. Any disagreements during the selection process were resolved through consensus among all the authors. 4.4. Data Extraction The findings from the full texts of eligible papers were summarized in tables based on the main categories of the outcome measures. The following information was extracted from the included articles and presented in the tables: name of the first author; publication year; country; cancer area; study design, sample size and sex of participants; age range or mean age; genetic variation in the FADS1/FADS2 gene cluster; dietary assessment; PUFA status (blood and tissue); intervention/supplementation and duration (Table 1); associations between FADS1/FADS2 and PUFA status (Table 2); gene–PUFA interactions; and cancer risk (Table 3). 5. Conclusions Current evidence underscores the complex relationship between genetic polymorphisms, fatty acid metabolism, and cancer development. Variants in the FADS1 and FADS2 genes may influence blood and tissue levels of LC-PUFAs, potentially shifting the balance toward more favorable anti-inflammatory omega-3 pathways. Notably, lower levels of omega-3 LC-PUFAs and elevated levels of omega-6 LC-PUFAs have been observed in cancer patients and malignant tissue, suggesting a potential link to disease progression. To date, the most consistent association identified is between the rs174537 variant and altered PUFA metabolism in prostate and breast cancer. While initial studies suggest that omega-3 supplementation may improve LC-PUFA profiles, data on the interaction between FADS1/FADS2 polymorphisms and therapeutic response remain limited. Only one study has examined omega-3 supplementation in relation to FADS gene variants in prostate cancer, and, to date, no studies have evaluated the role of GLA supplementation. These gaps underscore the need for further research into the molecular mechanisms—especially epigenetic modifications—linking genetic variation to cancer progression. Genome-tailored nutritional interventions hold promise as a novel strategy to enhance anti-inflammatory responses and improve outcomes in genetically defined cancer subgroups. 6. Current Problems and Future Directions Key challenges include the absence of large-scale, well-designed clinical trials and limited understanding of how genetic variability affects fatty acid metabolism and treatment outcomes in cancer. The lack of translational research bridging laboratory findings and clinical applications also hinders progress. Additionally, the influence of environmental and dietary factors on gene–nutrient interactions remains poorly understood. Future research should prioritize mechanistic studies—particularly at the epigenetic level—and conduct genome-informed nutritional intervention trials assessing the therapeutic potential of omega-3 and GLA supplementation in stratified patient populations. Advancing this Int. J. Mol. Sci. 2025,26, 4867 18 of 21 field will require the integration of nutrigenomics into clinical oncology, implementation of precision nutrition strategies based on individual genetic profiles, and interdisciplinary collaboration among geneticists, nutritionists, oncologists, and bioinformaticians to develop personalized dietary approaches that optimize cancer treatment outcomes. Author Contributions: Conceptualization, D.R.-M. and V.V.; methodology, D.R.-M.; writing—original draft preparation, V.Z. and M.P.; writing—review and editing, V.V., M.M.-K. and D.R.-M.; visualization, M.P.; supervision, D.R.-M.; project administration V.V. All authors have read and agreed to the published version of the manuscript. Funding: This study was supported by the Science Fund of the Republic of Serbia (Grant PRISMA No. 5050, project title: Anti-inflammatory dietary intervention in breast cancer patients receiving aromatase inhibitors-AID). 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