Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide, representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and have a worsening prognosis. Recent advances in the genetic understanding of lung cancer have opened new avenues for personalized treatments and targeted therapies. This review examines the latest discoveries in the genetics of lung cancer, discusses key biomarkers, and analyzes current clinical therapies based on this genetic information. It will conclude with a discussion of future prospects and potential research directions.

Background: Since the beginning of the anti-COVID-19 vaccination campaign, it has become evident that vaccinated subjects exhibit considerable inter-individual variability in the response to the vaccine that could be partly explained by host genetic factors. A recent study reported that the immune response elicited by the Oxford-AstraZeneca vaccine in individuals from the United Kingdom was influenced by a specific allele of the human leukocyte antigen geneHLA-DQB1.Methods: We carried out a genome-wide association study to investigate the genetic determinants of the antibody response to the Pfizer-BioNTech vaccine in an Italian cohort of 1351 subjects recruited in three centers. Linear regressions between normalized antibody levels and genotypes of more than 7 million variants was performed, using sex, age, centers, days between vaccination boost and serological test, and five principal components as covariates. We also analyzed the association between normalized antibody levels and 204 HLA alleles, with the same covariates as above.Results: Our study confirms the involvement of the HLA locus and shows significant associations with variants inHLA-A,HLA-DQA1, andHLA-DQB1genes. In particular, the HLA-A*03:01 allele is the most significantly associated with serum levels of anti-SARS-CoV-2 antibodies. Other alleles, from both major histocompatibility complex class I and II are significantly associated with antibody levels.Conclusions: These results support the hypothesis that HLA genes modulate the response to Pfizer-BioNTech vaccine and highlight the need for genetic studies in diverse populations and for functional studies aimed to elucidate the relationship between HLA-A*03:01 and CD8+ cell response upon Pfizer-BioNTech vaccination.

Lung cancer, including both non-small cell lung cancer and small cell lung cancer, remains the leading cause of cancer-related mortality worldwide representing 18% of the total cancer deaths in 2020. Many patients are identified already at an advanced stage with metastatic disease and have a worsening prognosis. Recent advances in the genetic understanding of lung cancer have opened new avenues for personalized treatments and targeted therapies. This review examines the latest discoveries in the genetics of lung cancer, discusses key biomarkers, and analyzes current clinical therapies based on this genetic information. It will conclude with a discussion of future prospects and potential research directions.

Background: Opioids in step III of the WHO analgesic ladder are the standard of care for treating cancer pain. However, a significant minority of patients do not benefit from therapy. Genetics might play a role in predisposing patients to a good or poor response to opioids. Here, we investigated this issue by conducting a genome‐wide association study (GWAS).Methods: We genotyped 2057 European advanced cancer patients treated with morphine, buprenorphine, fentanyl and oxycodone. We carried out a whole‐genome regression model (using REGENIE software) between genotypes and the opioid response phenotype, defined as a numerical score measuring patient pain intensity.Results: The GWAS identified five non‐coding variants on chromosome 20 with a p‐value <5.0 × 10⁻⁸. For all of them, the minor allele was associated with lower pain intensity. These variants were intronic to the PCMTD2 gene and were 200 kbp downstream of OPRL1, the opioid related nociceptin receptor 1. Notably according to the eQTLGen database, these variants act as expression quantitative trait loci, modulating the expression mainly of PCMTD2 but also of OPRL1. Variants in the same chromosomal region were recently reported to be significantly associated with pain intensity in a GWAS conducted in subjects with different chronic pain conditions.Conclusions: Our results support the role of genetics in the opioid response in advanced cancer patients. Further functional analyses are needed to understand the biological mechanism underlying the observed association and lead to the development of individualized pain treatment plans, ultimately improving the quality of life for cancer patients.Significance Statement: This genome‐wide association study on European advanced cancer patients treated with opioids identifies novel regulatory variants on chromosome 20 (near PCMTD2 and OPRL1 genes) associated with pain intensity. These findings enhance our understanding of the genetic basis of opioid response, suggesting new potential markers for opioid efficacy. The study is a significant advancement in pharmacogenomics, providing a robust dataset and new insights into the genetic factors influencing pain intensity, which could lead to personalized cancer pain management.

Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK, with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations.

Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1,464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than 7 million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK, with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue were already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations.