Annals of Human Genetics最新文献

Background: Neoadjuvant chemoradiotherapy (nCRT) is essential for treating locally advanced rectal cancer (LARC), however response to nCRT varies, and reliable predictors are lacking.

Methods: This study used whole exome sequencing analysis to investigate genetic differences between tumors highly responsive and non-responsive to nCRT. Five patients with good response and two patients without response to nCRT were used as a discovery set.

Results: The analysis identified 15 InDels and 202 non-synonymous SNVs exclusively present in tumors of non-responders, mainly in genes regulating the cell cycle, adhesion, and migration. In contrast, 9 InDels and 122 non-synonymous SNVs were exclusively present in tumors of good responders, primarily in extracellular matrix remodeling and immunity-related genes. Six variants in transmembrane transporter genes were selected as candidate biomarkers and validated in 33 LARC patients.

Conclusion: The results suggest that SLC16A6 rs7222013 and SLC25A2 rs3749780 may serve as potential predictors of poor nCRT response in LARC patients.

Purpose: The aim of this systematic review is to identify all genome-wide association study (GWAS)-based polygenic risk score (PRS) studies (with different PRS approaches) reported in African ancestry populations diagnosed with any type of cancer. Additionally, this review assessed the role of PRS in advancing precision medicine through its clinical utility across different cancer types in African populations.

Methods: We searched PubMed from January 2009 to April 2023 and included GWAS-based PRS studies for cancer patients of African genetic ancestry.

Results: Among the 33 eligible studies, prostate cancer and breast cancer were the most common types in adults, whereas only one publication reported the risk association of neuroblastoma (a pediatric cancer). The most common PRS approach used was ancestry-specific PRS. Clinical utility of the calculated PRS varies across cancer types, with inconsistent results. Our systematic review found a limited number of PRS studies on cancer patients (adult and pediatric) of African ancestry, and these studies showed less clinical utility compared to those conducted in European ancestry populations.

Conclusion: To make PRS clinically actionable for African ancestry populations, it is crucial to increase the number of large-scale, population-specific GWAS, improve the representation of African-ancestry cohorts, and refine PRS models to better reflect the genetic diversity within African populations.

This review addresses the genetics of acne vulgaris, the most common skin disease. It is characterized by the presence of comedones (blackheads), papules, and pustules. The condition is associated with sebaceous glands in the face and chest, which produce an oily substance called sebum. In developed nations, acne affects over 80% of adolescents. Mild disease usually resolves spontaneously. More severe acne can leave permanent, disfiguring scarring and strongly affects quality of life. In those cases, medical intervention is warranted. To date, antibiotics and retinoids (synthetic vitamin A derivatives) are the mainstays of treatment. Depending on the severity of the condition, these drugs may be administered either topically or systemically.

Whilst generally effective, they do come with significant drawbacks. Antibiotic use for treating acne is contributing to antimicrobial resistance. In addition, indiscriminate eradication of the skin microbiome negatively impacts skin health. Retinoids are teratogenic and have other undesirable side effects, such as skin irritation and increased UV sensitivity. Thus, there is a clear need for effective interventions that target the underlying disease mechanism, minimizing side effects.

Rapid progress has recently been made in understanding the mechanisms underlying acne. For decades, it was assumed that blackhead formation results from the accumulation of sebum in the hair follicle opening, due to increased sebum production at the onset of puberty. Subsequent colonization by the commensal bacterium Cutibacterium acnes then was thought to cause inflammation. It was also postulated that this micro-organism could induce blackheads. There are, however, several problems with this supposed sequence of events, not the least of which is that it doesn't explain how retinoids work, or why sebaceous glands associated with blackheads are atrophic and hence produce less sebum, not more.

Both GWAS and single gene disorders unequivocally indicate stem/progenitor cell maintenance and cellular migration as the most important processes in the pathogenesis of acne. Together with insights from mouse models, this new perspective is transforming the way we think about acne and its treatment.

Germline pathogenic variants (GPVs, ‘mutations’) causing inherited susceptibility to certain cancers (cancer susceptibility genes, CSGs) broadly belong to one of two main classes—loss of function variants in tumour suppressor genes (TSGs) or gain of function variants in proto-oncogenes (an over-simplification). Genomic analyses of tumours identify ‘driver mutations’ promoting tumour growth and somatic variants which contribute to ‘mutation signatures’ which, with histopathology, can be used to subclassify cancers with implications for causality and treatment. The identification of susceptible individuals is important, as they and their relatives may be at elevated risk of tumours, and this can influence optimal cancer treatment. Classically, cancer risk assessment utilises family history, lifestyle/environment factors, and any non-neoplastic clinical findings, followed by genetic testing of high/moderate penetrance CSGs. In cancer cases not caused by highly penetrant CSGs, multiple variants conferring relatively small risks play a major role. These were discovered by genome-wide association (GWAS) studies. The utility of polygenic risk scores (PRS) derived from multiple such variants for clinical risk profiling is being assessed. Access to genetic tests is improved by widening eligibility criteria for testing and empowering non-genetic clinicians to identify CSG GPVs and manage carriers. This will contribute to expanding programmes of screening, prevention and early detection (SPED), with personalised surveillance and prophylactic interventions, and exploit knowledge of the molecular mechanisms of cancer susceptibility to develop novel cancer therapies. In some jurisdictions, population testing is being considered, but GPV penetrance in this setting can be unclear, and the public health implications are complex.