The mutational landscape of an individual\'s cancer can inform on its molecular state and be used as prognostic and therapeutic markers. The study by Barbour et al.1 analyzes mutational patterns in bladder cancer samples to uncover new biological insights into the ERCC2 gene function and develop new predictive prognostic tools.

BACKGROUND: In Bangladesh, only a fraction of prostate cancer patients are diagnosed annually due to lack of symptom awareness and screening challenges, resulting in high mortality. Aiming to improve screening methods, we evaluated X-ray cross-complementing gene 1 (XRCC1) Arg194Gln and Xeroderma pigmentosum group D (XPD) Lys751Gln polymorphisms to determine their relevance as potential markers for predicting prostate cancer risk, severity and clinical parameters in Bangladeshi population.
RESULTS: This study included 132 prostate cancer patients and 135 healthy controls. Genotype analysis was done from blood samples by the PCR-RFLP method. The XRCC1 Trp/Trp genotype was associated with prostate cancer (ORadj = 5.51; 95% CI = 1.13-26.78; p-value = 0.03) compared to Arg/Arg genotype. No significant association was found between the XPD variants and prostate cancer risk. The XRCC1 Trp/Trp genotype increased prostate cancer risk in smokers and non-smokers but was statistically non-significant. In individuals without a family history of cancer, the XRCC1 Trp/Trp genotype had a non-significant 4.64-fold higher risk (ORadj=4.64; 95% CI = 0.88-24.36; p-value = 0.07), while the XPD Gln/Gln had a 2.66-fold non-significant higher risk (ORadj=2.66; 95% CI = 0.88-8.10; p-value = 0.09). The XRCC1 Trp/Trp variant was associated with hematuria risk, higher mean serum creatinine, and mean prostate-specific antigen (PSA) levels in prostate cancer patients. The XPD Gln/Gln variant was only associated with higher mean serum creatinine levels.
CONCLUSIONS: Our findings suggest that XRCC1 screening may be used as a biomarker for prostate cancer to improve early diagnosis in Bangladesh.

Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.

UNASSIGNED: Trichothiodystrophy-1 (TTD1) is an autosomal-recessive disease and caused by mutations in ERCC2, a gene coding for a subunit of the TFIIH transcription and nucleotide-excision repair (NER) factor. In almost half of these patients infectious susceptibility has been reported but the underlying molecular mechanism leading to immunodeficiency is largely unknown.
UNASSIGNED: The aim of this study was to perform extended molecular and immunological phenotyping in patients suffering from TTD1.
UNASSIGNED: Cellular immune phenotype was investigated using multicolor flow cytometry. DNA repair efficiency was evaluated in UV-irradiation assays. Furthermore, early BCR activation events and proliferation of TTD1 lymphocytes following DNA damage induction was tested. In addition, we performed differential gene expression analysis in peripheral lymphocytes of TTD1 patients.
UNASSIGNED: We investigated three unrelated TTD1 patients who presented with recurrent infections early in life of whom two harbored novel ERCC2 mutations and the third patient is a carrier of previously described pathogenic ERCC2 mutations. Hypogammaglobulinemia and decreased antibody responses following vaccination were found. TTD1 B-cells showed accumulation of γ-H2AX levels, decreased proliferation activity and reduced cell viability following UV-irradiation. mRNA sequencing analysis revealed significantly downregulated genes needed for B-cell development and activation. Analysis of B-cell subpopulations showed low numbers of naïve and transitional B-cells in TTD1 patients, indicating abnormal B-cell differentiation in vivo.
UNASSIGNED: In summary, our analyses confirmed the pathogenicity of novel ERCC2 mutations and show that ERCC2 deficiency is associated with antibody deficiency most likely due to altered B-cell differentiation resulting from impaired BCR-mediated B-cell activation and activation-induced gene transcription.

OBJECTIVE: Single nucleotide polymorphisms (SNPs) are common in genes and can lead to dysregulation of gene expression in tissues, which can affect carcinogenesis. Many studies reporting the association between xeroderma pigmentosum group D (XPD) polymorphisms of rs13181 and rs1799793 with oral cancer risk, but with conflicting and inconclusive results.
METHODS: We performed a comprehensive and systematic search through the PubMed, Elsevier, Web of science, and Embase databases, twelve studies were included in the meta-analysis to determine whether XPD rs13181 and rs1799793 polymorphism contributed to the risk of oral cancer.
RESULTS: The pooled date indicated a significant association between the rs13181 polymorphism and oral cancer risk for the allele comparison model (odds ratio, OR = 1.60, 95% confidence intervals, CI = 1.09-2.35, P = 0.02), the dominant model (OR = 1.74, 95% CI = 1.08-2.82, P = 0.02), and the heterozygote model (OR = 1.59, 95% CI = 1.02-2.49, P = 0.04). For the XPD rs1799793 polymorphism, it is not associated with the incidence of oral cancer under any model. Subgroup analyses based on ethnicity indicated that the rs13181 polymorphism increased the risk of oral cancer among Asians according to the allele comparison model (OR = 1.97, 95% CI = 1.10-3.51, P = 0.02), the dominant model (OR = 2.35, 95% CI = 1.25-4.44, P = 0.008), the heterozygote model (OR = 2.05, 95% CI = 1.15-3.66, P = 0.01), and the homozygous model (OR = 2.47, 95% CI = 1.06-5.76, P = 0.04).
CONCLUSIONS: Our meta-analysis suggests a positive correlation between XPD rs13181polymorphism and the development of oral cancer among Asians, but a negative correlation among Caucasians populations.

OBJECTIVE: ERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer.
METHODS: SNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate.
RESULTS: A total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001).
CONCLUSIONS: Genetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription.

ERCC2 plays a pivotal role in DNA damage repair, however, its specific function in cancer remains elusive. In this study, we made a significant breakthrough by discovering a substantial upregulation of ERCC2 expression in glioblastoma (GBM) tumor tissue. Moreover, elevated levels of ERCC2 expression were closely associated with poor prognosis. Further investigation into the effects of ERCC2 on GBM revealed that suppressing its expression significantly inhibited malignant growth and migration of GBM cells, while overexpression of ERCC2 promoted tumor cell growth. Through mechanistic studies, we elucidated that inhibiting ERCC2 led to cell cycle arrest in the G0/G1 phase by blocking the CDK2/CDK4/CDK6/Cyclin D1/Cyclin D3 pathway. Notably, we also discovered a direct link between ERCC2 and CDK4, a critical protein in cell cycle regulation. Additionally, we explored the potential of TRAIL, a low-toxicity death ligand cytokine with anticancer properties. Despite the typical resistance of GBM cells to TRAIL, tumor cells undergoing cell cycle arrest exhibited significantly enhanced sensitivity to TRAIL. Therefore, we devised a combination strategy, employing TRAIL with the nanoparticle DMC-siERCC2, which effectively suppressed the GBM cell proliferation and induced apoptosis. In summary, our study suggests that targeting ERCC2 holds promise as a therapeutic approach to GBM treatment.

Malignant pleural mesothelioma (MPM) is a rare type of cancer, and its main risk factor is exposure to asbestos. Accordingly, our knowledge of the genomic structure of an MPM tumor is limited when compared to other cancers. In this study, we aimed to characterize complex genomic rearrangement patterns and variations to better understand the genomics of MPM tumors. We comparatively scanned 3 MPM tumor genomes by Whole-Genome Sequencing and High-Resolution SNP array. We also used various computational algorithms to detect both CNAs and complex chromosomal rearrangements. Genomic data obtained from each bioinformatics tool are interpreted comparatively to better understand CNAs and cancer-related Nucleotide variations in MPM tumors. In patients 1 and 2, we found pathogenic nucleotide variants of BAP1, RB1, and TP53. These two MPM genomes exhibited a highly rearranged chromosomal rearrangement pattern resembling Chromomanagesis particularly in the form of Chromoanasynthesis. In patient 3, we found nucleotide variants of important cancer-related genes, including TGFBR1, KMT2C, and PALLD, to have lower chromosomal rearrangement complexity compared with patients 1 and 2. We also detected several actionable nucleotide variants including XRCC1, ERCC2. We also discovered the SKA3-DDX10 fusion in two MPM genomes, which is a novel finding for MPM. We found that MPM genomes are very complex, suggesting that this highly rearranged pattern is strongly related to driver mutational status like BAP1, TP53 and RB1.

Background: Publications on the associations of genetic variants with the response to platinum-based chemotherapy (PBC) in NSCLC patients have surged over the years, but the results have been inconsistent. Here, a comprehensive meta-analysis was conducted to combine eligible studies for a more accurate assessment of the pharmacogenetics of PBC in NSCLC patients. Methods: Relevant publications were searched in PubMed, Scopus, and Web of Science databases through 15 May 2021. Inclusion criteria for eligible publications include studies that reported genotype and allele frequencies of NSCLC patients treated with PBC, delineated by their treatment response (sensitive vs. resistant). Publications on cell lines or animal models, duplicate reports, and non-primary research were excluded. Epidemiological credibility of cumulative evidence was assessed using the Newcastle-Ottawa Scale (NOS) and Venice criteria. Begg\'s and Egger\'s tests were used to assess publication bias. Cochran\'s Q-test and I2 test were used to calculate the odds ratio and heterogeneity value to proceed with the random effects or fixed-effects method. Venice criteria were used to assess the strength of evidence, replication methods and protection against bias in the studies. Results: A total of 121 publications comprising 29,478 subjects were included in this study, and meta-analyses were performed on 184 genetic variants. Twelve genetic variants from 10 candidate genes showed significant associations with PBC response in NSCLC patients with strong or moderate cumulative epidemiological evidence (increased risk: ERCC1 rs3212986, ERCC2 rs1799793, ERCC2 rs1052555, and CYP1A1 rs1048943; decreased risk: GSTM1 rs36631, XRCC1 rs1799782 and rs25487, XRCC3 rs861539, XPC rs77907221, ABCC2 rs717620, ABCG2 rs2231142, and CDA rs1048977). Bioinformatics analysis predicted possible damaging or deleterious effects for XRCC1 rs1799782 and possible low or medium functional impact for CYP1A1 rs1048943. Conclusion: Our results provide an up-to-date summary of the association between genetic variants and response to PBC in NSCLC patients.

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients\' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413-9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251-1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.