Dhanya Ramachandran

Genetic profiling of a new HPV-negative cervical cancer model identified pathogenic variants in genes implicated in oncogenic signaling, cell cycle regulation, and DNA damage repair pathways, including homologous recombination, non-homologous end-joining, and mismatch repair. Deficiencies in BRCA 2, RAD51 and MLH1 were among these actionable targets. The newly described cervical cancer model revealed sensitivity towards the PARP inhibitor olaparib, which was further augmented upon combination with platinum-based chemotherapeutics. In contrast, BRCA1/2 -proficient cervical cancer cells exhibited greater resistance to these strategies. This study highlights the potential of in-depth genetic analysis to identify genetic susceptibilities to guide personalized medicine approaches.

Background: While genome-wide association studies (GWAS) have identified hundreds of cancer-associated genetic variants, the specific biological contexts where these variants exert their effects remain largely unknown. We aimed to prioritize context-specific genetic risk mechanisms for 11 solid cancers at both genome-wide and single-variant resolutions. Methods: We integrated cancer GWAS summary statistics from European ancestry samples (avg. n = 47 856 cases) with 1473 context-specific annotations representing candidate cis-regulatory elements. For genome-wide analysis, we applied cell-type fine-mapping (CT-FM), a method that jointly models heritability enrichments across annotations to select likely disease-relevant biological contexts. Following functionally informed fine-mapping to identify high-confidence causal single nucleotide polymorphisms (SNPs), we used CT-FM-SNP to identify relevant contexts for individual variants. A combined SNP-to-gene framework was applied to construct putative {regulatory SNP-context-gene-cancer} quadruplets. Results: Stratified LD score regression analysis identified 141 annotations showing significant heritability enrichment (false discovery rate, q ≤ 0.05). CT-FM prioritized 4 high-confidence biological contexts (posterior inclusion probability ≥ 0.5): mammary luminal epithelial cells for overall and estrogen receptor (ER)-positive breast cancer, the VCaP (Vertebral-Cancer of the Prostate) epithelial cell line for prostate cancer, and bulk tumor tissue contexts for colorectal and renal cancers. Variant-level analysis of hundreds of putatively causal SNPs aligned with these findings and identified additional high-confidence contexts for ER-negative breast, endometrial, lung, and bladder cancers. A total of 489 putative regulatory quadruplets were constructed, proposing specific molecular hypotheses underlying the observed GWAS signals. Conclusion: These findings advance our understanding of genetic susceptibility to different cancers. Future work in larger, more diverse GWAS, coupled with more comprehensive annotation atlases, is essential to expand upon and validate our results.

Purpose: Observational data suggest that women conceiving without a corpus luteum are at higher risk of developing preeclampsia. While the underlying mechanisms remain unclear, the absence of corpus luteum -derived secretory products may be a contributing factor. This study investigates whether the plasma proteome differs between women who conceive with or without a corpus luteum and examines the relationship with mode of conception. Methods: Plasma samples from 12 participants were collected at three time points: first trimester, third trimester, and postpartum. The cohort included women who conceived unassisted (UC) after infertility, via artificial cycle frozen embryo transfer (AC FET), or natural cycle frozen embryo transfer (NC FET). A total of 36 plasma protein samples were analyzed using mass spectrometry-based proteomics to compare the proteome of women who conceived with and without a corpus luteum , across different conception methods and pregnancy stages. Results: In total, 528 proteins were quantified. No differentially expressed plasma proteins were identified between women with and without a corpus luteum . However, 15 proteins showed differential expression between UC and FET at all time points, with Bonferroni-corrected p < 9.47 × 10 ⁻⁵ and FC ≥ |2|. Several altered proteins, including PAPPA and ANG, were linked to preeclampsia. SERPINA7 was differentially detected when comparing time points within the unassisted conception method. No significant differences were detected between AC FET and NC FET. Conclusion: This pilot study revealed a unique proteomic signature associated with the mode of conception. The findings suggest biologically plausible candidate proteins for further testing. Validation in larger cohorts or with alternative proteome analysis technologies is needed.

Purpose: In recent years, active surveillance has been introduced as an alternative to excisional treatment in younger women with cervical intraepithelial neoplasia grade 2 (CIN 2) because spontaneous regression rate is high and excisional treatment is associated with an increased risk of preterm birth. However, the potential effect of this conservative approach on the risk of developing cervical cancer has not been evaluated very well. Methods: The present study offers a real-life analysis of treatment pathways for patients diagnosed with CIN 2. Results: Following CIN 2 diagnosis, 84 cases out of 187 (44.9%) were managed conservatively for at least 7 months and 103 cases (55.1%) were admitted for an excisional procedure LEEP (loop electrosurgical excision procedure). Out of 84 patients observed with a CIN 2 diagnosis, 64 showed persistence of CIN 2 lesion (76.2%), 14 showed spontaneous remission under active surveillance (16.7%), 4 progressed to CIN 3 (4.8%) and 2 to carcinoma (one case of vaginal carcinoma and one case of cervical adenocarcinoma (Supplementary Fig. 1) (2.4%). We observed the regression of CIN 2 in 16.7% of patients on active surveillance and this was statistically significant during the observation period (95% CI 5.72–10.85, p < 0.001) (Supplementary Fig. 3). Conclusion: The choice of treatment was strongly associated with HPV typing in our study. Patients with HPV 16 infection underwent surgery more often than patients without HPV 16 infection. The difference in our study was statistically significant (p < 0.001). We observed regression of CIN 2 in 16.7% of patients on active surveillance and this was statistically significant to the observation period (95% CI 5.72–10.85, p < 0.001).

We investigated differential splicing between normal and preeclamptic pregnancies in endothelial colony-forming cells (ECFCs) from cord blood. Transcriptome-wide analysis identified exon 8 skipping of CADM1 mRNA to be upregulated in ECFCs from women with preeclampsia. In vitro splice switching studies indicated that induction of this isoform decreases the cell migration and tubule formation abilities of fetal ECFCs. Our findings link a specific splice isoform of CADM1 to preeclampsia, with potential implications for vascular health in the offspring.

Infection by high‐risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large‐scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome‐wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case‐control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene‐based analysis identified HLA‐DQA1 and HLA‐DQB1 as genome‐wide significant (GWS) genes. In validation genotyping, the genome‐wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78–0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59–0.91, n = 1431). This variant was found to be a robust eQTL for HLA‐DRB1 , HLA‐DQB1‐AS1 , C4B , HLA‐DRB5 , HLA‐DRB6 , HLA‐DQB1 , and HLA‐DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty‐four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type‐specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.

This study identifies and characterizes a novel type of splicing mutation in RAD50 deficiency, a rare genetic disorder.

While cervical cancer is associated with a persistent human papillomavirus (HPV) infection, the progression to cancer is influenced by genomic risk factors that have remained largely obscure. Pathogenic variants in genes of the homology‐directed repair (HDR) or mismatch repair (MMR) are known to predispose to diverse tumour entities including breast and ovarian cancer (HDR) or colon and endometrial cancer (MMR). We here investigate the spectrum of HDR and MMR germline variants in cervical cancer, with particular focus on the HPV status and histological subgroups. We performed targeted next‐generation sequencing for 5 MMR genes and 12 HDR genes on 728 German patients with cervical dysplasia or invasive cancer. In total, 4% of our patients carried a pathogenic germline variant, based on ClinVar classifications and additional ESM1b and AlphaMissense predictions. These included 15 patients with truncating variants in HDR genes (BARD1, BRCA1, BRCA2, BRIP1, FANCM, RAD51D and SLX4). MMR‐related gene variants were less prevalent and mainly of the missense type. While MMR‐related gene variants tended to associate with adenocarcinomas, HDR gene variants were commonly observed in squamous cancers. While one patient with HPV‐negative cancer carried a pathogenic MMR gene variant (in MSH6), the HDR germline variants were found in patients with HPV‐positive cancers and tended to associate with HPV18. Taken together, our study supports a potentially risk‐modifying role of MMR and HDR germline variants in cervical cancer but no association with HPV‐negative status. These variants may be exploitable in future therapeutic managements.

Endometrial cancer has been associated with pathogenic variants in mismatch repair (MMR) genes, especially in the context of the hereditary Lynch Syndrome. More recently, pathogenic variants in genes of homology‐directed repair (HDR) have also been suggested to contribute to a subset of endometrial cancers. In the present hospital‐based study, we investigated the relative distribution of pathogenic MMR or HDR gene variants in a series of 342 endometrial cancer patients from the Oncology Clinic in Almaty, Kazakhstan. In comparison, we also sequenced 178 breast cancer patients from the same population with the same gene panel. Identified variants were classified according to ClinVar, ESM1b, and AlphaMissense prediction tools. We found 10 endometrial cancer patients (2.9%) carrying pathogenic or likely pathogenic variants in MMR genes (7 MSH6, 1 MSH2, 2 MUTYH), while 14 endometrial cancer patients (4.1%) carried pathogenic variants in HDR genes (4 BRCA2, 3 BRCA1, 3 FANCM, 2 SLX4, 1 BARD1, 1 BRIP1). In the breast cancer series, we found 8 carriers (4.5%) of pathogenic or likely pathogenic variants in MMR genes (2 MSH2, 2 MSH6, 4 MUTYH) while 12 patients (6.7%) harbored pathogenic or likely pathogenic HDR gene variants (5 BRCA1, 3 BRCA2, 1 BRIP1, 1 ERRC4, 1 FANCM, 1 SLX4). One patient who developed breast cancer first and endometrial cancer later carried a novel frameshift variant in MSH6. Our results indicate that MMR and HDR gene variants with predicted pathogenicity occur at substantial frequencies in both breast and endometrial cancer patients from the Kazakh population.