bims-ovdlit 2022-05-22 papers

Issue of 2022–05–22
five papers selected by
Lara Paracchini, Humanitas Research

BMC Cancer. 2022 May 16. 22(1): 550

Homologous recombination deficiency in diverse cancer types and its correlation with platinum chemotherapy efficiency in ovarian cancer.

Hao Wen, Zheng Feng, Yutong Ma, Rui Liu, Qiuxiang Ou, Qinhao Guo, Yi Shen, Xue Wu, Yang Shao, Hua Bao, Xiaohua Wu.

BACKGROUND: Homologous recombination deficiency (HRD) is a molecular biomarker for administrating PARP inhibitor (PARPi) or platinum-based (Pt) chemotherapy. The most well-studied mechanism of causing HRD is pathogenic BRCA1/2 mutations, while HRD phenotype is also present in patients without BRCA1/2 alterations, suggesting other unknown factors.
METHODS: The targeted next-generation sequencing (GeneseeqPrime® HRD) was used to evaluate the HRD scores of 199 patients (Cohort I). In Cohort II, a total of 85 Pt-chemotherapy-treated high-grade serous ovarian cancer (HGSOC) patients were included for investigating the role of HRD score in predicting treatment efficacy. The concurrent genomic features analyzed along HRD score evaluation were studied in a third cohort with 416 solid tumor patients (Cohort III).
RESULTS: An HRD score ≥ 38 was predefined as HRD-positive by analyzing Cohort I (range: 0-107). Over 95% of the BRCA1/2-deficient cases of Cohort I were HRD-positive under this threshold. In Cohort II, Pt-sensitive patients have significantly higher HRD scores than Pt-resistant patients (median: 54 vs. 34, p = 0.031) and a significantly longer PFS was observed in HRD-positive patients (median: 548 vs. 343 days, p = 0.003). Furthermore, TP53, NCOR1, and PTK2 alterations were enriched in HRD-positive patients. In Cohort III, impaired homologous recombination repair pathway was more frequently observed in HRD-positive patients without BRCA1/2 pathogenic mutations. The alteration enrichment of TP53, NCOR1, and PTK2 observed in Cohort II was also validated by the ovarian subgroup in Cohort III.
CONCLUSIONS: Using an in-house HRD evaluation method, our findings show that overall HRR gene mutations account for a significant part of HRD in the absence of BRCA1/2 aberrations, and suggest that HRD positive status might be a predictive biomarker of Pt-chemotherapy.

Keywords: BRCA1/2; Homologous recombination deficiency; NGS; Platinum chemotherapy

DOI: https://doi.org/10.1186/s12885-022-09602-4

Med (N Y). 2021 Dec 10. pii: S2666-6340(21)00375-5. [Epub ahead of print]2(12): 1292-1313

Liquid biopsies for residual disease and recurrence.

Jonathan Chee Ming Wan, Tariq Imdadali Mughal, Pedram Razavi, Sarah-Jane Dawson, Esther Louise Moss, Ramaswamy Govindan, Iain Beehuat Tan, Yoon-Sim Yap, William Allen Robinson, Clive Dylan Morris, Benjamin Besse, Alberto Bardelli, Jeanne Tie, Scott Kopetz, Nitzan Rosenfeld.

Detection of minimal residual disease in patients with cancer, who are in complete remission with no cancer cells detectable, has the potential to improve recurrence-free survival through treatment selection. Studies analyzing circulating tumor DNA (ctDNA) in patients with solid tumors suggest the potential to accurately predict and detect relapse, enabling treatment strategies that may improve clinical outcomes. Over the past decade, assays for ctDNA detection in plasma samples have steadily increased in sensitivity and specificity. These are applied for the detection of residual disease after treatment and for earlier detection of recurrence. Novel clinical trials are now assessing how assays for "residual disease and recurrence" (RDR) may influence current treatment paradigms and potentially change the landscape of risk classification for cancer recurrence. In this review, we appraise the progress of RDR detection using ctDNA and consider the emerging role of liquid biopsy in the monitoring and management of solid tumors.

Keywords: MRD; RDR; clinical trials; ctDNA; residual disease and recurrence; solid tumors

DOI: https://doi.org/10.1016/j.medj.2021.11.001

Nat Commun. 2022 May 20. 13(1): 2830

Automated next-generation profiling of genomic alterations in human cancers.

The lack of validated, distributed comprehensive genomic profiling assays for patients with cancer inhibits access to precision oncology treatment. To address this, we describe elio tissue complete, which has been FDA-cleared for examination of 505 cancer-related genes. Independent analyses of clinically and biologically relevant sequence changes across 170 clinical tumor samples using MSK-IMPACT, FoundationOne, and PCR-based methods reveals a positive percent agreement of >97%. We observe high concordance with whole-exome sequencing for evaluation of tumor mutational burden for 307 solid tumors (Pearson r = 0.95) and comparison of the elio tissue complete microsatellite instability detection approach with an independent PCR assay for 223 samples displays a positive percent agreement of 99%. Finally, evaluation of amplifications and translocations against DNA- and RNA-based approaches exhibits >98% negative percent agreement and positive percent agreement of 86% and 82%, respectively. These methods provide an approach for pan-solid tumor comprehensive genomic profiling with high analytical performance.

DOI: https://doi.org/10.1038/s41467-022-30380-x

Nat Rev Genet. 2022 May 17.

Opportunities and challenges for the use of common controls in sequencing studies.

Genevieve L Wojcik, Jessica Murphy, Jacob L Edelson, Christopher R Gignoux, Alexander G Ioannidis, Alisa Manning, Manuel A Rivas, Steven Buyske, Audrey E Hendricks.

Genome-wide association studies using large-scale genome and exome sequencing data have become increasingly valuable in identifying associations between genetic variants and disease, transforming basic research and translational medicine. However, this progress has not been equally shared across all people and conditions, in part due to limited resources. Leveraging publicly available sequencing data as external common controls, rather than sequencing new controls for every study, can better allocate resources by augmenting control sample sizes or providing controls where none existed. However, common control studies must be carefully planned and executed as even small differences in sample ascertainment and processing can result in substantial bias. Here, we discuss challenges and opportunities for the robust use of common controls in high-throughput sequencing studies, including study design, quality control and statistical approaches. Thoughtful generation and use of large and valuable genetic sequencing data sets will enable investigation of a broader and more representative set of conditions, environments and genetic ancestries than otherwise possible.

DOI: https://doi.org/10.1038/s41576-022-00487-4