bims-tumhet 2023-10-15 papers

Issue of 2023–10–15
five papers selected by
Sergio Marchini, Humanitas Research

Clin Cancer Res. 2023 Oct 09.

OvaPrint™ - a cell-free DNA methylation liquid biopsy for the risk assessment of high-grade serous ovarian cancer.

David N Buckley, Juan Pablo Lewinger, Gerald Gooden, Monique Spillman, Monica Neuman, X Mona Guo, Ben Yi Tew, Heather Miller, Varun U Khetan, Lee P Shulman, Lynda Roman, Bodour Salhia.

Purpose High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathological assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study we developed a cfDNA methylation liquid biopsy for the risk assessment of early-stage HGSOC. Experimental Design We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMRs) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1677 DMRs and constructed a classifier (OvaPrint™) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade, and borderline samples to assess the generalizability of OvaPrint™. A total of 372 samples (tissue n=59, plasma n=313) were analyzed in this study. Results OvaPrint™ achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint™ was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential. Conclusions OvaPrint™ is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint™ for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.

DOI: https://doi.org/10.1158/1078-0432.CCR-23-1197

Ann Hum Genet. 2023 Oct 09.

Low-pass whole genome sequencing is a reliable and cost-effective approach for copy number variant analysis in the clinical setting.

Patricia C Mazzonetto, Darine Villela, Silvia Souza da Costa, Ana C V Krepischi, Fernanda Milanezi, Michele P Migliavacca, Paulo M Pierry, Adriano Bonaldi, Luiz Gustavo D Almeida, Camila Alves De Souza, José Eduardo Kroll, Marcelo G Paula, Rodrigo Guarischi-Sousa, Cristovam Scapulatempo-Neto, Carla Rosenberg.

INTRODUCTION: Next generation sequencing technology has greatly reduced the cost and time required for sequencing a genome. An approach that is rapidly being adopted as an alternative method for CNV analysis is the low-pass whole genome sequencing (LP-WGS). Here, we evaluated the performance of LP-WGS to detect copy number variants (CNVs) in clinical cytogenetics.
MATERIALS AND METHODS: DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison and used as positive controls; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, the vast majority being associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism.
RESULTS: All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA.
DISCUSSION: Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can easily be tested and implemented in a routine diagnostic setting.

Keywords: CNV; copy number variation; cytogenetics; low-pass whole genome sequencing; next-generation sequencing (NGS); postnatal diagnosis; prenatal diagnosis; structural variant

DOI: https://doi.org/10.1111/ahg.12532

Am J Clin Oncol. 2023 Oct 12.

Treatment of Recurrent Low-grade Serous Ovarian Cancer With MEK Inhibitors: A Systematic Review.

Anjali Kulkarni, Carly Cooke, Rouhi Fazelzad, Michael Fung-Kee-Fung, Taymaa May, Tiffany Zigras.

OBJECTIVE: Low-grade serous ovarian cancer (LGSC) represents 5% of all epithelial ovarian cancers. They are characterized by indolent growth and KRAS and BRAF mutations, differing from high-grade serous ovarian cancer both clinically and molecularly. LGSC has low response rates to traditional systemic therapies, including chemotherapy and hormonal therapy. The objective of this systematic review was to appraise the literature describing the efficacy of MEK inhibitors in the treatment of LGSC.
METHODS: A comprehensive search was conducted of the following databases: Medline ALL, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Web of Sciences, ClinicalTrials.gov, International Clinical Trials Registry Platform (ICFRP), and International Standard Randomized Controlled Trials Number (ISRCTN) Registry. All studies investigating MEKi in the treatment of LGSC in the adjuvant or recurrent setting for patients 18 years of age or older were included. All titles/abstracts were then screened by 2 independent reviewers (A.K. and C.C.). The full-text articles were then screened. All disagreements were resolved by a third independent reviewer (T.Z.). Two independent reviewers (A.K. and C.C.) extracted data from the studies deemed eligible for final review.
RESULTS: A total of 2108 studies were identified in the initial search. Of these, a total of 4 studies met the eligibility criteria for systematic review. In these studies, 416 patients were treated with an MEKi alone. All patients included in the studies were being treated for LGSC in the recurrent setting. Varied results and efficacy of the MEKi were reported in each study.
CONCLUSIONS: The results highlighted in this systematic review demonstrate varied responses to MEKi for recurrent LGSC. Further research is needed in this field comparing the efficacy to current therapies, as well as to further evaluate the safety and toxicity profile with long-term use of MEKi.

DOI: https://doi.org/10.1097/COC.0000000000001049

Ann Oncol. 2023 Oct 08. pii: S0923-7534(23)04017-6. [Epub ahead of print]

WGS/WES-RNAseq compared to targeted NGS in oncology: is there something to unlock?

M Aldea, D Vasseur, A Italiano, S Nikolaev.

Cancer panel designs focus on identifying specific genes or mutations relevant to cancer diagnosis, prognosis, or treatment indications. There is an extensive array of gene panel kits in use today within cancer research and diagnostics, each with variations in the genes and target regions they cover. The relatively small size of these target regions allows for deep coverage, ranging from several hundred to several thousand-fold. High coverage, achievable through targeted NGS, enables more flexible requirements for the purity of tumor samples. Various centers might employ different kits from various manufacturers, and the use of cancer-specific panels or custom panels is also common. However, there is currently no universally recognized "gold" standard for targeted sequencing methods within the community.

DOI: https://doi.org/10.1016/j.annonc.2023.09.3118

Lancet. 2023 Oct 07. pii: S0140-6736(23)01700-2. [Epub ahead of print]402(10409): 1251-1260

Blood-based tests for multicancer early detection (PATHFINDER): a prospective cohort study.

Deb Schrag, Tomasz M Beer, Charles H McDonnell, Lincoln Nadauld, Christina A Dilaveri, Robert Reid, Catherine R Marinac, Karen C Chung, Margarita Lopatin, Eric T Fung, Eric A Klein.

BACKGROUND: Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening.
METHODS: In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants' doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed.
FINDINGS: Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) in true-positive and 162 days (44-248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result).
INTERPRETATION: This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility.
FUNDING: GRAIL.

DOI: https://doi.org/10.1016/S0140-6736(23)01700-2