bims-ovdlit 2024-05-05 papers

Issue of 2024–05–05
five papers selected by
Lara Paracchini, Humanitas Research

Nat Commun. 2024 May 02. 15(1): 3700

Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions.

Jiaqi Liu, Lijun Dai, Qiang Wang, Chenghao Li, Zhichao Liu, Tongyang Gong, Hengyi Xu, Ziqi Jia, Wanyuan Sun, Xinyu Wang, Minyi Lu, Tongxuan Shang, Ning Zhao, Jiahui Cai, Zhigang Li, Hongyan Chen, Jianzhong Su, Zhihua Liu.

Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.

DOI: https://doi.org/10.1038/s41467-024-47886-1

Lancet Oncol. 2024 May;pii: S1470-2045(24)00015-9. [Epub ahead of print]25(5): e183-e192

Considerations for using potential surrogate endpoints in cancer screening trials.

Alexis B Webb, Christine D Berg, Philip E Castle, David Crosby, Ruth Etzioni, Larry G Kessler, Usha Menon, Mahesh Parmar, Robert J C Steele, Peter D Sasieni.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

DOI: https://doi.org/10.1016/S1470-2045(24)00015-9

Cold Spring Harb Perspect Med. 2024 May 01. pii: a041584. [Epub ahead of print]

New Paradigms in the Clinical Management of Li-Fraumeni Syndrome.

Camilla Giovino, Vallijah Subasri, Frank Telfer, David Malkin.

Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.

DOI: https://doi.org/10.1101/cshperspect.a041584

Hered Cancer Clin Pract. 2024 May 02. 22(1): 5

Information needs of Lynch syndrome and BRCA 1/2 mutation carriers considering risk-reducing gynecological surgery: a qualitative study of the decision-making process.

Lucy Zhao, Lorrie Lynch, Lua Eiriksson.

BACKGROUND: Risk-reducing gynecological surgery (RRGS) is a prophylactic procedure that may be offered to BRCA1, BRCA2, and Lynch syndrome (LS) mutation carriers to reduce the risk of developing gynecological cancer. This study was conducted to better understand patients' information needs and evaluate how patients weigh different sources of information in their decision-making process surrounding RRGS.
METHODS: This study used a qualitative approach to understanding women's perspectives towards RRGS. Semi-structured interviews were conducted virtually with 8 women. Women offered RRGS between 35 and 70 years of age who are English-speaking and have an identifiable BRCA or LS mutation were included. Data from interviews was coded with constant comparative analysis to develop themes.
RESULTS: Of the eight women, six had selected to undergo either prophylactic hysterectomy or oophorectomy: 5 decided yes to RRGS; 1 decided no; 2 were undecided. Thematic analysis found that the key factors affecting women's decisions around prophylactic surgery were cancer risk, surgical menopause, and psychological readiness. To make an informed decision, women relied most heavily on information provided by healthcare professionals (e.g. doctors, genetic counselors) and family members with prior cancer experience. However, some women reported that they did not feel adequately informed enough to make a decision and identified COVID-19 as a significant barrier affecting access to information.
CONCLUSION: This qualitative study revealed the key sources of information influencing attitudes regarding RRGS and how women consulted different sources of information to reach a decision. Results underscore the need for greater attention to women's information needs in the context of psychological readiness, particularly amidst the pandemic. Research involving a larger sample size may help to better inform how support can be provided to individuals with BRCA and LS mutations considering RRGS.

Keywords: BRCA; Decision-making; Lynch syndrome; Prophylactic surgery

DOI: https://doi.org/10.1186/s13053-024-00278-4

Int J Gynecol Cancer. 2024 Apr 27. pii: ijgc-2024-005295. [Epub ahead of print]

Copy number variations in endometrial cancer: from biological significance to clinical utility.

Erica Dugo, Francesco Piva, Matteo Giulietti, Luca Giannella, Andrea Ciavattini.

The molecular basis of endometrial cancer, which is the most common malignancy of the female reproductive organs, relies not only on onset of mutations but also on copy number variations, the latter consisting of gene gains or losses. In this review, we introduce copy number variations and discuss their involvement in endometrial cancer to determine the perspectives of clinical applicability. We performed a literature analysis on PubMed of publications over the past 30 years and annotated clinical information, including histological and molecular subtypes, adopted molecular techniques for identification of copy number variations, their locations, and the genes involved. We highlight correlations between the presence of some specific copy number variations and myometrial invasion, lymph node metastasis, advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high grade, drug response, and cancer progression. In particular, type I endometrial cancer cells have few copy number variations and are mainly located in 8q and 1q, while type II, high grade, and advanced FIGO stage endometrial cancer cells are aneuploid and have a greater number of copy number variations. As expected, the higher the number of copy number variations the worse the prognosis, especially if they amplify CCNE1, ERBB2, KRAS, MYC, and PIK3CA oncogenes. Great variability in copy number and location among patients with the same endometrial cancer histological or molecular subtype emerged, making them interesting candidates to be explored for the improvement of patient stratification. Copy number variations have a role in endometrial cancer progression, and therefore their detection may be useful for more accurate prediction of prognosis. Unfortunately, only a few studies have been carried out on the role of copy number variations according to the molecular classification of endometrial cancer, and even fewer have explored the correlation with drugs. For these reasons, further studies, also using single cell RNA sequencing, are needed before reaching a clinical application.

Keywords: Carcinoma; Endometrial Neoplasms; Homologous recombination

DOI: https://doi.org/10.1136/ijgc-2024-005295