bims-ovdlit 2024-11-10 papers

Issue of 2024–11–10
three papers selected by
Lara Paracchini, Humanitas Research

Hum Genet. 2024 Nov 04.

Germline copy number variants and endometrial cancer risk.

ABCTB Investigators

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10-63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

DOI: https://doi.org/10.1007/s00439-024-02707-9

Int J Gynecol Cancer. 2024 Nov 04. pii: ijgc-2024-005964. [Epub ahead of print]

Oncologic outcomes of incidental serous tubal intraepithelial carcinoma and associated high-grade serous carcinoma in high-risk patients undergoing risk-reducing surgery.

Eliane Aoun, Barrett Lawson, Chika Awujo, Denise Nebgen, Beth R Soletsky, Gary B Chisholm, Karen H Lu, Roni Nitecki Wilke.

OBJECTIVE: We sought to describe the oncologic outcomes of isolated serous tubal intraepithelial carcinomas compared to an intraepithelial carcinoma found concurrently with microscopic high-grade serous carcinoma among patients with hereditary predisposition to ovarian cancer who underwent risk-reducing surgery.
METHODS: We conducted a retrospective analysis of 32 high-risk patients with BRCA1, BRCA2, RAD51C/D, BRIP1, or PALB2 pathogenic variants who were diagnosed with either isolated serous tubal intraepithelial carcinoma or concurrent serous tubal intraepithelial carcinoma and microscopic high-grade serous carcinoma following risk-reducing surgery between January 2006 and December 2023. Our population included patients who underwent surgery at our institution as well as those who had surgery elsewhere, but sought second opinions, follow-up care, or treatment at our institution. Data were gathered from medical and pathologic records, and pathologic specimens were re-reviewed by a gynecologic pathologist. Standard statistical methods were used to describe oncologic outcomes per group.
RESULTS: Among 32 patients in the cohort, we found that 68.7% had a pathologic diagnosis of an incidental serous tubal intraepithelial carcinoma, while 31.3% had a pathologic diagnosis of microscopic high-grade serous carcinoma with associated serous tubal intraepithelial carcinoma. Notably, two patients (9%) with isolated serous tubal intraepithelial carcinoma developed primary peritoneal carcinoma within a median of 29 months after surgery. One-third of patients with microscopic cancer experienced recurrence despite receiving standard staging surgery and chemotherapy for early-stage disease. Most of the patients in the cohort were older at the time of risk-reducing surgery than recommended for their pathologic variant.
CONCLUSIONS: The study supports the critical need for timely risk-reducing surgery in high-risk populations, as well as a comprehensive pathologic examination along with vigilant post-operative surveillance. Consensus guidelines for management of serous tubal intraepithelial carcinoma are necessary to identify a group of patients at higher risk of progression to primary peritoneal carcinoma and optimize patient care.

Keywords: BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; Gynecologic Surgical Procedures; Pathology

DOI: https://doi.org/10.1136/ijgc-2024-005964

Hum Genomics. 2024 11 05. 18(1): 120

Best practices for germline variant and DNA methylation analysis of second- and third-generation sequencing data.

Omics Sciences - Bioinformatics and Epigenetics Working Groups of the Italian Society of Human Genetics (SIGU)

This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies.

Keywords: Bioinformatics; DNA methylation; Genetic diagnostics; Germline variants; Hereditary diseases; NGS

DOI: https://doi.org/10.1186/s40246-024-00684-8