bims-lifras 2023-01-01 papers

Issue of 2023‒01‒01
six papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

United European Gastroenterol J. 2022 Dec 26.

Real-time use of artificial intelligence (CADEYE) in colorectal cancer surveillance of patients with Lynch syndrome-A randomized controlled pilot trial (CADLY).

Robert Hüneburg, Karolin Bucksch, Friederike Schmeißer, Dominik Heling, Tim Marwitz, Stefan Aretz, Dominik J Kaczmarek, Glen Kristiansen, Oliver Hommerding, Christian P Strassburg, Christoph Engel, Jacob Nattermann.

BACKGROUND: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance.OBJECTIVE: Our aim was to investigate the diagnostic performance of artificial intelligence (AI)-assisted colonoscopy in comparison to High-Definition white-light endoscopy (HD-WLE) for the first time.
METHODS: Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10-36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI-assisted vs. HD white-light endoscopy) in this exploratory pilot trial.
RESULTS: Between Dec-2021 and Dec-2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD-WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3-41.1] vs. 36.0% [22.9-50.8]; p = 0.379). The use of AI-assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0-IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD-WLE and AI (14 vs. 15 min; p = 0.170).
CONCLUSION: We here present first data suggesting that real-time AI-assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Keywords: endoscopy

DOI: https://doi.org/10.1002/ueg2.12354

Reprod Biomed Online. 2022 Dec 05. pii: S1472-6483(22)00832-X. [Epub ahead of print]

The neglected role of preimplantation genetic testing for Lynch syndrome.

Chiara Dallagiovanna, Francesca Filippi, Alessandra Riccaboni, Paola Vigano', Fabio Martinelli, Edgardo Somigliana, Maria Teresa Ricci, Marco Vitellaro.

Preimplantation genetic testing for monogenic/single-gene disorders (PGT-M) is a procedure employed in the field of assisted reproductive technology to avoid the transmission of genetic diseases to the offspring. Hereditary cancer syndromes represent a diffuse and accepted indication for PGT-M, but take-up differs among the different disorders. Its use is markedly lower for the genes causing Lynch syndrome compared with the breast cancer type 1 or 2 susceptibility genes (BRCA1/2), despite the similar prevalence and severity of the two conditions. Reasons to explain this difference have not been explored. First, Lynch syndrome may be more frequently undiagnosed compared with hereditary breast and ovarian cancer syndrome. In addition, the different take-up may be due to different patient perceptions of the conditions and of the management options. Finally, this distinct attitude may depend on the awareness and sensibility of the professionals caring for affected patients. The authors' considerations are, however, speculative, and specific studies aimed at disentangling the causes of the different receptions of PGT-M are warranted to understand how to tackle this gap. In the meantime, we believe that empowerment regarding PGT-M of all individuals with hereditary cancer syndromes, including Lynch syndrome, is ethically due, and plead for a more active involvement of caregivers.

Keywords: BRCA; Hereditary cancer syndromes; Lynch syndrome; Monogenic disorders; Preimplantation genetic testing; Preimplantation genetic testing for monogenic/single-gene defects (PGT-M)

DOI: https://doi.org/10.1016/j.rbmo.2022.12.001

BMC Cancer. 2022 Dec 30. 22(1): 1365

Mainstream germline genetic testing in men with metastatic prostate cancer: design and protocol for a multicenter observational study.

Michiel Vlaming, Eveline M A Bleiker, Inge M van Oort, Lambertus A L M Kiemeney, Margreet G E M Ausems.

BACKGROUND: In international guidelines, germline genetic testing is recommended for patients with metastatic prostate cancer. Before undergoing germline genetic testing, these patients should receive pre-test counseling. In the standard genetic care pathway, pre-test counseling is provided by a healthcare professional of a genetics department. Because the number of patients with metastatic prostate cancer is large, the capacity in the genetics departments might be insufficient. Therefore, we aim to implement so-called mainstream genetic testing in the Netherlands for patients with metastatic prostate cancer. In a mainstream genetic testing pathway, non-genetic healthcare professionals discuss and order germline genetic testing. In our DISCOVER study, we will assess the experiences among patients and non-genetic healthcare professionals with this new pathway.METHODS: A multicenter prospective observational cohort study will be conducted in 15 hospitals, in different regions of the Netherlands. We developed an online training module on genetics in prostate cancer and the counseling of patients. After completion of this module, non-genetic healthcare professionals will provide pre-test counseling and order germline genetic testing in metastatic prostate cancer patients. Both non-genetic healthcare professionals and patients receive three questionnaires. We will determine the experience with mainstream genetic testing, based on satisfaction and acceptability. Patients with a pathogenic germline variant will also be interviewed. We will determine the efficacy of the mainstreaming pathway, based on time investment for non-genetic healthcare professionals and the prevalence of pathogenic germline variants.
DISCUSSION: This study is intended to be one of the largest studies on mainstream genetic testing in prostate cancer. The results of this study can improve the mainstream genetic testing pathway in patients with prostate cancer.
TRIAL REGISTRATION: The study is registered in the WHO's International Clinical Trials Registry Platform (ICTRP) under number NL9617.

Keywords: Genetic counseling; Germline genetic testing; Mainstream genetic testing; Prostate cancer

DOI: https://doi.org/10.1186/s12885-022-10429-2

Mol Biol Rep. 2022 Dec 28.

Germline variants associated with breast cancer in Khakass women of North Asia.

Polina Gervas, Aleksey Molokov, Aleksei Zarubin, Evgenii Topolnitskiy, Nikolay Shefer, Lubov Pisareva, Evgeny Choynzonov, Nadezda Cherdyntseva.

INTRODUCTION: Variants in the BRCA1/2 genes are responsible for familial breast cancer. Numerous studies showed a different spectrum of BRCA variants among breast cancer patients of different Ethnicity origin. In the available literature, no previous research has focused on breast cancer-associated variants among the Khakass people (the indigenous people of the Russian Federation).METHODS: Twenty-six Khakass breast cancer patients were enrolled in the study. Genomic DNA was isolated from blood samples and used to prepare libraries using a Hereditary Cancer Solution kit. Next-generation sequencing (NGS) was performed using the MiSeq System (Illumina, USA).
RESULTS: In our study, 12% of patients (3/26) carried a single pathogenic variant; 54% of patients (14/26) carried variants of uncertain significance (VUS) or conflicting variants; and 35% of patients (9/26) did not carry any clinically significant variants. Germline pathogenic variant in the ATM gene (rs780619951, NC_000011.10:g.108259022C > T) was identified in two unrelated patients with a family history of cancer (7.6%, 2/26). The pathogenic truncating variant in the ATM gene (p. R805* or c.2413C > T) leads to the nonfunctional version of the protein. This variant has been earlier reported in individuals with a family history of breast cancer.
CONCLUSIONS: Our pilot study describes the germline variant in the ATM gene associated with breast cancer in Khakass women of North Asia.

Keywords: BRCA; Breast cancer; Germline variant; Indigenous peoples; Khakass; Peoples under threat

DOI: https://doi.org/10.1007/s11033-022-08215-1

J Pers Med. 2022 Nov 04. pii: 1842. [Epub ahead of print]12(11):

Laboratory Cross-Comparison and Ring Test Trial for Tumor BRCA Testing in a Multicenter Epithelial Ovarian Cancer Series: The BORNEO GEICO 60-0 Study.

Germline and tumor BRCA testing constitutes a valuable tool for clinical decision-making in the management of epithelial ovarian cancer (EOC) patients. Tissue testing is able to identify both germline (g) and somatic (s) BRCA variants, but tissue preservation methods and the widespread implementation of NGS represent pre-analytical and analytical challenges that need to be managed. This study was carried out on a multicenter prospective GEICO cohort of EOC patients with known gBRCA status in order to determine the inter-laboratory reproducibility of tissue sBRCA testing. The study consisted of two independent experimental approaches, a bilateral comparison between two reference laboratories (RLs) testing 82 formalin-paraffin-embedded (FFPE) EOC samples each, and a Ring Test Trial (RTT) with five participating clinical laboratories (CLs) evaluating the performance of tissue BRCA testing in a total of nine samples. Importantly, labs employed their own locally adopted next-generation sequencing (NGS) analytical approach. BRCA mutation frequency in the RL sub-study cohort was 23.17%: 12 (63.1%) germline and 6 (31.6%) somatic. Concordance between the two RLs with respect to BRCA status was 84.2% (gBRCA 100%). The RTT study distributed a total of nine samples (three commercial synthetic human FFPE references, three FFPE, and three OC DNA) among five CLs. The median concordance detection rate among them was 64.7% (range: 35.3-70.6%). Analytical discrepancies were mainly due to the minimum variant allele frequency thresholds, bioinformatic pipeline filters, and downstream variant interpretation, some of them with consequences of clinical relevance. Our study demonstrates a wide range of concordance in the identification and interpretation of BRCA sequencing data, highlighting the relevance of establishing standard criteria for detecting, interpreting, and reporting BRCA variants.

Keywords: BRCA mutations; BRCA testing; NGS; Ring Test Trial; ovarian cancer

DOI: https://doi.org/10.3390/jpm12111842