bims-lifras 2023-09-03 papers

Front Oncol. 2023 ;13 1190305

The clinical relevance of broad mutational screening of myeloproliferative neoplasms at diagnosis.

Helna Pettersson, Jenni Adamsson, Peter Johansson, Staffan Nilsson, Lars Palmqvist, Björn Andréasson, Julia Asp.

Introduction: Myeloproliferative neoplasm (MPN) is a heterogenous group of hematological malignancies including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). JAK2V617F is the most frequent driver mutation in all three entities, but in PMF and ET mutations in CALR and MPL are also frequent. Mutations seen in additional genes are also often the same regardless of subtype of MPN. The aim of this study was to analyze a population based MPN cohort for genetic variants with prognostic value that can guide clinical decisions.
Methods: MPN patients from Western Sweden diagnosed between 2008-2013 (n=248) were screened for mutations in 54 genes associated with myeloid malignancy.
Results: Mutations in the genes SRSF2 and U2AF1 correlated significantly with impaired overall survival but did not correlate to increased risk for vascular events, neither before nor after diagnosis. Rather, mutations in these genes showed an association with disease transformation. Several recurrent gene variants with allele frequency close to 50% were confirmed to be germline. However, none of these variants was found to have an earlier onset of MPN.
Discussion: In conclusion, we identified gene mutations to be independent markers of impaired survival in MPN. This indicates the need for more individualized assessment and treatment of MPN patients and a wider gene mutation screening already at diagnosis. This could ensure the identification of patients with high-risk mutations early on. In addition, several genetic variants were also identified as germline in this study but gave no obvious clinical relevance. To avoid conclusions from non-informative genetic variants, a simultaneous analysis of normal cell DNA from patients at diagnosis should be considered.

Keywords: CALR; JAK2; MPL; MPN; germline; mutation; prognosis

DOI: https://doi.org/10.3389/fonc.2023.1190305

J Cancer Res Clin Oncol. 2023 Aug 28.

Germline CDH1 variants in hereditary diffuse gastric cancer syndrome with focus on younger women.

Giovanni Corso, Giovanni Comelli, Paolo Veronesi, Beatrice Bianchi, Salvatore Petitto, Andrea Polizzi, Antonia Girardi, Antonio Cioffi, Carlo La Vecchia, Vincenzo Bagnardi, Francesca Magnoni.

PURPOSE: The objective of this study was to determine the male and female frequency of diffuse gastric cancer (DGC), the age at diagnosis, and the country of origin in a selected population with germline CDH1 variants from families with the hereditary diffuse gastric cancer (HDGC) syndrome.
METHODS: Relevant literature dating from 1998 to 2021 was systematically searched for data on CDH1 gene. The Wilcoxon rank sum test and the Chi-square test were used to estimate if the difference observed between patients with gastric cancer (GC) and unaffected individuals was significant.
RESULTS: We identified 80 families fulfilling the established clinical criteria for HDGC CDH1 genetic screening. There were more women than men with DGC and germline CDH1 variant (65.5%). Stratifying the age at diagnosis, we identified an association between DGC, positive CDH1 screening and young women (≤ 40 years) (p = 0.015). The mean age at diagnosis was 39.6 ys for women and 42.5 ys for men. There was an association between CDH1 carrier status and DGC (p = 0.021).
CONCLUSIONS: Young women carrying germline CDH1 variants with DGC are comparatively frequent in the HDGC syndrome, and potentially at higher risk to develop DGC particularly in low-incidence areas for GC.

Keywords: CDH1 gene; Germline variants; Hereditary diffuse gastric cancer; Women cancer risk

DOI: https://doi.org/10.1007/s00432-023-05318-5

Cancer Discov. 2023 Sep 01. OF1

Germline BRCA2 Mutations Are Prevalent in Pancreatic Acinar Cell Carcinoma.

Pancreatic acinar cell carcinoma (PACC) has a high prevalence of BRCA2 germline pathogenic variants.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-138

Sci Rep. 2023 Aug 31. 13(1): 14259

Challenging interpretation of germline TP53 variants based on the experience of a national comprehensive cancer centre.

Henriett Butz, Anikó Bozsik, Vince Grolmusz, Erika Szőcs, János Papp, Attila Patócs.

TP53 variant interpretation is still challenging, especially in patients with attenuated Li-Fraumeni syndrome (LFS). We investigated the prevalence of pathogenic/likely pathogenic (P/LP) variants and LFS disease in the Hungarian population of cancer patients. By testing 893 patients with multiplex or familial cancer, we identified and functionally characterized novel splice variants of TP53 helping accurate variant classification. The differences among various semi-automated interpretation platforms without manual curation highlight the importance of focused interpretation as the automatic classification systems do not apply the TP53-specific criteria. The predicted frequency of the TP53 P/LP variants in Hungary is 0.3 per million which most likely underestimates the real prevalence. The higher detection rate of disease-causing variants in patients with attenuated LFS phenotype compared to the control population (OR 12.5; p < 0.0001) may raise the potential benefit of the TP53 genetic testing as part of the hereditary cancer panels of patients with multiple or familial cancer even when they do not meet Chompret criteria. Tumours developed at an earlier age in phenotypic LFS patients compared to the attenuated LFS patients which complicates genetic counselling as currently there are no different recommendations in surveillance protocols for LFS, phenotypic LFS, and attenuated LFS patients.

DOI: https://doi.org/10.1038/s41598-023-41481-y

medRxiv. 2023 Aug 15. pii: 2023.08.11.23293956. [Epub ahead of print]

LFSPROShiny: an interactive R/Shiny app for prediction and visualization of cancer risks in families with deleterious germline TP53 mutations.

Nam H Nguyen, Elissa B Dodd-Eaton, Gang Peng, Jessica L Corredor, Wenwei Jiao, Jacynda Woodman-Ross, Banu K Arun, Wenyi Wang.

Purpose: LFSPRO is an R library that implements risk prediction models for Li-Fraumeni syndrome (LFS), a genetic disorder characterized by deleterious germline mutations in the TP53 gene. To facilitate the use of these models in clinics, we developed LFSPROShiny, an interactive R/Shiny interface of LFSPRO that allows genetic counselors (GCs) to perform risk predictions without any programming components, and further visualize the risk profiles of their patients to aid the decision-making process.
Methods: LFSPROShiny implements two models that have been validated on multiple LFS patient cohorts: a competing-risk model that predicts cancer-specific risks for the first primary, and a recurrent-event model that predicts the risk of a second primary tumor. Starting with a visualization template, we keep regular contact with GCs, who ran LFSPROShiny in their counseling sessions, to collect feedback and discuss potential improvement. Upon receiving the family history as input, LFSPROShiny renders the family into a pedigree, and displays the risk estimates of the family members in a tabular format. The software offers interactive overlaid side-by-side bar charts for visualization of the patients' cancer risks relative to the general population.
Results: We walk through a detailed example to illustrate how GCs can run LFSPROShiny in clinics, from data preparation to downstream analyses and interpretation of results with an emphasis on the utilities that LFSPROShiny provides to aid decision making.
Conclusion: Since Dec 2021, we have applied LFSPROShiny to over 100 families from counseling sessions at MD Anderson Cancer Center. Our study suggests that software tools with easy-to-use interfaces are crucial for the dissemination of risk prediction models in clinical settings, hence serving as a guideline for future development of similar models.

DOI: https://doi.org/10.1101/2023.08.11.23293956