bims-lifras 2023-03-19 papers

Issue of 2023‒03‒19
five papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Transl Androl Urol. 2023 Feb 28. 12(2): 308-319

Prevalence of germline mutations in cancer susceptibility genes in Chinese patients with renal cell carcinoma.

Huayi Feng, Shouqing Cao, Qing Ouyang, Huaikang Li, Xiubin Li, Ke Chen, Xiangyi Zhang, Yan Huang, Xu Zhang, Xin Ma.

Background: Germline pathogenic variants are estimated to affect 3-5% of patients with renal cell carcinoma (RCC). The identification of patients with hereditary RCC is important for cancer screening and treatment guidance.Methods: Whole-exome sequencing (WES) (n=69) or gene panel sequencing containing 139 genes (n=54) related to germline cancer predisposition was used to analyze germline mutations in 123 patients with RCC admitted to Department of Urology, The Third Medical Center of Chinese PLA General Hospital. Chi-square test (χ2) was used to analyze relationship between clinicopathologic parameters and germline mutations.
Results: A total of 13 (10.57%) patients carried pathogenic or likely pathogenic germline mutations in 10 cancer predisposition genes, including VHL, FH, FLCN, SDHB, MUTYH, RAD51C, NBN, RAD50, FANCI, and FANCM. A total of 6 of these 10 cancer predisposition genes were associated with maintenance of genomic stability and DNA repair. Patients harboring pathogenic germline mutations tended to have an earlier RCC onset. The prevalence of deleterious mutations was higher in patients with bilateral or multifocal RCC compared to patients without bilateral or multifocal RCC. Patients with non-clear cell RCC (nccRCC) were significantly more likely to have RCC-associated gene mutations.
Conclusions: To our knowledge, this is the first report of pathogenic germline mutations in the FANCI and FANCM genes and heterozygous germline missense mutation in exon 5 of the FH gene c.563A>T:p.N188I in RCC. Young RCC patients, patients with bilateral or multifocal RCC, or patients with nccRCC are more likely to have pathogenic/potentially pathogenic germline mutations.

Keywords: FANCI; FANCM; Renal cell carcinoma (RCC); pathogenic germline mutation

DOI: https://doi.org/10.21037/tau-23-32

World J Clin Oncol. 2023 Feb 24. 14(2): 40-68

Hereditary cancer syndromes.

Evgeny N Imyanitov, Ekaterina S Kuligina, Anna P Sokolenko, Evgeny N Suspitsin, Grigoriy A Yanus, Aglaya G Iyevleva, Alexandr O Ivantsov, Svetlana N Aleksakhina.

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

Keywords: Cancer predisposition; Cancer treatment; Germline pathogenic variants; Hereditary cancer syndromes; Next-generation sequencing

DOI: https://doi.org/10.5306/wjco.v14.i2.40

J Gastrointest Oncol. 2023 Feb 28. 14(1): 458-462

A rare case of sporadic mismatch repair deficient pancreatic ductal adenocarcinoma that responded to ipilimumab and nivolumab combination treatment: case report.

Margaret Y Han, Erkut Borazanci.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a poor prognosis. Despite high efficacy in multiple cancers, immunotherapy has had very little success in treating PDAC due to unfavorable characteristics such as low tumor mutational burden (TMB), low microsatellite instability (MSI), and non-immunogenic tumor microenvironment. Recently, however, there have been reports of rare PDAC cases with high TMB and DNA mismatch repair deficiency (dMMR) that have demonstrated positive response to immunotherapy. All these cases have also presented with Lynch Syndrome, or germline mutations in MMR genes.Case Description: Here, we report a 57-year-old male with stage IV PDAC whose tumor profile revealed high TMB, high MSI, and dMMR, but no germline mutations in genes associated with hereditary cancers including those associated with Lynch Syndrome. After a series of ineffective treatments, the patient showed positive response to combined ipilimumab and nivolumab immunotherapy. To our knowledge, this is the first report of an advanced PDAC case with sporadic dMMR, high TMB, and no Lynch Syndrome having a good response to immunotherapy.
Conclusions: This case further supports TMB and high MSI/dMMR being possible biomarkers for immunotherapy of PDAC as well as highlights the importance of both germline and somatic testing of patients with PDAC.

Keywords: DNA mismatch repair deficiency (dMMR); Pancreas cancer; case report; microsatellite instability (MSI); tumor mutational burden (TMB)

DOI: https://doi.org/10.21037/jgo-22-587

Geburtshilfe Frauenheilkd. 2023 Mar;83(3): 310-320

Breast Cancer and Genetic BRCA1/2 Testing in Routine Clinical Practice: Why, When and For Whom?

Michael P Lux, Peter A Fasching.

Pathogenic variants of the tumor suppressor genes BRCA1 and BRCA2 are responsible for the majority of hereditary breast cancers; they are also becoming increasingly important to identify whether patients are suitable for targeted therapy with poly ADP-ribose polymerase inhibitors (PARPi). Patients with HER2-negative breast cancer and BRCA1/2 germline mutations can benefit significantly from PARPi therapy, and the findings of the OlympiAD and the EMBRACA phase III clinical trials for regulatory approval were recently expanded by the addition of the most recent OlympiA data on the treatment of patients with early disease and a high risk of recurrence. This means that BRCA1/2 germline testing to plan patient therapy is now also relevant for patients with early breast cancer and therefore has a direct impact on survival. Healthcare research data shows, however, that BRCA1/2 testing rates are strongly affected by familial history, cancer subtype (particularly triple-negative subtypes), and patient age at onset of disease (especially with regards to younger patients with breast cancer), despite the existing clear recommendations for BRCA1/2 germline testing to identify whether PARPi therapy is indicated. This article presents the clinical implications of identifying BRCA1/2 germline mutations in patients with breast cancer, the current recommendations on molecular diagnostics, and their implementation in practice. The treatment of patients with breast cancer has progressed greatly in recent years and now offers individual treatment concepts which can only be implemented after the targeted identification of individual parameters. As detection of a BRCA1/2 germline mutation is essential for planning individual therapy, where indicated, testing should be arranged as early as possible. It is the only way of identifying patients suitable for PARPi therapy and ensuring they receive the best possible treatment. This also applies to patients with a negative familial history, HR-positive disease, or who are older at onset of disease.

Keywords: BRCA1/2 diagnostics ; PARP inhibitors; breast cancer; olaparib; talazoparib; therapy planning

DOI: https://doi.org/10.1055/a-1929-2629

Front Oncol. 2023 ;13 1120829

Hereditary predisposition to malignant myeloid hemopathies: Caution in use of saliva and guideline based on our experience.

Alexandre Perani, Sylvie Bourthoumieu, David Rizzo, Jasmine Chauzeix, Benjamin Dauriat, Pascal Turlure, Stéphane Girault, Léa Veyrune, Maxime Roubinet, Jean Feuillard, Catherine Yardin, Nathalie Gachard.

Background: Predisposition to myeloid malignancies is a field at the border of hematology and genetics. Knowledge in this domain has so rapidly increased that WHO defined in 2016 the new "Myeloid Neoplasms with Germline Predisposition" category of tumors. High throughput sequencing is frequently performed in tumors either for diagnosis or prognosis, but this approach may identify potential germline variants that have to be confirmed on non-infiltrated tissues.Method: In this study, we systematically compared NGS data from genetic analysis performed on all sample types (bone marrow, blood, saliva, skin fibroblasts and hair follicles) in 29 patients, and 44 of their relatives (blood and saliva).
Results: We showed that saliva was usable for relatives, but only for 24% (7/29) of our patients. Most of patients' saliva were either "non-contributive" (14/29 i.e., 48% because clearly or probably infiltrated) or "inconclusive" (8/29 corresponding to 28%).
Conclusion: The recommendations for the use of saliva we present here focus on the importance of collecting saliva during remission when possible. Moreover, we propose hair follicles as an alternative to skin biopsy, that remains the gold standard especially in case of allogenic hematopoietic stem cells transplantation. Technological progresses have revolutionized the diagnosis of predisposition to solid or hematological malignancies, and it is very likely that new techniques will help to manage the familial predisposition in the future.

Keywords: DDX41; genetic counseling; myeloid hemopathies; predisposition; saliva

DOI: https://doi.org/10.3389/fonc.2023.1120829