bims-lifras 2023-05-14 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023‒05‒14
seven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Suspected Germline TP53 Variants and Clonal Hematopoiesis of Indeterminate Potential: Lessons Learned From a Molecular Tumor Board.
DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation.
A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.
Germline multigene panel testing of patients with endometrial cancer.
Diverse genetic spectrum among patients who met the criteria of hereditary breast, ovarian and pancreatic cancer syndrome.
Melanoma in a patient with DNMT3A overgrowth syndrome.
Dppa3 Improves the Germline Competence of Pluripotent Stem Cells.

Oncologist. 2023 May 09. pii: oyad105. [Epub ahead of print]

Suspected Germline TP53 Variants and Clonal Hematopoiesis of Indeterminate Potential: Lessons Learned From a Molecular Tumor Board.

Camila B Xavier, Rudinei Link, Leonília Abreu, Fabiana Bettoni, Fabiane Marson, Pedro A F Galante, Cibele Masotti, Mariane T Amano, Vinicius de Molla, Anamaria A Camargo, Paula F Asprino, Jorge Sabbaga.

OBJECTIVE: Li-Fraumeni syndrome (LFS) is a pan-cancer predisposition syndrome caused by germline pathogenic variants in the gene TP53. The interpretation of TP53 variants in clinical scenarios outside the classic LFS criteria may be challenging. Here, we report a patient affected by 2 primary cancers at later ages, who harbored a likely pathogenic TP53 at low allele frequency detected in a blood sample.METHODS: The Molecular Tumor Board committee at our institution revisited the case of a patient who was enrolled in a research protocol for the investigation of genetic conditions associated with neuroendocrine tumors. Clinical, familial, and molecular data were reviewed. The patient received germline testing using a next generation sequencing multi-gene panel and was incidentally found to harbor a TP53 likely pathogenic variant, with 22% of variant allele fraction. Additional samples, including a second blood sample, oral swab, and saliva, were collected for DNA analysis. A new TP53 sequencing round was performed with the attempt to distinguish between a true constitutional germline variant and a somatically acquired variant due to aberrant clonal expansion of bone marrow precursors.
RESULTS: Patient's personal and familial history of cancer did not meet classic nor Chompret LFS criteria. Environmental risk factors for cancer were identified, such as alcohol abuse and tobacco exposure. The TP53 variant initially found in the next-generation sequencing was confirmed by Sanger sequencing in the previous DNA sample extracted from blood for the first analysis and in a second blood sample collected 6 years later. The TP53 variant was not detected in the DNA extracted from the oral swab and saliva samples.
CONCLUSION: Considering the low TP53 variant allele fraction in blood, absence of variant detection in oral swab and saliva samples, the lack of LFS clinical criteria, and history of exposure to environmental risk factors for cancer, the main hypothesis for this case was aberrant clonal expansion due to clonal hematopoiesis. Oncologists should interpret TP53 findings during germline testing with caution.

DOI: https://doi.org/10.1093/oncolo/oyad105
Blood Cancer J. 2023 05 10. 13(1): 73

DDX41 germline variants causing donor cell leukemia indicate a need for further genetic workup in the context of hematopoietic stem cell transplantation.

Benjamin Rolles, Robert Meyer, Matthias Begemann, Miriam Elbracht, Edgar Jost, Matthias Stelljes, Ingo Kurth, Tim H Brümmendorf, Gerda Silling.

DOI: https://doi.org/10.1038/s41408-023-00846-2
Am J Respir Crit Care Med. 2023 May 11.

A Large-Scale Exome-Wide Association Study Identifies Novel Germline Mutations in Lung Cancer.

Sipeng Shen, Zaiming Li, Yunke Jiang, Weiwei Duan, Hongru Li, Sha Du, Manel Esteller, Hongbing Shen, Zhibin Hu, Yang Zhao, David C Christiani, Feng Chen.

  RATIONALE: Genome-wide association studies (GWAS) have identified common variants of lung cancer. However, the contribution of rare exome-wide variants, especially protein-coding variants, to cancers remains largely unexplored.OBJECTIVES: To evaluate the role of human exomes in genetic predisposition to lung cancer.
MEASUREMENTS AND METHODS: We performed exome-wide association studies (ExWAS) to detect the association of exomes with lung cancer in 30,312 patients and 652,902 controls. A Scalable and Accurate Implementation of GEneralized (SAIGE) mixed model was used to detect the association signals for loss of function (LoF), missense and synonymous variants, and gene-level sets. Furthermore, we performed association and Bayesian co-localization analyses to evaluate their relationships with intermediate exposures.
MAIN RESULTS: We systematically analyzed 216,739 single nucleotide variants (SNVs) in the human exome. The LoF variants exhibited the most notable effects on lung cancer risk. We identified four novel variants, including two missense variants (rs202197044TET3 [Pmeta = 3.60×10-8] and rs202187871POT1 [Pmeta = 2.21×10-8]) and two synonymous variants (rs7447927TMEM173 [Pmeta = 1.32×10-9] and rs140624366ATRN [Pmeta = 2.97×10-9]). rs202197044TET3 was significantly associated with emphysema (OR = 3.55, Pfdr = 0.015), whereas rs7447927POT1 was strongly associated with telomere length (beta = 1.08, Pfdr = 3.76×10-53). Functional evidence of expression quantitative trait loci (eQTL), splicing QTL (sQTL), and isoform expression was found for the four novel genes. Gene-level association tests identified several novel genes, including POT1, RTEL1, BSG, and ZNF232.
CONCLUSIONS: Our findings provide insights into the genetic architecture of human exomes and their role in lung cancer predisposition.

Keywords:  exome sequencing; exome-wide association study; germline mutation; lung cancer; trans-omics

DOI:  https://doi.org/10.1164/rccm.202212-2199OC
Oncol Lett. 2023 Jun;25(6): 216

Germline multigene panel testing of patients with endometrial cancer.

Jan Kral, Sandra Jelinkova, Petra Zemankova, Michal Vocka, Marianna Borecka, Leona Cerna, Marta Cerna, Lukas Dostalek, Petra Duskova, Lenka Foretova, Ondrej Havranek, Klara Horackova, Milena Hovhannisyan, Stepan Chvojka, Marta Kalousova, Marcela Kosarova, Monika Koudova, Vera Krutilkova, Eva Machackova, Petr Nehasil, Jan Novotny, Barbora Otahalova, Alena Puchmajerova, Marketa Safarikova, Jiri Slama, Viktor Stranecky, Ivan Subrt, Spiros Tavandzis, Michal Zikan, Tomas Zima, Jana Soukupova, Petra Kleiblova, Zdenek Kleibl, Marketa Janatova.

  Endometrial cancer (EC) is the most common gynecological malignancy in developed countries. The present study aimed to determine the frequency of germline pathogenic variants (PV) in patients with EC. In this multicenter retrospective cohort study, germline genetic testing (GGT) was performed in 527 patients with EC using a next generation sequencing panel targeting 226 genes, including 5 Lynch syndrome (LS) and 14 hereditary breast and ovarian cancer (HBOC) predisposition genes, and 207 candidate predisposition genes. Gene-level risks were calculated using 1,662 population-matched controls (PMCs). Patients were sub-categorized to fulfill GGT criteria for LS, HBOC, both or none. A total of 60 patients (11.4%) carried PV in LS (5.1%) and HBOC (6.6%) predisposition genes, including two carriers of double PV. PV in LS genes conferred a significantly higher EC risk [odds ratio (OR), 22.4; 95% CI, 7.8-64.3; P=1.8×10-17] than the most frequently altered HBOC genes BRCA1 (OR, 3.9; 95% CI, 1.6-9.5; P=0.001), BRCA2 (OR, 7.4; 95% CI, 1.9-28.9; P=0.002) and CHEK2 (OR, 3.2; 95% CI, 1.0-9.9; P=0.04). Furthermore, >6% of patients with EC not fulfilling LS or HBOC GGT indication criteria carried a PV in a clinically relevant gene. Carriers of PV in LS genes had a significantly lower age of EC onset than non-carriers (P=0.01). Another 11.0% of patients carried PV in a candidate gene (the most frequent were FANCA and MUTYH); however, their individual frequencies did not differ from PMCs (except for aggregated frequency of loss-of-function variants in POLE/POLD1; OR, 10.44; 95% CI, 1.1-100.5; P=0.012). The present study demonstrated the importance of GGT in patients with EC. The increased risk of EC of PV carriers in HBOC genes suggests that the diagnosis of EC should be included in the HBOC GGT criteria.

Keywords:  EC; germline mutations; multigene panel testing; uterine malignancies

DOI:  https://doi.org/10.3892/ol.2023.13802
J Gynecol Oncol. 2023 May 02.

Diverse genetic spectrum among patients who met the criteria of hereditary breast, ovarian and pancreatic cancer syndrome.

Po-Han Lin, Yun-Wen Tien, Wen-Fang Cheng, Ying-Cheng Chiang, Chien-Huei Wu, Karen Yang, Chiun-Sheng Huang.

  OBJECTIVE: Genetic high-risk assessment combines hereditary breast, ovarian and pancreatic cancer into one syndrome. However, there is a lack of data for comparing the germline mutational spectrum of the cancer predisposing genes between these three cancers.METHODS: Patients who met the criteria of the hereditary breast, ovarian and pancreatic cancer were enrolled and received multi-gene sequencing.
RESULTS: We enrolled 730 probands: 418 developed breast cancer, 185 had ovarian cancer, and 145 had pancreatic cancer. Out of the 18 patients who had two types of cancer, 16 had breast and ovarian cancer and 2 had breast and pancreatic cancer. A total of 167 (22.9%) patients had 170 mutations. Mutation frequency in breast, ovarian and pancreatic cancer was 22.3%, 33.5% and 17.2%, respectively. The mutation rate was significantly higher in patients with double cancers than those with a single cancer (p<0.001). BRCA1 and BRCA2 were the most dominant genes associated with hereditary breast and ovarian cancer, whereas ATM was the most prevalent gene related to hereditary pancreatic cancer. Genes of hereditary colon cancer such as lynch syndrome were presented in a part of patients with pancreatic or ovarian cancer but seldom in those with breast cancer. Families with a history of both ovarian and breast cancer were associated with a higher mutation rate than those with other histories.
CONCLUSION: The mutation spectrum varies across the three cancer types and family histories. Our analysis provides guidance for physicians, counsellors, and counselees on the offer and uptake of genetic counseling.

Keywords:  ATM; BRCA; Breast Cancer; Hereditary; Ovarian Cancer; Pancreatic Cancer

DOI:  https://doi.org/10.3802/jgo.2023.34.e66
Cold Spring Harb Mol Case Stud. 2023 04;pii: a006267. [Epub ahead of print]9(2):

Melanoma in a patient with DNMT3A overgrowth syndrome.

David Y Chen, Leslie A Sutton, Sai Mukund Ramakrishnan, Eric J Duncavage, Sharon E Heath, Leigh A Compton, Christopher A Miller, Timothy J Ley.

  Alterations in epigenetic regulators are increasingly recognized as early events in tumorigenesis; thus, patients with acquired or inherited variants in epigenetic regulators may be at increased risk for developing multiple types of cancer. DNMT3A overgrowth syndrome (DOS), caused by germline pathogenic variants in the DNA methyltransferase gene DNMT3A, has been associated with a predisposition toward development of hematopoietic and neuronal malignancies. DNMT3A deficiency has been described to promote keratinocyte proliferation in mice. Although altered DNA methylation patterns are well-recognized in melanoma, the role of DNA methyltransferases in melanoma pathogenesis is not clear. We report the case of an adult DOS patient with a germline DNMT3A loss-of-function mutation, who developed an early-onset melanoma with regional lymph node metastatic disease. Exome sequencing of the primary tumor identified an additional acquired, missense DNMT3A mutation in the dominant tumor clone, suggesting that the loss of DNMT3A function was relevant for the development of this tumor.

Keywords:  cutaneous melanoma; overgrowth

DOI:  https://doi.org/10.1101/mcs.a006267
Stem Cell Rev Rep. 2023 May 12.

Dppa3 Improves the Germline Competence of Pluripotent Stem Cells.

Siying Liu, Shuang Zhao, Chuanyu Zhang, Chenglei Tian, Dan Wang, Huaxin Yu, Zongjin Li, Lin Liu, Na Liu.

  BACKGROUND: Chimera formation and germline competence are critical features of mouse pluripotent stem cells (PSCs). However, the factors that contribute to germline competence in the chimeras remain to be understood.METHODS: To determine the role of Dppa3 in PSCs, we first constructed Dppa3 knockout (Dppa3 KO) and Dppa3 overexpression (Dppa3 OE) PSCs, respectively. Using Dppa3 KO and Dppa3 OE PSCs, we then investigated the role of Dppa3 in PSCs by evaluating the chimera generation, DNA methylation, and pluripotent state conversion.
RESULTS: We show that Dppa3 plays an important role in chimera formation and germline competence of mouse PSCs. PSC lines with high expression of Dppa3 show high germline competence. In contrast, Dppa3 deficiency reduces chimera formation and abrogates the germline transmission capacity of PSCs. Molecularly, Dppa3 facilitates establishing global DNA hypomethylation in PSCs. High levels of Dppa3 in PSCs reduce the expression of Dnmt3a/b and impede Uhrf1-Dnmt1 complex binding to DNA replication forks, maintaining DNA hypomethylation. Additionally, Dppa3 facilitates two-cell-stage (2C) genes expression and promotes conversion to a 2C-like state.
CONCLUSION: These data show that Dppa3 is involved in maintaining DNA hypomethylation homeostasis and is required for high chimera formation and germline competence of PSCs.

Keywords:  DNA methylation; Dppa3; Germline competency; Pluripotent stem cells

DOI:  https://doi.org/10.1007/s12015-023-10552-y