bims-lifras 2023-06-04 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–06–04
eleven papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.
Risk-reducing surgery for individuals with cancer-predisposing germline pathogenic variants and no personal cancer history: a review of current UK guidelines.
Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.
Case report: Neuroendocrine breast carcinoma with a germline EGFR T790M mutation.
NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report.
Clinical considerations at the intersection of hematopoietic cell transplantation and hereditary hematopoietic malignancy.
Fine-tuning germline mutation rates across evolution.
BAP1 genetic testing among melanoma and cancer-prone families in Sweden.
Functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in RAD51C.
Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.
Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631.

Breast Care (Basel). 2023 May;18(2): 106-112

Prevalence of Pathogenic Germline Variants in Women with Non-Familial Unilateral Triple-Negative Breast Cancer.

Kerstin Rhiem, Silke Zachariae, Anke Waha, Sabine Grill, Anna Hester, Michael Golatta, Marion van Mackelenbergh, Tanja Fehm, Tanja Schlaiß, Tim Ripperger, Susanne Ledig, Cornelia Meisel, Dorothee Speiser, Kristina Veselinovic, Christopher Schröder, Isabell Witzel, Julia Gallwas, Bernhard H F Weber, Christine Solbach, Bariyhe Aktas, Eric Hahnen, Christoph Engel, Rita Schmutzler.

   Introduction: International guidelines recommend genetic testing for women with familial breast cancer at an expected prevalence of pathogenic germline variants (PVs) of at least 10%. In a study sample of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC), we have previously shown that women with TNBC diagnosed before the age of 50 years but without a family history of breast or ovarian cancer (sTNBC) meet this criterion. The present study investigates the PV prevalence in BRCA1, BRCA2, and nine additional cancer predisposition genes in an extended sTNBC study sample including a cohort of women with a later age at sTNBC diagnosis.
Patients and Methods: In 1,600 women with sTNBC (median age at diagnosis: 41 years, range 19-78 years), we investigated the association between age at diagnosis and PV occurrence in cancer predisposition genes using logistic regression.
Results: 260 sTNBC patients (16.2%) were found to have a PV in cancer predisposition genes (BRCA1: n = 170 [10.6%]; BRCA2: n = 46 [2.9%], other: n = 44 [2.8%]). The PV prevalence in women diagnosed between 50 and 59 years (n = 194) was 11.3% (22/194). Logistic regression showed a significant increase in PV prevalence with decreasing age at diagnosis (OR 1.41 per 10 years younger age at diagnosis; 95% confidence interval: 1.21-1.65; p < 0.001). The PV prevalence predicted by the model was above 10% for diagnoses before the age of 56.8 years.
Conclusion: Based on the data presented, we recommend genetic testing by gene panel analysis for sTNBC patients diagnosed before the age of 60 years. Due to the still uncertain estimate for women with sTNBC diagnosed above the age of 60 years, further studies are needed.

Keywords:  BRCA1; BRCA2, triple negative; Breast cancer; Hereditary breast and ovarian cancer

DOI:  https://doi.org/10.1159/000528972
Br J Cancer. 2023 May 31.

Risk-reducing surgery for individuals with cancer-predisposing germline pathogenic variants and no personal cancer history: a review of current UK guidelines.

Rebecca L McCarthy, Ellen Copson, William Tapper, Helen Bolton, Alex H Mirnezami, J Robert O'Neill, Nimesh N Patel, Marc Tischkowitz, Ramsey I Cutress.

Identifying healthy carriers of germline pathogenic variants in high penetrance cancer susceptibility genes offers the potential for risk-reducing surgery. The NHS England National Genomic Test Directory offers germline and somatic testing to patients with certain cancers or rare and inherited diseases, or, in some cases, to their relatives. This review summarises current UK guidelines for risk-reducing surgical interventions available for individuals with no personal history of cancer, who are determined to carry germline pathogenic variants. An electronic literature search of NICE guidelines and PubMed citable articles was performed. NICE guidelines are available for bilateral mastectomy and are currently in development for risk-reducing bilateral salpingo-oophorectomy. Guidelines developed with affiliation to, or through relevant British Surgical Societies or international consensus, are available for risk-reducing hysterectomy, polypectomy, gastrectomy, and thyroidectomy. There is a disparity in the development and distribution of national guidelines for interventions amongst tumour types. Whilst we are focusing on UK guidelines, we anticipate they will be relevant much more generally and so of interest to a wider audience including where there are no national guidelines to refer to. We suggest that, as genetic testing becomes rapidly more accessible, guideline development for interventions should be more closely aligned to those for testing.

DOI: https://doi.org/10.1038/s41416-023-02296-w
Gastric Cancer. 2023 May 30.

Combined loss of CDH1 and downstream regulatory sequences drive early-onset diffuse gastric cancer and increase penetrance of hereditary diffuse gastric cancer.

Solve-RD DITF-GENTURIS

   BACKGROUND: Germline CDH1 pathogenic or likely pathogenic variants cause hereditary diffuse gastric cancer (HDGC). Once a genetic cause is identified, stomachs' and breasts' surveillance and/or prophylactic surgery is offered to asymptomatic CDH1 carriers, which is life-saving. Herein, we characterized an inherited mechanism responsible for extremely early-onset gastric cancer and atypical HDGC high penetrance.
METHODS: Whole-exome sequencing (WES) re-analysis was performed in an unsolved HDGC family. Accessible chromatin and CDH1 promoter interactors were evaluated in normal stomach by ATAC-seq and 4C-seq, and functional analysis was performed using CRISPR-Cas9, RNA-seq and pathway analysis.
RESULTS: We identified a germline heterozygous 23 Kb CDH1-TANGO6 deletion in a family with eight diffuse gastric cancers, six before age 30. Atypical HDGC high penetrance and young cancer-onset argued towards a role for the deleted region downstream of CDH1, which we proved to present accessible chromatin, and CDH1 promoter interactors in normal stomach. CRISPR-Cas9 edited cells mimicking the CDH1-TANGO6 deletion display the strongest CDH1 mRNA downregulation, more impacted adhesion-associated, type-I interferon immune-associated and oncogenic signalling pathways, compared to wild-type or CDH1-deleted cells. This finding solved an 18-year family odyssey and engaged carrier family members in a cancer prevention pathway of care.
CONCLUSION: In this work, we demonstrated that regulatory elements lying down-stream of CDH1 are part of a chromatin network that control CDH1 expression and influence cell transcriptome and associated signalling pathways, likely explaining high disease penetrance and very young cancer-onset. This study highlights the importance of incorporating scientific-technological updates and clinical guidelines in routine diagnosis, given their impact in timely genetic diagnosis and disease prevention.

Keywords:  CDH1; Copy number variants; Deletion; Hereditary diffuse gastric cancer; Regulatory elements; Type-I interferon immune response

DOI:  https://doi.org/10.1007/s10120-023-01395-0
Front Oncol. 2023 ;13 1176868

Case report: Neuroendocrine breast carcinoma with a germline EGFR T790M mutation.

Olivia A Sagan, Anna Rothstein, Bhaghyasree Jambunathan, Mersiha Hadziahmetovic, Anita Antoniolli, M Hammad Rashid.

   Background: The epidermal growth factor receptor (EGFR) p.Thr790Met (T790M) mutation was discovered as a resistance mechanism in patients with lung cancer treated with first- and second-generation tyrosine kinase inhibitors. Further studies revealed the EGFR T790M mutation in treatment-naive non-small cell lung carcinoma (NSCLC) and as a rare germline mutation strongly associated with NSCLC. Somatic EGFR T790M mutations have been reported in a limited population of patients with triple-negative breast cancer. There are no previous reports of a germline EGFR T790M mutation found in a patient with breast cancer.
Case presentation: We present a rare case of a 42-year-old woman with a rapidly progressing 8 cm mass in the right lateral breast. An additional right breast mass with multiple lymph nodes characteristic or suspicious of metastasis was found. Ultrasound-guided biopsy showed high-grade, poorly differentiated invasive neuroendocrine carcinoma of the right breast and metastatic carcinoma of a right axillary lymph node. Genetic testing revealed a germline EGFR T790M mutation. The patient underwent neoadjuvant chemotherapy, right mastectomy with lymph node dissection, adjuvant radiation to the right chest wall and axilla, and adjuvant chemotherapy.
Conclusion: This is the first reported case of a patient with high-grade neuroendocrine carcinoma, triple-negative breast cancer and a germline EGFR T790M mutation. Further investigation is needed to find a possible correlation between the cancer in this patient and her mutation. Since there are no current guidelines, further research is also needed to define screening protocols for patients with germline EGFR T790M mutations. Additional treatment options and cancer risk could also be found with further research, which would benefit all patients with a germline EGFR T790M mutation.

Keywords:  EGFR mutation; chemotherapy; germline EGFR T790M mutation; neuroendocrine breast cancer; triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.3389/fonc.2023.1176868
JTO Clin Res Rep. 2023 Jun;4(6): 100521

NSCLC With Synchronous EGFR Mutations in Li Fraumeni Syndrome: A Case Report.

Jennifer A Marks, Stephen V Liu.

  We report a case of a patient with Li Fraumeni Syndrome (LFS) who developed synchronous EGFR exon deletion 19 and EGFR exon 20 insertion NSCLC and characterize the diagnostic and therapeutic challenges in managing her care. Osimertinib was effective in the EGFR deletion 19 population but did not garner a response in the EGFR exon 20 insertion population, which was treated definitively with surgical resection. At the time of oligoprogression, she underwent surgical resection, and radiation therapy was minimized. The biologic link between LFS and EGFR mutation remains unclear, and using larger, real-world cohorts could help to clarify the relationship between LFS and EGFR-mutant NSCLC.

Keywords:  Case report; EGFR mutations; Li Fraumeni Syndrome; NSCLC

DOI:  https://doi.org/10.1016/j.jtocrr.2023.100521
Front Oncol. 2023 ;13 1180439

Clinical considerations at the intersection of hematopoietic cell transplantation and hereditary hematopoietic malignancy.

Timothy E O'Connor, Reid Shaw, Rafael Madero-Marroquin, Gregory W Roloff.

  In recent years, advances in genetics and the integration of clinical-grade next-generation sequencing (NGS) assays into patient care have facilitated broader recognition of hereditary hematopoietic malignancy (HHM) among clinicians, in addition to the identification and characterization of novel HHM syndromes. Studies on genetic risk distribution within affected families and unique considerations of HHM biology represent exciting areas of translational research. More recently, data are now emerging pertaining to unique aspects of clinical management of malignancies arising in the context of pathogenic germline mutations, with particular emphasis on chemotherapy responsiveness. In this article, we explore considerations surrounding allogeneic transplantation in the context of HHMs. We review pre- and post-transplant patient implications, including genetic testing donor selection and donor-derived malignancies. Additionally, we consider the limited data that exist regarding the use of transplantation in HHMs and safeguards that might be pursued to mitigate transplant-related toxicities.

Keywords:  AML; MDS; genetic testing; hereditary hematopoietic malignancy; stem cell transplant

DOI:  https://doi.org/10.3389/fonc.2023.1180439
Trends Genet. 2023 May 25. pii: S0168-9525(23)00124-5. [Epub ahead of print]

Fine-tuning germline mutation rates across evolution.

Stephen J Bush, Anne Goriely.

The germline mutation rate (GMR) sets the pace at which mutations, the raw material of evolution, are introduced into the genome. By sequencing a dataset of unprecedently broad phylogenetic scope, Bergeron et al. estimated species-specific GMR, offering numerous insights into how this parameter shapes and is shaped by life-history traits.

DOI: https://doi.org/10.1016/j.tig.2023.05.001
Acta Oncol. 2023 Jun 02. 1-6

BAP1 genetic testing among melanoma and cancer-prone families in Sweden.

Hildur Helgadottir, Karina Schultz, Jan Lapins, Ismini Vassilaki, Charlotta All-Eriksson, Veronica Höiom.

DOI: https://doi.org/10.1080/0284186X.2023.2216338
Cancer Res. 2023 May 30. pii: CAN-22-2319. [Epub ahead of print]

Functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in RAD51C.

Chunling Hu, Anil Belur Nagaraj, Hermela Shimelis, Gemma Montalban, Kun Y Lee, Huaizhi Huang, Carolyn A Lumby, Jie Na, Lisa R Susswein, Maegan E Roberts, Megan L Marshall, Susan Hiraki, Holly LaDuca, Elizabeth Chao, Amal Yussuf, Tina Pesaran, Susan L Neuhausen, Christopher A Haiman, Peter Kraft, Sara Lindström, Julie R Palmer, Lauren R Teras, Celine M Vachon, Song Yao, Irene Ong, Katherine L Nathanson, Jeffrey N Weitzel, Nicholas Boddicker, Rohan Gnanaolivu, Eric C Polley, Georges Mer, Gaofeng Cui, Rachid Karam, Marcy E Richardson, Susan M Domchek, Siddhartha Yadav, Kathleen S Hruska, Jill Dolinsky, S John Weroha, Steven N Hart, Jacques Simard, Jean-Yves Masson, Yuan-Ping Pang, Fergus J Couch.

Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 non-functional (deleterious) variants, including 18 in a hotspot within the ATP binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and non-cancer controls showed associations with moderate breast cancer risk (odds ratio (OR)=3.92; 95%CI:2.18-7.59) and high ovarian cancer risk (OR=14.8; 95%CI:7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-2319
Curr Hematol Malig Rep. 2023 Jun 01.

Sporadic and Familial Acute Myeloid Leukemia with CEBPA Mutations.

Ji Yuan, Rong He, Hassan B Alkhateeb.

   PURPOSE OF REVIEW: CCAAT enhancer binding protein A (CEBPA) gene mutation is one of the common genetic alterations in acute myeloid leukemia (AML), which can be associated with sporadic and familial AML.
RECENT FINDINGS: Due to the recent advances in molecular testing and the prognostic role of CEBPA mutation in AML, the definition for AML with CEBPA mutation (AML-CEBPA) has significantly changed. This review provides the rationale for the updates on classifications, and the impacts on laboratory evaluation and clinical management for sporadic and familial AML-CEBPA patients. In addition, minimal residual disease assessment post therapy to stratify disease risk and stem cell transplant in selected AML-CEBPA patients are discussed. Taken together, the recent progresses have shifted the definition, identification, and management of patients with AML-CEBPA.

Keywords:  Acute myeloid leukemia; CEBPA; Familial; Germline

DOI:  https://doi.org/10.1007/s11899-023-00699-3
Pediatr Blood Cancer. 2023 May 31. e30467

Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631.

Kelly E Faulk, John A Kairalla, ZoAnn E Dreyer, Andrew J Carroll, Nyla A Heerema, Meenakshi Devidas, William L Carroll, Elizabeth A Raetz, Mignon L Loh, Stephen P Hunger, Michael Borowitz, Cindy Wang, Erin Guest, Patrick A Brown.

  We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.01%) was: TP1: 25% (±6%) versus 49% (±7%; p = .0009); TP2: 21% (±8%) versus 47% (±7%; p < .0001); and TP3: 22% (±14%) versus 51% (±6%; p = .0178). For KMT2A-germline patients, 3-year EFS was: TP1: 88% (±12%) versus 87% (±5%; p = .73); TP2: 100% versus 88% (±5%; p = .24); and TP3: 100% versus 87% (±5%; p = .53). MRD was a strong independent outcome predictor in KMT2A-rearranged, but not KMT2A-germline infant ALL.

Keywords:  acute lymphoblastic leukemia; infant leukemia; minimal residual disease

DOI:  https://doi.org/10.1002/pbc.30467