bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2024–06–16
eight papers selected by
Joanna Zawacka, Karolinska Institutet
  1. A second hereditary cancer predisposition syndrome in a patient with lynch syndrome and three primary cancers.
  2. Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.
  3. Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multi-Site Single-Institution Prospective Study.
  4. Germline CDH1 Variants and Lifetime Cancer Risk.
  5. Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.
  6. Identification of EGFR R776H germline mutations in a patient with multifocal lung adenocarcinoma: A case report and literature review.
  7. Prevention, diagnosis and clinical management of hereditary breast cancer beyond BRCA1/2 genes.
  8. A highly malignant succinate dehydrogenase A‑deficient renal cell carcinoma with bone metastasis misdiagnosed as hereditary leiomyomatosis and renal cell carcinoma: A case report.
  1. Hered Cancer Clin Pract. 2024 Jun 12. 22(1): 8
    A second hereditary cancer predisposition syndrome in a patient with lynch syndrome and three primary cancers.
    Annmarie Taheny, Haylie McSwaney, Julia Meade.
      Current National Comprehensive Cancer Network ® (NCCN ®) guidelines for Colorectal Genetic/Familial High-Risk Assessment provide limited guidance for genetic testing for individuals with already diagnosed hereditary cancer conditions. We are presenting the case of a 36-year-old woman who was diagnosed with Lynch Syndrome at age 23 after genetic testing for a familial variant (c.283del) in the MLH1 gene. The patient had a previous history of Hodgkin Lymphoma at the time of familial variant testing, and she would later develop stage IIIa cecal adenocarcinoma at age 33 and metastatic papillary thyroid carcinoma at age 35. The patient's family history included a first-degree relative who was diagnosed with colorectal cancer at age 39, multiple second-degree relatives with colorectal, endometrial, and stomach cancer, and third and fourth-degree relatives with breast cancer. In light of her personal and family history, a comprehensive cancer panel was recommended. This panel found a second hereditary cancer predisposition syndrome: a likely pathogenic variant (c. 349 A > G) in the CHEK2 gene. This specific CHEK2 variant was recently reported to confer a moderately increased risk for breast cancer. The discovery of this second cancer predisposition syndrome had important implications for the patient's screening and risk management. While uncommon, the possibility of an individual having multiple cancer predisposition syndromes is important to consider when evaluating patients and families for hereditary cancer, even when a familial variant has been identified.
    Keywords:  CHEK2 hereditary cancer predisposition; Case report; Hereditary cancer conditions; Lynch syndrome; Multiple hereditary cancer conditions; NCCN guidelines
    DOI:  https://doi.org/10.1186/s13053-024-00281-9
  2. Breast Cancer Res Treat. 2024 Jun 14.
    Spectrum of germline pathogenic variants in Brazilian hereditary breast/ovarian cancer cases.
    João Paulo Faria, Juliana Godoy Assumpção, Lorena de Oliveira Matos, Fernanda Caroline Soardi, Gabriel Pissolati Mattos Bretz, Eitan Friedman, Luiz De Marco.
       PURPOSE: To define the spectrum of germline pathogenic variants (PVs) and copy number variant (CNV) in cancer susceptibility genes to the burden of breast and ovarian cancer (BC, OvC) in high-risk Brazilians in Minas Gerais with health insurance, southeast Brazil, undergoing multigene panel testing (MGPT).
    METHODS: Genotyping eligible individuals with health insurance in the Brazilian healthcare system for Hereditary Breast and Ovarian Cancer Syndrome to undergo molecular testing for 44 or 141-gene panels, a decision that was insurance driven.
    RESULTS: Overall, 701 individuals clinically defined as high BC/OvC risk, underwent MGPT from 1/2021 to 10/2022, with ~ 50% genotyped with a 44-gene panel and the rest with a 141-gene panel. Overall, 16.4% and 22.6% of genotyped individuals harbored PVs using 44-gene and the 141 gene panel, respectively. The most frequently mutated genes were: BRCA2 (3.7%); BRCA1 (3.6%) and monoallelic MUTYH (3.1%).
    CONCLUSION: The rate of PVs detected in high-risk individuals in this study was twice the 10% threshold used in Brazilian health guidelines. MGPT doubled the detection rate of PVs in cancer susceptibility genes in high-risk individuals compared with BRCA1/BRCA2 genotyping alone. The spectrum of PVs in Southern Brazil is diverse, with few recurring variants such as TP53 (0.6%), suggesting regional founder effects. The use of MGPT in hereditary cancer in Minas Gerais significantly increased the detection rate of P/LPVs compared to existing guidelines and should be considered as the primary genotyping modality in assessing hereditary cancer risk in Brazil.
    Keywords:   BRCA1 ; BRCA2 ; Germline pathogenic variants; Hereditary breast/ovarian cancer; High-risk individuals genotyping; Multigene panel testing
    DOI:  https://doi.org/10.1007/s10549-024-07383-x
  3. J Urol. 2024 Jun 11. 101097JU0000000000004089
    Germline Pathogenic Variants Identified in Patients With Genitourinary Malignancies Undergoing Universal Testing: A Multi-Site Single-Institution Prospective Study.
    Mouneeb M Choudry, Adri M Durant, Victoria S Edmonds, Christopher J Warren, Katie L Kunze, Michael A Golafshar, Sarah M Nielsen, Edward D Esplin, Jack R Andrews, N Jewel Samadder, Mark D Tyson.
       INTRODUCTION: This study aimed to investigate the prevalence of pathogenic germline variants (PGV) in hereditary cancer genes utilizing a universal testing approach and to determine the rate of PGV that would have been missed based on National Comprehensive Cancer Network (NCCN) guidelines in genitourinary (GU) malignancies.
    METHODS: A multi-site, single-institution prospective germline genetic test (GGT) was universally offered to patients with new or active diagnoses of GU malignancies (prostate, bladder, and renal) from April 2018 to March 2020 at Mayo Clinic sites. Participants were offered GGT using a next-generation sequencing panel of > 80 genes. Demographic, tumor characteristics, and genetic results were evaluated. NCCN GU cancer guidelines were used to identify whether patients had incremental findings, defined as PGV-positive patients who would not have received testing based on NCCN guidelines.
    RESULTS: Of 3095 individuals enrolled in the study, 601 patients had GU cancer (prostate = 358, bladder = 106, and renal = 137). The mean enrollment age was 67 years (SD 9.1), 89% were male, and 86% of patients were non-Hispanic white. PGV were identified in 82 (14%) of all GU patients. PGV prevalence breakdown by cancer type was: 14% prostate, 14% bladder, and 13% renal cancer. Nearly one-third of identified PGV were high-penetrance and the majority of these (67%) were clinically actionable. Incremental PGV were identified in 28 (57%) prostate, 15 (100%) bladder, and renal 14 (78%) cancer patients. Of the 82 patients with PGV findings, 29 (35%) had at least one relative undergo cascade testing for the familial variant(s) identified.
    CONCLUSION: More than 1 in 8 patients with GU malignancies were found to carry a PGV, with 67% of patients with high penetrance PGV undergoing clinically actionable changes. The majority of these PGV would not have been identified based on current testing criteria. These findings support universal GGT for GU malignancies and underscore its potential to enhance risk-assessment and guide precision interventions in urologic oncology.
    DOI:  https://doi.org/10.1097/JU.0000000000004089
  4. JAMA. 2024 Jun 14.
    Germline CDH1 Variants and Lifetime Cancer Risk.
    Carrie E Ryan, Grace-Ann Fasaye, Amber F Gallanis, Lauren A Gamble, Paul H McClelland, Anna Duemler, Sarah G Samaranayake, Andrew M Blakely, Christine M Drogan, Kerry Kingham, Devanshi Patel, Linda Rodgers-Fouche, Ava Siegel, Sonia S Kupfer, James M Ford, Daniel C Chung, James G Dowty, Joshua Sampson, Jeremy L Davis.
       Importance: Approximately 1% to 3% of gastric cancers and 5% of lobular breast cancers are hereditary. Loss of function CDH1 gene variants are the most common gene variants associated with hereditary diffuse gastric cancer and lobular breast cancer. Previously, the lifetime risk of gastric cancer was estimated to be approximately 25% to 83% and for breast cancer it was estimated to be approximately 39% to 55% in individuals with loss of function CDH1 gene variants.
    Objective: To describe gastric and breast cancer risk estimates for individuals with CDH1 variants.
    Design, Setting, and Participants: Multicenter, retrospective cohort and modeling study of 213 families from North America with a CDH1 pathogenic or likely pathogenic (P/LP) variant in 1 or more family members conducted between January 2021 and August 2022.
    Main Outcomes and Measures: Hazard ratios (HRs), defined as risk in variant carriers relative to noncarriers, were estimated for each cancer type and used to calculate cumulative risks and risks per decade of life up to age 80 years.
    Results: A total of 7323 individuals from 213 families were studied, including 883 with a CDH1 P/LP variant (median proband age, 53 years [IQR, 42-62]; 4% Asian; 4% Hispanic; 85% non-Hispanic White; 50% female). In individuals with a CDH1 P/LP variant, the prevalence of gastric cancer was 13.9% (123/883) and the prevalence of breast cancer among female carriers was 26.3% (144/547). The estimated HR for advanced gastric cancer was 33.5 (95% CI, 9.8-112) at age 30 years and 3.5 (95% CI, 0.4-30.3) at age 70 years. The lifetime cumulative risk of advanced gastric cancer in male and female carriers was 10.3% (95% CI, 6%-23.6%) and 6.5% (95% CI, 3.8%-15.1%), respectively. Gastric cancer risk estimates based on family history indicated that a carrier with 3 affected first-degree relatives had a penetrance of approximately 38% (95% CI, 25%-64%). The HR for breast cancer among female carriers was 5.7 (95% CI, 2.5-13.2) at age 30 years and 3.9 (95% CI, 1.1-13.7) at age 70 years. The lifetime cumulative risk of breast cancer among female carriers was 36.8% (95% CI, 25.7%-62.9%).
    Conclusions and Relevance: Among families from North America with germline CDH1 P/LP variants, the cumulative risk of gastric cancer was 7% to 10%, which was lower than previously described, and the cumulative risk of breast cancer among female carriers was 37%, which was similar to prior estimates. These findings inform current management of individuals with germline CDH1 variants.
    DOI:  https://doi.org/10.1001/jama.2024.10852
  5. Clin Cancer Res. 2024 Jun 11. OF1-OF7
    Neuroblastoma Predisposition and Surveillance-An Update from the 2023 AACR Childhood Cancer Predisposition Workshop.
    Junne Kamihara, Lisa R Diller, William D Foulkes, Orli Michaeli, Yoshiko Nakano, Kristian W Pajtler, Melissa Perrino, Sarah R Scollon, Douglas R Stewart, Stephan Voss, Rosanna Weksberg, Jordan R Hansford, Garrett M Brodeur.
      Genetic predisposition to neuroblastoma (NB) is relatively rare. Only 1% to 2% of patients have a family history of NB, 3% to 4% of cases present with bilateral or multifocal primary tumors, and occasional patients have syndromes that are associated with increased NB risk. Previously, a germline pathogenic variant (GPV) in PHOX2B was associated with Hirschsprung disease and congenital central hypoventilation syndrome. Recently, certain GPVs were shown to be responsible for congenital central hypoventilation syndrome and NB predisposition. Also, several groups determined that activating GPVs in ALK accounted for a substantial number of familial NB. Finally, there are additional genes and cancer predisposition syndromes in which NB occurs with greater frequency or that have been associated with NB based on genome-wide association studies. We review the evidence for all these genes and whether there is sufficient evidence to warrant surveillance. We review recommended surveillance for hereditary patients with NB, including minor updates to surveillance recommendations that were published previously in 2017.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-0237
  6. Respir Med Case Rep. 2024 ;50 102051
    Identification of EGFR R776H germline mutations in a patient with multifocal lung adenocarcinoma: A case report and literature review.
    Tianli Wang, Qin Zheng, Cong Deng, Xiang Li, Jia Huang, Jun Fan, Bo Huang, Jiwei Zhang, Xiaona Chang, Xiu Nie.
      The advancement of molecular pathology techniques has led to the discovery of rare EGFR mutations for targeted therapy in lung cancer. Additionally, a substantial body of evidence indicates a connection between the development of lung cancer and genetic variations in the EGFR gene. Here, we present a case report of a patient with multifocal lung adenocarcinoma who possessed a rare germline mutation, EGFR R776H. An investigation into the family history of the patient exposed the notable incidence of lung adenocarcinoma, indicating a plausible genetic vulnerability to the ailment. To be specific, the patient's older brother and sister both suffered from lung cancer, which underlines the hereditary predisposition. Furthermore, it should be noted that the patient's daughter has inherited the germline mutation and also presented with multiple lung ground-glass nodules, emphasizing the clinical importance of this genetic variation. Following the lobectomy, the patient received treatment with almonertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), and at the latest follow-up, the patient has achieved partial remission. This case highlights the significance of taking into account germline possibilities when multiple lesions carry the same mutation. It stresses the importance of acquiring a comprehensive family history and performing genetic testing on leukocytes. Moreover, for the infrequent EGFR R776H mutation, third generation EGFR-TKIs may be a viable option.
    Keywords:  Almonertinib; EGFR R776H; Multifocal lung adenocarcinoma; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.rmcr.2024.102051
  7. Cancer Treat Rev. 2024 Jun 11. pii: S0305-7372(24)00113-0. [Epub ahead of print]129 102785
    Prevention, diagnosis and clinical management of hereditary breast cancer beyond BRCA1/2 genes.
    A Calabrese, C von Arx, A A Tafuti, M Pensabene, M De Laurentiis.
      The detection of germline pathogenic variants (gPVs) in BRCA1/2 and other breast cancer (BC) genes is rising exponentially thanks to the advent of multi-gene panel testing. This promising technology, coupled with the availability of specific therapies for BC BRCA-related, has increased the number of patients eligible for genetic testing. Implementing multi-gene panel testing for hereditary BC screening holds promise to maximise benefits for patients at hereditary risk of BC. These benefits range from prevention programs to antineoplastic-targeted therapies. However, the clinical management of these patients is complex and requires guidelines based on recent evidence. Furthermore, applying multi-gene panel testing into clinical practice increases the detection of variants of uncertain significance (VUSs). This augments the complexity of patients' clinical management, becoming an unmet need for medical oncologists. This review aims to collect updated evidence on the most common BC-related genes besides BRCA1/2, from their biological role in BC development to their potential impact in tailoring prevention and treatment strategies.
    Keywords:  BRCA genes; Hereditary breast cancer; Multi-gene panel testing; NGS; VUS
    DOI:  https://doi.org/10.1016/j.ctrv.2024.102785
  8. Oncol Lett. 2024 Aug;28(2): 351
    A highly malignant succinate dehydrogenase A‑deficient renal cell carcinoma with bone metastasis misdiagnosed as hereditary leiomyomatosis and renal cell carcinoma: A case report.
    Zhicheng Dai, Xiaohui Wang, Yinghao Zhang, Ying Qiu, Jie Liu.
      Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants of the SDH gene. SDH mutations are associated with an increased risk of developing RCC, although studies describing SDH-deficient RCC are currently limited. The present study reported a case of SDH-deficient RCC with high malignancy and rare bone metastasis. The patient was diagnosed with a right renal mass through B-mode ultrasound imaging and showed a carcinoma embolus in the right renal vein and inferior vena cava through kidney contrast-enhanced computed tomography. A whole-body bone scan showed radionuclide accumulation in the upper end of the left humerus, which indicated possible pathological bone destruction. As a result, surgical resection was performed. The postoperative pathology indicated a high-grade RCC and although the specific classification remained uncertain, hereditary leiomyomatosis and RCC was suspected. Subsequently, a germline mutation of the succinate dehydrogenase complex flavoprotein subunit A gene was identified through high-throughput sequencing (c.1A>G, p. Met1?) and immunohistochemistry demonstrated the loss of succinate dehydrogenase complex flavoprotein subunit B expression. Postoperatively, the patient underwent radiotherapy and targeted therapy. After 6 months of follow-up treatment, there was no indication of recurrence or metastasis on thoracoabdominal CT and whole-body bone scintigraphy. Based on the present report, germline screening should potentially be encouraged in early-onset patients as family history or pathological results may not provide sufficient information for the early, differential diagnosis of SDH-deficient RCC.
    Keywords:  diagnose; misdiagnosed; renal cell carcinoma; succinate dehydrogenase; succinate dehydrogenase-deficient renal cell carcinoma
    DOI:  https://doi.org/10.3892/ol.2024.14485
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