bims-lifras 2024-02-11 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–02–11
nine papers selected by
Joanna Zawacka, Karolinska Institutet

Germline CSF3R, RUNX1 and ETV6 Pathogenic Variants in a Case of Atypical Chronic Myeloid Leukemia: Individual to Familial Unravelling by Next Generation Sequencing.
Precursor lesions in familial and hereditary pancreatic cancer.
Correlation between choroid plexus carcinoma and Li-Fraumeni syndrome: implications of TP53 mutations and management strategies-a case-based narrative review.
Challenges to genetic testing for germline mutations associated with breast cancer among African Americans Authors.
Clonal hematopoiesis in children with predisposing conditions.
Germline predisposition for clonal hematopoiesis.
Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.
Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing.
Frequency of radiotherapy-induced malignancies in Li-Fraumeni Syndrome patients with early-stage breast cancer and influence of the radiotherapy technique.

Indian J Hematol Blood Transfus. 2024 Jan;40(1): 177-178

Germline CSF3R, RUNX1 and ETV6 Pathogenic Variants in a Case of Atypical Chronic Myeloid Leukemia: Individual to Familial Unravelling by Next Generation Sequencing.

Aastha Gupta, Aditi Aggarwal, Sanjeev Sharma, Varun Bafana, Shivani Sharma.



Keywords:  Atypical chronic myeloid leukemia; Germline mutations; NGS

DOI:  https://doi.org/10.1007/s12288-023-01656-z
Fam Cancer. 2024 Feb 06.

Precursor lesions in familial and hereditary pancreatic cancer.

Michael J Pflüger, Lodewijk A A Brosens, Ralph H Hruban.

  Infiltrating ductal adenocarcinoma of the pancreas, referred to here as "pancreatic cancer," is one of the deadliest of all of the solid malignancies. The five-year survival rate in the United States for individuals diagnosed today with pancreatic cancer is a dismal 12%. Many invasive cancers, including pancreatic cancer, however, arise from histologically and genetically well-characterized precursor lesions, and these precancers are curable. Precursor lesions therefore are an attractive target for early detection and treatment. This is particularly true for individuals with an increased risk of developing invasive cancer, such as individuals with a strong family history of pancreatic cancer, and individuals with a germline variant known to increase the risk of developing pancreatic cancer. There is therefore a need to understand the precursor lesions that can give rise to invasive pancreatic cancer in these individuals.

Keywords:  BRCA; CDKN2A; Familial; Germline; Intraductal papillary mucinous neoplasm; Pancreatic cancer; Precancer; Precursor

DOI:  https://doi.org/10.1007/s10689-024-00359-2
Childs Nerv Syst. 2024 Feb 06.

Correlation between choroid plexus carcinoma and Li-Fraumeni syndrome: implications of TP53 mutations and management strategies-a case-based narrative review.

Dattatraya Mallik, Swaroop Gopal, Gianluca Scalia, Giuseppe Umana, R T Rajeswarie, Bipin Chaurasia.

   BACKGROUND: Choroid plexus carcinomas (CPCs) are rare, aggressive grade 3 tumors of the central nervous system associated with Li-Fraumeni syndrome (LFS) in a notable percentage of cases due to TP53 germline mutations. Understanding the correlation between CPCs and LFS is crucial for tailored management strategies. However, distinguishing CPCs from benign choroid plexus papillomas (CPPs) remains challenging, relying largely on histologic features. This study aimed to explore the association between CPCs and LFS, emphasizing the impact of TP53 mutations on diagnosis, treatment, and clinical outcomes.
MATERIALS AND METHODS: Scientific databases such as PubMed, Scopus, and Web of Science were systematically searched up to January 2024 using keywords related to CPCs, LFS, TP53 mutation, and central nervous system tumors. Selection criteria included studies investigating the link between CPCs and LFS, their management approaches, and genetic implications of TP53 mutations. Ten relevant studies were selected for analysis after screening titles, abstracts, and full-text articles. Data extraction focused on clinical, genetic, and management factors related to CPCs associated with LFS.
RESULTS: The review highlighted the strong association (36%) between CPCs and LFS, primarily due to TP53 germline mutations. Studies emphasized the need for genetic testing in patients with CPCs, especially in pediatric cases, to identify LFS implications. Furthermore, the impact of TP53 mutations on treatment strategies was emphasized, recommending irradiation-sparing therapies due to inferior survival rates associated with radiotherapy in LFS patients with CPCs. Cases illustrated the challenges in diagnosing CPCs and the importance of immunohistochemistry and genetic testing for TP53 mutations.
CONCLUSION: CPCs pose challenges in diagnosis and management, particularly in distinguishing them from benign tumors. The association with LFS, often due to TP53 germline mutations, underscores the importance of genetic testing for early detection and tailored treatment strategies. Irradiation-sparing therapies are recommended for LFS-associated CPCs to mitigate the risk of secondary malignancies. Comprehensive profiling of CPC patients, especially in pediatric cases, is crucial for early detection and management of potential secondary cancers associated with LFS.

Keywords:  Choroid plexus carcinoma; Genetic; Li-Fraumeni; Recurrence; TP53

DOI:  https://doi.org/10.1007/s00381-024-06313-y
Cancer Treat Rev. 2024 Feb 01. pii: S0305-7372(24)00013-6. [Epub ahead of print]124 102695

Challenges to genetic testing for germline mutations associated with breast cancer among African Americans Authors.

S Kamaraju, M Conroy, A Harris, M Georgen, H Min, M Powell, R Kurzrock.

  Inequities in preventive cancer screening, diagnosis, treatment, and inferior cancer outcomes continue to pose challenges across the cancer continuum. While the exact reasons for these inferior outcomes are unknown, multiple barriers to various domains of social determinants of health (SDOH) play a vital role, leading to inequities in cancer care. These include barriers to transportation, housing, and food insecurities, contributing to delays in preventive screening and treatment. Furthermore, aggressive biologies also exist across various racial profiles with accompanying germline mutations. For example, African Americans (AAs) have a higher incidence of triple-negative breast cancer subtype and a high prevalence of BRCA1/2 gene mutations, increasing the risk of multiple cancers, warranting high-risk screening for these populations. Unfortunately, other barriers, such as financial insecurities, low health literacy rates, and lack of awareness, lead to delays in cancer screening and genetic testing, even with available high-risk screening and risk reduction procedures. In addition, physicians receive minimal interdisciplinary training to address genetic assessment, interpretation of the results, and almost no additional training in addressing the unique needs of racial minorities, leading to suboptimal delivery of genetic assessment provision resources among AAs. In this review, we discuss the confluence of factors and barriers limiting genetic testing among AAs and highlight the prevalence of germline mutations associated with increased risk of breast cancer among AAs, reflecting the need for multi-panel germline testing as well as education regarding hereditary cancer risks in underserved minorities.

Keywords:  African Americans; And cancer disparities; Breast cancer; Germline mutations; Social determinants of health

DOI:  https://doi.org/10.1016/j.ctrv.2024.102695
Semin Hematol. 2024 Jan 14. pii: S0037-1963(24)00006-4. [Epub ahead of print]

Clonal hematopoiesis in children with predisposing conditions.

Enrico Attardi, Seth J Corey, Marcin W Wlodarski.

  Clonal hematopoiesis in children and young adults differs from that occuring in the older adult population. A variety of stressors drive this phenomenon, sometimes independent of age-related processes. For the purposes of this review, we adopt the term clonal hematopoiesis in predisposed individuals (CHIPI) to differentiate it from classical, age-related clonal hematopoiesis of indeterminate potential (CHIP). Stress-induced CHIPI selection can be extrinsic, such as following immunologic, infectious, pharmacologic, or genotoxic exposures, or intrinsic, involving germline predisposition from inherited bone marrow failure syndromes. In these conditions, clonal advantage relates to adaptations allowing improved cell fitness despite intrinsic defects affecting proliferation and differentiation. In certain contexts, CHIPI can improve competitive fitness by compensating for germline defects; however, the downstream effects of clonal expansion are often unpredictable - they may either counteract the underlying pathology or worsen disease outcomes. A more complete understanding of how CHIPI arises in young people can lead to the definition of preleukemic states and strategies to assess risk, surveillance, and prevention to leukemic transformation. Our review summarizes current research on stress-induced clonal dynamics in individuals with germline predisposition syndromes.

Keywords:  clonal hematopoiesis in predisposed individuals; inherited bone marrow failure syndromes; pediatric clonal hematopoiesis; somatic genetic rescue

DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.005
Semin Hematol. 2024 Jan 14. pii: S0037-1963(24)00005-2. [Epub ahead of print]

Germline predisposition for clonal hematopoiesis.

Yasuo Kubota, Aaron D Viny.

  Clonal hematopoiesis (CH) is an entity hallmarked by skewed hematopoiesis with persistent overrepresentation of cells from a common stem/progenitor lineage harboring single-nucleotide variants and/or insertions/deletions. CH is a common and age-related phenomenon that is associated with an increased risk of hematological malignancies, cardiovascular disease, and all-cause mortality. While CH is a term of the hematological aspect, there exists a complex interaction with other organ systems, especially the cardiovascular system. The strongest factor in the development of CH is aging, however, other multiple factors also affect the development of CH including lifestyle-related factors and co-morbid diseases. In recent years, germline genetic factors have been linked to CH risk. In this review, we synthesize what is currently known about how genetic variation affects the risk of CH, how this genetic architecture intersects with myeloid neoplasms, and future prospects for CH.

Keywords:  CH; Germline predisposition; Myeloid malignancies

DOI:  https://doi.org/10.1053/j.seminhematol.2024.01.007
J Neurosurg Case Lessons. 2024 Feb 05. pii: CASE23595. [Epub ahead of print]7(6):

Laser interstitial thermal therapy as a radiation-sparing approach for central nervous system tumors in children with cancer predisposition syndromes: report of a child with Li-Fraumeni syndrome. Illustrative case.

Sergio W Guadix, Abhinav Pandey, Carson Gundlach, Michael Walsh, Nelson S Moss, Mark M Souweidane.

   BACKGROUND: Ionizing radiation and alkylating chemotherapies increase secondary malignancy risk in patients with cancer predisposition syndromes (CPSs), such as Li-Fraumeni syndrome. Laser interstitial thermal therapy (LITT) is a minimally invasive ablation technique that has not been associated with mutagenic risks. We describe the case of a child with LFS and a history of treated choroid plexus carcinoma (CPC) who developed a second primary glial tumor that was safely treated with magnetic resonance imaging (MRI)-guided LITT.
OBSERVATIONS: A 4-year-old male with left parietal World Health Organization grade III CPC associated with a TP53 germline mutation was evaluated. The patient underwent neoadjuvant platinum-based chemotherapy before near-total resection, followed by 131I-8H9 immunotherapy and 30 fractions of 54-Gy proton radiotherapy. He remained without evidence of disease for 2 years before developing a slow-growing mass adjacent to the left frontal ventricular horn. Stereotactic biopsy revealed a glial neoplasm. Given the nonsuperficial location and focality of the lesion, MRI-guided LITT was performed for ablative therapy. There were no complications, and 2 years of surveillance revealed continued retraction of the ablated tumor focus and no subsequent disease.
LESSONS: Alternatives to mutagenic therapies for brain tumors should be explored for patients with CPS. LITT paired with imaging surveillance is a logical strategy to ensure durable outcomes and mitigate treatment-related secondary neoplasms.

Keywords:  Li-Fraumeni syndrome; cancer predisposition; choroid plexus carcinoma; laser interstitial thermal therapy; pediatric

DOI:  https://doi.org/10.3171/CASE23595
J Immunother Precis Oncol. 2024 Feb;7(1): 7-17

Limited Independent Follow-Up with Germline Testing of Variants Detected in BRCA1 and BRCA2 by Tumor-Only Sequencing.

Carol J Nowlen, Molly Daniels, Burak Uzunparmak, Ecaterina E Ileana Dumbrava, Ying Yuan, Keyur P Patel, Nadine Rayes, Jacqueline Harkenrider, Chetna Wathoo, Jennifer Veazie, Krystle A Luna, Wanlin Wang, Chacha Horombe, Milind Javle, Jordi Rodon Ahnert, Timothy A Yap, Banu Arun, Karen H Lu, Funda Meric-Bernstam.

   Introduction: Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 (BRCA1/2) via tumor-only profiling, then determined the germline testing outcomes for those patients.
Methods: A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing.
Results: This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing.
Conclusion: Tumor-only testing is likely to identify P/LPVs in BRCA1/2. Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations.

Keywords:  BRCA1; BRCA2; germline testing; tumor-only testing

DOI:  https://doi.org/10.36401/JIPO-23-2
Int J Radiat Oncol Biol Phys. 2024 Feb 01. pii: S0360-3016(24)00249-9. [Epub ahead of print]

Frequency of radiotherapy-induced malignancies in Li-Fraumeni Syndrome patients with early-stage breast cancer and influence of the radiotherapy technique.

Vanessa Petry, Renata Colombo Bonadio, Karina Moutinho, Luiz Senna Leite, Laura Testa, Daniela J B Heinemann Cohn, Allyne Carneiro Cagnacci, Veronica Eh Kim, Maria Del Pilar Estevez-Diz, Maria Candida Barrisson Villares Fragoso.

   INTRODUCTION: Breast cancer (BC) is the most common malignancy in female patients with Li-Fraumeni Syndrome (LFS), a condition associated with an increased risk of various malignancies, including radiotherapy-induced malignancies (RIM) within previously irradiated areas. Our study aimed to assess the incidence of RIM in LFS patients with early-stage breast cancer (eBC) treated with adjuvant radiotherapy (RT), including the impact of RT dose and technique.
METHODS: We examined patients with a germline pathogenic/likely pathogenic TP53 variant diagnosed with eBC and monitored by a Hereditary Cancer Team at a single cancer center. The study endpoints included RIM frequency, the association of RIM with the dose and type of radiotherapy (2D RT, 3D RT, and IMRT), and BC recurrence.
RESULTS: We analyzed 48 patients with a median age of 39 years (range 21 - 62). A majority (71%) had the TP53 R337H variant, and 87% were unaware of their LFS diagnosis at the time of BC treatment. Treatment modalities included mastectomy (62%), (neo)adjuvant chemotherapy (66%), and RT (62%), with RT being more common after breast-conserving surgery (87% vs. 46% with mastectomy, P=0.010). Among the 30 patients treated with RT, 10% developed RIM in the irradiated field, consisting of three soft tissue malignancies. RT dose (≤40.8 or >40.8 Gy) did not influence RIM occurrence, but the type of RT did. RIM was observed in 100% of cases with 2D RT (2/2), 50% with IMRT (1/2), and 0% with 3D RT (0/16) (P=0.004).
CONCLUSION: Our study underscores a concerning rate of RIM following adjuvant RT, emphasizing the importance of a thorough risk-benefit evaluation before recommending RT, with preference for its avoidance if possible. Although subgroup sizes were limited, the risk of RIM appeared to be influenced by the RT technique, with higher rates observed with 2D RT and IMRT compared to 3D RT. Early TP53 testing is essential to guide the BC treatment plan.

Keywords:  Breast Cancer; Li-Fraumeni Syndrome; Radiotherapy; TP53

DOI:  https://doi.org/10.1016/j.ijrobp.2024.01.204