bims-lifras 2024-05-19 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–05–19
nine papers selected by
Joanna Zawacka, Karolinska Institutet

Rare germline structural variants increase risk for pediatric solid tumors.
Mutant p53 reactivation restricts the protumorigenic consequences of wild type p53 loss of heterozygosity in Li-Fraumeni syndrome patient-derived fibroblasts.
A de novo germline RUNX1 variant preceding development of concurrent T-lymphoblastic leukemia and myelodysplastic syndrome.
Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome.
Gastrointestinal Cancer Precursor Conditions and Their Detection.
Expanding access to genetic testing for pancreatic cancer.
Germline Genetic Mutations in Adult Patients with Sarcoma: Insight into the Middle East Genetic Landscape.
Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.
Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

bioRxiv. 2024 Apr 29. pii: 2024.04.27.591484. [Epub ahead of print]

Rare germline structural variants increase risk for pediatric solid tumors.

Riaz Gillani, Ryan L Collins, Jett Crowdis, Amanda Garza, Jill K Jones, Mark Walker, Alba Sanchis-Juan, Chris Whelan, Emma Pierce-Hoffman, Michael Talkowski, Harrison Brand, Kevin Haigis, Jaclyn LoPiccolo, Saud H AlDubayan, Alexander Gusev, Brian D Crompton, Katie A Janeway, Eliezer M Van Allen.

Pediatric solid tumors are rare malignancies that represent a leading cause of death by disease among children in developed countries. The early age-of-onset of these tumors suggests that germline genetic factors are involved, yet conventional germline testing for short coding variants in established predisposition genes only identifies pathogenic events in 10-15% of patients. Here, we examined the role of germline structural variants (SVs)-an underexplored form of germline variation-in pediatric extracranial solid tumors using germline genome sequencing of 1,766 affected children, their 943 unaffected relatives, and 6,665 adult controls. We discovered a sex-biased association between very large (>1 megabase) germline chromosomal abnormalities and a four-fold increased risk of solid tumors in male children. The overall impact of germline SVs was greatest in neuroblastoma, where we revealed burdens of ultra-rare SVs that cause loss-of-function of highly expressed, mutationally intolerant, neurodevelopmental genes, as well as noncoding SVs predicted to disrupt three-dimensional chromatin domains in neural crest-derived tissues. Collectively, our results implicate rare germline SVs as a predisposing factor to pediatric solid tumors that may guide future studies and clinical practice.

DOI: https://doi.org/10.1101/2024.04.27.591484
Cell Death Differ. 2024 May 14.

Mutant p53 reactivation restricts the protumorigenic consequences of wild type p53 loss of heterozygosity in Li-Fraumeni syndrome patient-derived fibroblasts.

Himanshi Agarwal, Perry Tal, Naomi Goldfinger, Esita Chattopadhyay, David Malkin, Varda Rotter, Ayush Attery.

The p53 tumor suppressor, encoded by the TP53 gene, serves as a major barrier against malignant transformation. Patients with Li-Fraumeni syndrome (LFS) inherit a mutated TP53 allele from one parent and a wild-type TP53 allele from the other. Subsequently, the wild-type allele is lost and only the mutant TP53 allele remains. This process, which is termed loss of heterozygosity (LOH), results in only mutant p53 protein expression. We used primary dermal fibroblasts from LFS patients carrying the hotspot p53 gain-of-function pathogenic variant, R248Q to study the LOH process and characterize alterations in various pathways before and after LOH. We previously described the derivation of mutant p53 reactivating peptides, designated pCAPs (p53 Conformation Activating Peptides). In this study, we tested the effect of lead peptide pCAP-250 on LOH and on its associated cellular changes. We report that treatment of LFS fibroblasts with pCAP-250 prevents the accumulation of mutant p53 protein, inhibits LOH, and alleviates its cellular consequences. Furthermore, prolonged treatment with pCAP-250 significantly reduces DNA damage and restores long-term genomic stability. pCAPs may thus be contemplated as a potential preventive treatment to prevent or delay early onset cancer in carriers of mutant p53.

DOI: https://doi.org/10.1038/s41418-024-01307-4
Leuk Lymphoma. 2024 May 11. 1-5

A de novo germline RUNX1 variant preceding development of concurrent T-lymphoblastic leukemia and myelodysplastic syndrome.

Cassandra P Wang, Juanita E Ferreira, Alexander Placek, Paibel Aguayo-Hiraldo, Gordana Raca, Brent L Wood, Karin P Miller, Thomas Coates, David R Freyer, Alexandra E Kovach.

  Germline variants of the RUNX1 gene are associated with RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (RUNX1-FPDMM), which is characterized by an increased risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. Patients with FPDMM have also been described to develop B- or T-cell acute lymphoblastic leukemia. We present a pediatric patient with RUNX1-FPDMM that evolved into concurrent MDS and T-cell acute lymphoblastic leukemia after a decade of monitoring with serial blood counts. We aim to highlight the treatment challenges and clinical decision-making that may be anticipated in this unique disorder, as well as the potentially curative role for allogenic hematopoietic stem cell transplant in the first complete remission.

Keywords:  MDS; RUNX1 variant; T-ALL

DOI:  https://doi.org/10.1080/10428194.2024.2347577
JAMA Dermatol. 2024 May 17.

Multiple Onychopapillomas and BAP1 Tumor Predisposition Syndrome.

Alexandra Lebensohn, Azam Ghafoor, Luke Bloomquist, Michael C Royer, Leslie Castelo-Soccio, Kelli Karacki, Olanda Hathaway, Tenin Maglo, Cathy Wagner, Maria G Agra, Andrew M Blakely, David S Schrump, Raffit Hassan, Edward W Cowen.

Importance: BRCA1-associated protein (BAP1) tumor predisposition syndrome (TPDS) is a cancer genodermatosis associated with high risk of uveal and cutaneous melanoma, basal cell carcinoma, and multiple internal malignant neoplasms, including mesothelioma and renal cell carcinoma. Early detection of the syndrome is important for cancer surveillance and genetic counseling of family members who are at risk.
Objective: To determine the prevalence of nail abnormalities in individuals with pathogenic germline variants in BAP1.
Design, Setting, and Participants: In this prospective cohort study, individuals who were known carriers of pathogenic BAP1 germline variants were consecutively enrolled between October 10, 2023, and March 15, 2024. Dermatologic evaluation for nail abnormalities was performed, including a history of nail abnormalities and associated symptoms, physical examination, medical photography, and nail biopsy for histopathology. This was a single-center study conducted at the National Institutes of Health Clinical Center.
Main Outcomes and Measures: Primary outcomes were the prevalence and spectrum of nail changes and histopathologic characterization.
Results: Among 47 participants (30 female [63.8%]; mean [SD] age, 46.4 [15.1] years) ranging in age from 13 to 72 years from 35 families, nail abnormalities were detected in 41 patients (87.2%) and included leukonychia, splinter hemorrhage, onychoschizia, and distal nail hyperkeratosis. Clinical findings consistent with onychopapilloma were detected in 39 patients (83.0%), including 35 of 40 individuals aged 30 years or older (87.5%). Nail bed biopsy was performed in 5 patients and was consistent with onychopapilloma. Polydactylous involvement with onychopapillomas was detected in nearly all patients who had nail involvement (38 of 39 patients [97.4%]).
Conclusions and Relevance: This study found that BAP1 TPDS was associated with a high rate of nail abnormalities consistent with onychopapillomas in adult carriers of the disease. Findings suggest that this novel cutaneous sign may facilitate detection of the syndrome in family members who are at risk and patients with cancers associated with BAP1 given that multiple onychopapillomas are uncommon in the general population and may be a distinct clue to the presence of a pathogenic germline variant in the BAP1 gene.

DOI: https://doi.org/10.1001/jamadermatol.2024.1804
Hematol Oncol Clin North Am. 2024 May 16. pii: S0889-8588(24)00044-3. [Epub ahead of print]

Gastrointestinal Cancer Precursor Conditions and Their Detection.

Asaf Maoz, Nicolette J Rodriguez, Matthew B Yurgelun, Sapna Syngal.

  Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

Keywords:  CDH1; Cancer detection; Cancer prevention; Hereditary pancreatic cancer; Lynch syndrome; Polyposis

DOI:  https://doi.org/10.1016/j.hoc.2024.04.002
Fam Cancer. 2024 May 11.

Expanding access to genetic testing for pancreatic cancer.

Nicolette Juliana Rodriguez, Sapna Syngal.

  Among individuals with pancreatic ductal adenocarcinoma (PDAC) 5-10% have a pathogenic germline variant (PGV) in a PDAC susceptibility gene. Guidelines recommend genetic testing among all individuals with PDAC. Additionally, at-risk relatives of PDAC patients benefit from their own genetic education, risk assessment, and testing. Multigene panel testing (MGPT) can identify individuals with inherited cancer risk who can benefit from early cancer surveillance and risk reduction strategies. This manuscript discusses various healthcare delivery models for MGPT including traditional in-person genetic counseling, novel integrated in-person infrastructures, telemedicine genetics care via telephone- or video-visits and direct-to-consumer testing. Barriers and facilitators to care on the individual, provider, and system level are also outlined including specific considerations for historically marginalized communities.

Keywords:  Disparities to cancer genetics care; Genetic testing; Healthcare delivery models; Pancreatic cancer; Remote genetics care

DOI:  https://doi.org/10.1007/s10689-024-00389-w
Cancers (Basel). 2024 Apr 25. pii: 1668. [Epub ahead of print]16(9):

Germline Genetic Mutations in Adult Patients with Sarcoma: Insight into the Middle East Genetic Landscape.

Ramiz Abu-Hijlih, Baha Sharaf, Samer Salah, Hira Bani Hani, Mohammad Alqaisieh, Abdulla Alzibdeh, Layan Ababneh, Suleiman Mahafdah, Hikmat Abdel-Razeq.

  Data on germline mutations in soft tissue and bone sarcomas are scarce. We sought to identify the prevalence of germline mutations in adult sarcoma patients treated at a tertiary cancer center. Newly diagnosed patients were offered germline genetic testing via an 84-gene panel. The prevalence of pathogenic germline variants (PGVs) and their association with disease-, and patient- related factors are reported. A total of 87 patients were enrolled, the median age was 48 (19-78) years, and 47 (54%) were females. Gastrointestinal stromal tumors (n = 12, 13.8%), liposarcoma (n = 10, 11.5%), and Ewing sarcoma (n = 10, 11.5%) were the main subtypes. A total of 20 PGVs were detected in 18 (20.7%) patients. Variants of uncertain significance, in the absence of PGVs, were detected in 40 (45.9%) patients. Young age (p = 0.031), presence of a second primary cancer (p = 0.019), and female gender (p = 0.042) were correlated with the presence of PGVs. All identified PGVs have potential clinical actionability and cascade testing, and eight (44.44%) suggested eligibility for a targeted therapy. Almost one in five adult patients with soft tissue and bone sarcomas harbor pathogenic or likely pathogenic variants. Many of these variants are potentially actionable, and almost all have implications on cancer screening and family counselling. In this cohort from the Middle East, younger age, presence of a second primary tumor, and female gender were significantly associated with higher PGVs rates. Larger studies able to correlate treatment outcomes with genetic variants are highly needed.

Keywords:  osteosarcoma; pathogenic germline variants; sarcoma; soft tissue sarcoma

DOI:  https://doi.org/10.3390/cancers16091668
J Transl Med. 2024 May 15. 22(1): 462

Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort.

I Vanni, L Pastorino, V Andreotti, D Comandini, G Fornarini, M Grassi, A Puccini, E T Tanda, A Pastorino, V Martelli, L Mastracci, F Grillo, F Cabiddu, A Guadagno, S Coco, E Allavena, F Barbero, W Bruno, B Dalmasso, S E Bellomo, C Marchiò, F Spagnolo, S Sciallero, E Berrino, P Ghiorzo.

   BACKGROUND: Comprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling.
METHODS: Seventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification.
RESULTS: The overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1, VHL, CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition.
CONCLUSIONS: Our study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

Keywords:  Circulating cell-free DNA; Clinically actionable variants; Droplet digital pcr (ddPCR); Germline pathogenic variants; Next-generation sequencing; Targeted therapy

DOI:  https://doi.org/10.1186/s12967-024-05227-2
J Clin Oncol. 2024 May 17. JCO2400662

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

Nadine Tung, Charité Ricker, Hans Messersmith, Judith Balmaña, Susan Domchek, Elena Martinez Stoffel, Khaldoun Almhanna, Banu Arun, Yanin Chavarri-Guerra, Stephanie A Cohen, Deborah Cragun, Katherine D Crew, Michael J Hall, Gregory Idos, Ghecemy Lopez, Tuya Pal, Sara Pirzadeh-Miller, Colin Pritchard, Huma Q Rana, Umang Swami, Gregory A Vidal.

PURPOSE: To guide use of multigene panels for germline genetic testing for patients with cancer.
METHODS: An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing.
RESULTS: Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4.
RECOMMENDATIONS: Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

DOI: https://doi.org/10.1200/JCO.24.00662