TP53, a gene for colorectal cancer predisposition in the absence of Li-Fraumeni-associated phenotypes

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321825
Author(s):  
Mariona Terradas ◽  
Pilar Mur ◽  
Sami Belhadj ◽  
Emma R Woodward ◽  
George J Burghel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
International Agency ◽  
Loss Of Function ◽  
Total N ◽  
Li Fraumeni Syndrome ◽  
Clinical Criteria ◽  
Panel Testing ◽  
Background Population ◽  
Li Fraumeni

ObjectiveGermline TP53 pathogenic (P) variants cause Li-Fraumeni syndrome (LFS), an aggressive multitumor-predisposing condition. Due to the implementation of multigene panel testing, TP53 variants have been detected in individuals without LFS suspicion, for example, patients with colorectal cancer (CRC). We aimed to decipher whether these findings are the result of detecting the background population prevalence or the aetiological basis of CRC.DesignWe analysed TP53 in 473 familial/early-onset CRC cases and evaluated the results together with five additional studies performed in patients with CRC (total n=6200). Control population and LFS data were obtained from Genome Aggregation Database (gnomAD V.2.1.1) and the International Agency for Research on Cancer (IARC) TP53 database, respectively. All variants were reclassified according to the guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP), following the ClinGen TP53 Expert Panel specifications.ResultsP or likely pathogenic (LP) variants were identified in 0.05% of controls (n=27/59 095) and 0.26% of patients with CRC (n=16/6200) (p<0.0001) (OR=5.7, 95% CI 2.8 to 10.9), none of whom fulfilled the clinical criteria established for TP53 testing. This association was still detected when patients with CRC diagnosed at more advanced ages (>50 and>60 years) were excluded from the analysis to minimise the inclusion of variants caused by clonal haematopoiesis. Loss-of-function and missense variants were strongly associated with CRC as compared with controls (OR=25.44, 95% CI 6.10 to 149.03, for loss of function and splice-site alleles, and OR=3.58, 95% CI 1.46 to 7.98, for missense P or LP variants).ConclusionTP53 P variants should not be unequivocally associated with LFS. Prospective follow-up of carriers of germline TP53 P variants in the absence of LFS phenotypes will define how surveillance and clinical management of these individuals should be performed.

Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers

2015 ◽  
Vol 33 (21) ◽  
pp. 2345-2352 ◽  
Author(s):  
Gaëlle Bougeard ◽  
Mariette Renaux-Petel ◽  
Jean-Michel Flaman ◽  
Camille Charbonnier ◽  
Pierre Fermey ◽  
...  
Keyword(s):  
Tp53 Mutation ◽  
Soft Tissue Sarcomas ◽  
Dominant Negative ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Li Fraumeni Syndrome ◽  
Tumor Onset ◽  
Mutation Carriers ◽  
The Mean ◽  
Li Fraumeni

Purpose The aim of the study was to update the description of Li-Fraumeni syndrome (LFS), a remarkable cancer predisposition characterized by extensive clinical heterogeneity. Patients and Methods From 1,730 French patients suggestive of LFS, we identified 415 mutation carriers in 214 families harboring 133 distinct TP53 alterations and updated their clinical presentation. Results The 322 affected carriers developed 552 tumors, and 43% had developed multiple malignancies. The mean age of first tumor onset was 24.9 years, 41% having developed a tumor by age 18. In childhood, the LFS tumor spectrum was characterized by osteosarcomas, adrenocortical carcinomas (ACC), CNS tumors, and soft tissue sarcomas (STS) observed in 30%, 27%, 26%, and 23% of the patients, respectively. In adults, the tumor distribution was characterized by the predominance of breast carcinomas observed in 79% of the females, and STS observed in 27% of the patients. The TP53 mutation detection rate in children presenting with ACC or choroid plexus carcinomas, and in females with breast cancer before age 31 years, without additional features indicative of LFS, was 45%, 42% and 6%, respectively. The mean age of tumor onset was statistically different (P < .05) between carriers harboring dominant-negative missense mutations (21.3 years) and those with all types of loss of function mutations (28.5 years) or genomic rearrangements (35.8 years). Affected children, except those with ACC, harbored mostly dominant-negative missense mutations. Conclusion The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

scholarly journals Evaluation of TP53 Variants Detected on Peripheral Blood or Saliva Testing: Discerning Germline From Somatic TP53 Variants

2021 ◽  
pp. 1677-1686
Author(s):  
Alison N. Schwartz ◽  
Sophie R. Hyman ◽  
Samantha M. Stokes ◽  
Danielle Castillo ◽  
Nadine M. Tung ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Cancer Genetics ◽  
Hematologic Malignancy ◽  
Clonal Expansion ◽  
Somatic Tissue ◽  
Ancillary Data ◽  
Germline Variants ◽  
Li Fraumeni Syndrome ◽  
Panel Testing ◽  
Li Fraumeni

PURPOSE Multigene panel testing (MGPT) identifies TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes, of which only one is classic Li-Fraumeni syndrome. Low variant allelic fraction (VAF) in TP53 found on germline testing may suggest aberrant clonal expansion or constitutional mosaicism. We evaluated TP53-positive probands seen in a cancer genetics program to determine germline versus somatic status. METHODS We reviewed TP53-positive probands from 2012 to 2019 identified by MGPT on blood or saliva (N = 84). Available VAFs were collected. Probands with a familial variant, who met Li-Fraumeni syndrome testing criteria or who carried a founder variant, were considered germline. For those with uncertain germline status, TP53 variants were further examined using ancillary data of family members and somatic tissue. RESULTS Of the 84 probands, 54.7% had germline variants with 33.3% meeting criteria for germline status and 21.4% confirmed through ancillary testing. Aberrant clonal expansion comprised 13.1% with clonal hematopoiesis of indeterminate potential and 2.4% with a hematologic malignancy. Constitutional mosaicism was confirmed in 8.3% probands. Definitive status could not be determined in 3.6% despite ancillary assessment, and 17.9% did not have ancillary testing. CONCLUSION A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, approximately half of the patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism require intensified surveillance. A framework of multiple strategies enables discernment of germline from constitutional mosaic and acquired variants, which is essential for appropriate management.

Nearly half of TP53 variants are misattributed to Li-Fraumeni syndrome: A clinical evaluation of individuals with TP53 variants detected by hereditary cancer panel assays on blood or saliva.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10501-10501
Author(s):  
Alison Schwartz ◽  
Sophie Hyman ◽  
Samantha Stokes ◽  
Danielle Castillo ◽  
Jeffrey N. Weitzel ◽  
...  
Keyword(s):  
Cancer Genetics ◽  
Hematologic Malignancy ◽  
Tissue Samples ◽  
Cultured Fibroblasts ◽  
Li Fraumeni Syndrome ◽  
Panel Testing ◽  
Cultured Skin ◽  
Somatic Status ◽  
Li Fraumeni ◽  
Status Data

10501 Background: Multigene panel testing (MGPT) has identified TP53 pathogenic or likely pathogenic (P/LP) variants in patients with diverse phenotypes from no cancer to classic Li-Fraumeni syndrome (LFS). There is increasing recognition of variants at low allelic fraction (VAF) for TP53 in particular, which can be suggestive of post-zygotic mosaicism or aberrant clonal expansion (ACE), comprising clonal hematopoiesis of indeterminate potential (CHIP) or occult hematologic neoplasia. Distinguishing among these categories is essential because of widely different cancer risk and management implications for patients and their relatives. We report an evaluation of TP53 positive probands to determine germline versus somatic status from a cancer genetics clinic. Methods: We reviewed probands with TP53 P/LP variants by MGPT on blood (N = 83) or saliva (N = 1) samples from 2012-2019. Available VAFs were collected from commercial testing laboratories. Probands positive for a known familial variant, who met LFS testing criteria without indication of low VAF, or who carried the Brazil founder p.R337H variant were considered germline. For those with uncertain germline status, data was obtained from ancillary testing of family members, cultured skin fibroblasts, and other somatic benign or tumor tissues. TP53 variants were further categorized based on all available data. Results: Of the 84 probands, 28 (33%) had germline TP53 P/LP variants determined by above initial criteria; 18 (21%) were confirmed germline through ancillary testing. Seven (8%) individuals were classified as having constitutional mosaicism. In eleven (13%) individuals, the TP53 variants were consistent with ACE, in 9 (11%) with CHIP and in 2 (2%) with a hematologic malignancy (1 CLL, 1 NHL). Five (6%) cases could not be categorized despite ancillary testing. Fifteen (18%) probands declined any further workup. Conclusions: A TP53 P/LP variant found on peripheral blood or saliva MGPT does not always originate in the germline. In a clinical cancer genetics cohort, only 54% of patients had TP53 P/LP germline variants; these patients plus those with constitutional mosaicism (8%) require intensified surveillance. Assessment of VAF, family member testing, and analysis of TP53 in cultured fibroblasts or other tissue samples may distinguish germline and constitutional mosaic variants from the ACE spectrum. Expanding use of MGPT will increase this clinical challenge, which may motivate the modification of lab reports to include VAF and possible non-germline explanations. The findings of this study support a framework of multiple strategies to discern true constitutional status of a TP53 P/LP variant.

Prevalence of Early Onset Colorectal Cancer in 397 Patients With Classic Li–Fraumeni Syndrome

2006 ◽  
Vol 130 (1) ◽  
pp. 73-79 ◽  
Author(s):  
Patricia Wong ◽  
Sigitas J. Verselis ◽  
Judy E. Garber ◽  
Katherine Schneider ◽  
Lisa DiGianni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Early Onset ◽  
Li Fraumeni Syndrome ◽  
Li Fraumeni ◽  
Early Onset Colorectal Cancer

scholarly journals Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome

2021 ◽  
pp. 1141-1150
Author(s):  
Renata Lazari Sandoval ◽  
Cibele Masotti ◽  
Mariana Petaccia de Macedo ◽  
Maurício Fernando Silva Almeida Ribeiro ◽  
Ana Carolina Rathsam Leite ◽  
...  
Keyword(s):  
Founder Mutation ◽  
Care Center ◽  
Tertiary Care ◽  
Brazilian Population ◽  
Genomic Profiling ◽  
Li Fraumeni Syndrome ◽  
Clinical Criteria ◽  
Worldwide Population ◽  
Li Fraumeni ◽  
Germline Testing

PURPOSE Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer. MATERIALS AND METHODS We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil. RESULTS The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria. CONCLUSION The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

Gliomas in the context of Li-Fraumeni syndrome: An international cohort.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1517-1517
Author(s):  
Orli Michaeli ◽  
Uri Tabori ◽  
Joshua David Schiffman ◽  
Anne Naumer ◽  
Wendy Kohlmann ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Tp53 Mutation ◽  
Close Relative ◽  
Low Grade ◽  
Free Survival ◽  
Li Fraumeni Syndrome ◽  
Mutation Carriers ◽  
History Of ◽  
Li Fraumeni

1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age < 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.

Primary Orbital Liposarcoma in Li-Fraumeni Cancer Family Syndrome: A Case Report

2005 ◽  
Vol 91 (1) ◽  
pp. 96-100 ◽  
Author(s):  
Tito Poli ◽  
Francesco Laganà ◽  
Luigi Caradonna ◽  
Roberta Gobbi ◽  
Domenico Corradi ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Genetic Disorder ◽  
Molecular Profile ◽  
Prognostic Information ◽  
Upper Eyelid ◽  
Li Fraumeni Syndrome ◽  
Clinical Criteria ◽  
Li Fraumeni ◽  
Cellular Markers ◽  
The Right

Aims and background The aim of this study was to describe a case of primary orbital liposarcoma in Li-Fraumeni syndrome. Methods and study design In July 1998 a 20-year-old woman with a histological diagnosis of orbital myxoid liposarcoma underwent surgical treatment in our department. Since the patient's family pedigree met the clinical criteria for the diagnosis of LFS, molecular analysis was performed, which resulted in a molecular profile consistent with Li-Fraumeni syndrome. Results The patient underwent orbital exenteration extended to the upper eyelid; surgical reconstructive steps were performed to permit placement of an orbital prosthesis. Two years after primary surgery the patient underwent a quadrantectomy with lymphadenectomy of the right axilla because of the presence of a nodule of 1.5 cm in diameter in the upper-lateral quadrant of the right breast. One year after the last surgery, the patient is disease free. Conclusion The diagnosis of an orbital malignancy in a young patient with a family history of cancer should suggest the presence of an underlying genetic disorder like LFS; with molecular analysis we can now determine the genetic disorder and the exact location of the mutation, and also obtain important prognostic data using specific cellular markers. More prognostic information increases the chances of adequate personalized treatment.

scholarly journals TP53 Germline Variations Influence the Predisposition and Prognosis of B-Cell Acute Lymphoblastic Leukemia in Children

2018 ◽  
Vol 36 (6) ◽  
pp. 591-599 ◽  
Author(s):  
Maoxiang Qian ◽  
Xueyuan Cao ◽  
Meenakshi Devidas ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Outcomes ◽  
Lymphoblastic Leukemia ◽  
Malignant Neoplasms ◽  
Loss Of Function ◽  
Childhood All ◽  
Li Fraumeni Syndrome ◽  
Pathogenic Variants ◽  
Second Malignant Neoplasms ◽  
Li Fraumeni

Purpose Germline TP53 variation is the genetic basis of Li-Fraumeni syndrome, a highly penetrant cancer predisposition condition. Recent reports of germline TP53 variants in childhood hypodiploid acute lymphoblastic leukemia (ALL) suggest that this type of leukemia is another manifestation of Li-Fraumeni syndrome; however, the pattern, prevalence, and clinical relevance of TP53 variants in childhood ALL remain unknown. Patients and Methods Targeted sequencing of TP53 coding regions was performed in 3,801 children from the Children’s Oncology Group frontline ALL clinical trials, AALL0232 and P9900. TP53 variant pathogenicity was evaluated according to experimentally determined transcriptional activity, in silico prediction of damaging effects, and prevalence in non-ALL control populations. TP53 variants were analyzed for their association with ALL presenting features and treatment outcomes. Results We identified 49 unique nonsilent rare TP53 coding variants in 77 (2.0%) of 3,801 patients sequenced, of which 22 variants were classified as pathogenic. TP53 pathogenic variants were significantly over-represented in ALL compared with non-ALL controls (odds ratio, 5.2; P < .001). Children with TP53 pathogenic variants were significantly older at ALL diagnosis (median age, 15.5 years v 7.3 years; P < .001) and were more likely to have hypodiploid ALL (65.4% v 1.2%; P < .001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival and overall survival (hazard ratio, 4.2 and 3.9; P < .001 and .001, respectively). In particular, children with TP53 pathogenic variants were at a dramatically higher risk of second cancers than those without pathogenic variants, with 5-year cumulative incidence of 25.1% and 0.7% ( P < .001), respectively. Conclusion Loss-of-function germline TP53 variants predispose children to ALL and to adverse treatment outcomes with ALL therapy, particularly the risk of second malignant neoplasms.

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