Germline TP53 Mutations Research Articles

Whole-body magnetic resonance imaging of Li-Fraumeni syndrome patients: observations from a two rounds screening of Brazilian patients

BackgroundLi-Fraumeni syndrome (LFS) is an autosomal dominant disease that is associated with germline TP53 mutations and it predisposes affected individuals to a high risk of developing multiple tumors. In Brazil, LFS is characterized by a different pattern of TP53 variants, with the founder TP53 p.R337H mutation being predominant. The adoption of screening strategies to diagnose LFS in its early stages is a major challenge due to the diverse spectrum of tumors that LFS patients can develop. The purpose of this study was to evaluate two rounds of whole-body magnetic resonance imaging (WB-MRI) which were conducted as a screening strategy for LFS patients.MethodsOver a 4-year period, 59 LFS patients underwent two rounds of WB-MRI. Each MRI was characterized as positive or negative, and positive cases were further investigated to establish a diagnosis. The parameters used to evaluate the WB-MRI results included: positive rate, number of invasive investigations of positive results, and cancer detection rate.ResultsA total of 118 WB-MRI scans were performed. Positive results were associated with 11 patients (9.3%). Seven of these patients (11.8%) were identified in the first round of screening and 4 patients (6.7%) were identified in the second round of screening. Biopsies were performed in three cases (2.5%), two (3.4%) after the first round of screening and one (1.7%) after the second round of screening. The histopathological results confirmed a diagnosis of cancer for all three cases. There was no indication of unnecessary invasive procedures.ConclusionsWB-MRI screening of LFS carriers diagnosed cancers in their early stages. When needed, positive results were further examined with non-invasive imaging techniques. False positive results were less frequent after the first round of WB-MRI screening.

Survival in males with glioma and gastric adenocarcinoma correlates with mutant p53 residual transcriptional activity.

There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant-specific residual transcriptional activity scores. Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4-3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7-5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7-3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8-2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. Canadian Institutes of Health Research (no. 148556).

Contribution of genotoxic anticancer treatments to the development of multiple primary tumours in the context of germline TP53 mutations

IntroductionLi-Fraumeni syndrome (LFS), due to TP53 germline mutations, is characterised by a remarkably high incidence of multiple primary cancers (MPCs), and the key role of p53 in response to DNA damage questions the contribution of anticancer treatments to MPCs development. Materials and methodsWe first evaluated genotoxicity of X-rays and different classes of conventional chemotherapies, thanks to genotoxicity assays, based on the measurement of transcriptional response to DNA damage and performed in murine splenocytes, either exposed ex vivo or extracted from exposed mice. We then exposed a total of 208 Trp53Δ/Δ, wt/Δ or wt/wt mice to clinical doses of X-rays or genotoxic or non-genotoxic chemotherapies. Tumour development was monitored using whole-body magnetic resonance imaging and pathological examination at death. Results:X-rays and conventional chemotherapies, except mitotic spindle poisons, were found to be genotoxic in both p53 genotoxicity assays. Exposition to X-rays and the topoisomerase inhibitor etoposide, analysed as genotoxic anticancer treatment, drastically increase the tumour development risk in Trp53Δ/Δ and wt/Δ mice (hazard ration [HR] = 4.4, 95% confidence interval [CI] [2.2–8.8], p < 0.001*** and HR = 4.7, 95% CI [2.4–9.3], p < 0.001***, respectively). In contrast, exposure to the non-genotoxic mitotic spindle poison, docetaxel, had no impact on tumour development. ConclusionsThis study shows that radiotherapy and genotoxic chemotherapies significantly increase the risk of tumour development in a LFS mice model. These results strongly support the contribution of genotoxic anticancer treatments to MPC development in LFS patients. Therefore, to reduce the risk of MPCs in germline TP53 mutation carriers, radiotherapy should be avoided whenever possible, surgical treatment prioritised, and non-genotoxic treatments considered.

A Systematic Review of How Young People Live with Inherited Disease: What Can We Learn for Li-Fraumeni Syndrome?

Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition caused by germline TP53 mutations, confers significant cancer risks for young people (15-39 years). Yet evidence of how individuals experience this condition and the psychosocial implications are lacking. Therefore, this systematic review assessed the psychosocial implications of living with, or at risk of, an autosomal dominant condition as a young person, to draw evidence that may be analogous for young people with LFS. We conducted a systematic search for studies published in peer-reviewed journals using Medline, CINAHL, PsycINFO, and Embase databases. Findings were synthesized and are reported thematically. We screened 352 articles and identified 39 studies, representing the perspectives of 765 young people. Most studies addressed hereditary breast and ovarian cancer (n = 22) and used qualitative methodologies (n = 35). Only one LFS study was identified, highlighting the distinct lack of psychosocial research describing experiences of young people with LFS. Translatable evidence showed that familial factors strongly influenced young people's experiences of genetic testing and their mutation status. Major adverse reactions to genetic test results were rare, although young people with a gene mutation experienced various psychosocial concerns at key developmental milestones, including family planning, developing romantic relationships, and making risk management decisions. Young people undergoing genetic testing for inherited disease require individualized support and recognition of previous lived experiences. We recommend that longitudinal care be made available to young people with inherited disease as they reach developmental milestones that intersect with risk management, risk perception, and family formation.

Abstract 3421: Genomic correlates of patient age in diffuse-type gastric cancer

Abstract Background: Gastric cancer is increasing in incidence among young white populations in the US. Gastric cancer in young patients is notable for its enrichment of diffuse histology as well as female predominance and aggressive clinical course, whereas gastric cancer is generally more frequent in males. Thus, clinicopathological characteristics of diffuse-type gastric cancer differ according to patient age, but the molecular mechanisms for early-onset gastric cancer's unique clinicopathological characteristics have not been elucidated. While the incidence of intestinal-type gastric cancer is decreasing worldwide, that of diffuse-type gastric cancer remained constant. Nonetheless, relatively small numbers of diffuse-type gastric cancers have been represented in whole exome sequencing studies such as TCGA project. We therefore investigated germline and somatic mutation profiles of diffuse-type gastric cancers with regards to patient age. Methods: We conducted whole exome and targeted sequencing and SNP6.0 array analyses of resected tumor tissue and blood samples collected from young (45 years old or younger) Korean patients with diffuse-type gastric cancer, and compared the genomic data with those from older Korean patients with diffuse-type gastric cancer. Genomic data of Korean diffuse-type gastric cancers were also compared with TCGA diffuse-type gastric cancers, 70% of which were from Caucasians. Results: Among 84 young Korean patients with DGC, 7 patients (8.3%) harbored germline mutations in TP53, CDH1, ATM, RAD51D, or PALB2. Three tumors with strong mutation signatures for inherited DNA repair defects harbored germline mutations in either RAD51D or PALB2, with loss-of-heterozygosity in the tumors. The most significant somatic mutations in young patients with diffuse gastric cancer were CDH1, TP53, ARID1A, KRAS, PIK3CA, ERBB3, TGFBR1, FBXW7, RHOA, and MAP2K1. Within the Korean population and within populations of other ethnicities, mutations in CDH1 (42.2%) or TGFBR1 (7.3%) were more frequent in younger patients than in older patients (17.4% and 0.9%, respectively). In contrast, the RHOA mutation (9.2%) was less frequent in younger patients than in older patients (19.1%). CDH1 alterations, but not RHOA mutations, were associated with poor prognosis (hazard ratio, 3.4 (95% CI, 1.5-7.7)), which may be associated with the aggressive clinical course of diffuse-type gastric cancers in young patients. Conclusions: Our largest-ever genomic analysis of diffuse-type gastric cancer reveals young age-specific mutation profiles (supported by National Cancer Center Grant 1710809 and Multi-omic Research Program). Citation Format: Hark K. Kim, Soo Y. Cho. Genomic correlates of patient age in diffuse-type gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3421.

Abstract 3389: Clonal evolution of atypical proliferative lesions into breast cancers

Abstract [Introduction] Non-malignant proliferative lesions in the breast have been implicated in the development of invasive breast cancer. Previous studies showed that adjacent atypical proliferative lesions and breast cancers shared common genetic alterations, suggesting that these evolved from the same ancestral cell. However, the clonal structure of atypical proliferative lesions and their clonal dynamics during progression to cancer are poorly understood. In this study, we compared genetic profiles of normal ducts, non-malignant proliferative lesions and cancers in the same patients to illustrate the clonal evolution of cancer from a non-malignant epithelial cell. [Methods] Multiple samples were collected from different atypical proliferative lesions within the cancer-borne breast, including invasive cancers, using micro-dissection from formalin-fixed, paraffin-embedded surgical specimens. Somatic mutations and copy number alterations (CNAs) were then evaluated by whole exome sequencing. [Results] A total of 34 samples from 5 premenopausal females carrying estrogen receptor-positive cancers were analyzed, where the samples were obtained from normal ducts (N = 6), non-atypical (N = 1) and atypical (N = 8) proliferative lesions, and invasive (N = 3) and non-invasive (N = 16) cancers. The number of somatic mutations per sample was ranging from 1 to 276 and increased with an elevation of atypical-level. Two cases with bilateral cancers had a pathogenic germline mutation of either BRCA2 and TP53, where no somatic mutations or CNAs were shared by individual proliferative lesions, suggesting multifocal independent cancerous evolutions. By contrast, in the remaining three unilateral cases, no pathogenic germline mutations were detected, but all proliferative lesions, which were separated by a distance of 7-25 mm, shared one or more driver alterations, such as an AKT1 mutation (UID: KU01), concurrent 1q gain and 16q loss (der(1;16)) (UID: KU02), and a GATA3 mutation and der(1;16) (UID: KU03), while harboring private mutations/CNAs of their own. The analysis of phylogenic trees based on the number of shared mutations predicted an early origin of these founder mutations, which frequently predated decades before the onset of cancer. [Conclusions] Early breast cancer development is thought to be shaped by the simultaneous evolution of multiple precancerous clones. It may be multi-focally initiated by a germline mutation, frequently terminated in bilateral cancers. Otherwise, in unilateral cases, cancer clones might be derived from a common ancestral clone, which has acquired a driver founder mutation long before the onset of cancer, and undergo independent evolution, giving rise to multiple proliferative lesions, from which invasive cancer finally evolves. Our findings provide unique insight into the early development of breast cancer. Citation Format: Tomomi Nishimura, Kenichi Yoshida, Yukiko Kawata, Yasuhide Takeuchi, Nobuyuki Kakiuchi, Yusuke Shiozawa, Kosuke Aoki, Masahiro Hirata, Tatsuki R. Kataoka, Takaki Sakurai, Yuichi Shiraishi, Kenichi Chiba, Kengo Takeuchi, Hironori Haga, Satoru Miyano, Masakazu Toi, Seishi Ogawa. Clonal evolution of atypical proliferative lesions into breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3389.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

New insights into the performance of multigene panel testing: Two novel nonsense variants in BRIP1 and TP53 in a young woman with breast cancer

Li-Fraumeni syndrome is an autosomal-dominant disorder caused by germline mutations in the tumour suppressor gene TP53. Here we report the case of a family whose index case was a woman diagnosed with bilateral breast cancer at the age of 18 and who had a non-informative result after BRCA1 and BRCA2 testing. After extending the study through multigene panel testing, two clinically relevant variants in the TP53 and BRIP1 genes, respectively, were found. Afterwards, the patient developed a glioblastoma. Both tumours were consistent with Li-Fraumeni syndrome. Thanks to the possibility of studying different genes related with hereditary breast and ovarian cancer, it was possible to find out the gene variant that caused the early onset cancers in the patient. Furthermore, genetic counselling was provided to the index case and her family.

Evaluation of whole body MRI for early detection of cancer in TP53 mutation carriers: Final results of the LIFSCREEN study.

1527Background: Li Fraumeni syndrome (LFS) is a rare cancer predisposition caused by TP53 germline mutation associated with a broad tumor spectrum making surveillance very complex. Whole body MRI (...

Germline mutation in the TP53 gene in uveal melanoma

We performed comprehensive molecular analysis of five cases of metastasizing uveal malignant melanoma (UM) (fresh-frozen samples) with an NGS panel of 73 genes. A likely pathogenic germline TP53 mutation c.760A > G (p.I254V) was found in two tumor samples and matched nontumor tissue. In three cases, pathogenic BAP1 mutation was detected together with germline missense variants of uncertain significance in ATM. All cases carried recurrent activating GNAQ or GNA11 mutation. Moreover, we analyzed samples from another 16 patients with primary UM by direct Sanger sequencing focusing only on TP53 coding region. No other germline TP53 mutation was detected in these samples. Germline TP53 mutation, usually associated with Li-Fraumeni syndrome, is a rare event in UM. To the best of our knowledge, only one family with germline TP53 mutation has previously been described. In our study, we detected TP53 mutation in two patients without known family relationship. The identification of germline aberrations in TP53 or BAP1 is important to identify patients with Li-Fraumeni syndrome or BAP1 cancer syndrome, which is also crucial for proper genetic counseling.

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

SummaryBackgroundMedulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.MethodsIn this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.FindingsWe included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40–69) and 5-year overall survival was 65% (95% CI 52–81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.InterpretationGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.FundingGerman Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

TP53 mutations and hematological malignancies

TP53 is a tumor-suppressor gene, and it is the most commonly mutated somatic gene in human cancer. Germline TP53 mutations correlate with a hereditary predisposition to cancer. Comprehensive genetic analysis revealed the role of germline and somatic TP53 gene mutations in hematological malignancies. TP53 mutations affect the prognosis and therapeutic decision-making. Hence, genetic screening and tumor surveillance, including family members, should be performed when a germline TP53 mutation is detected in a patient.

The first two confirmed sub-Saharan African families with germline TP53 mutations causing Li-Fraumeni syndrome.

Li-Fraumeni syndrome is a rare inherited cancer syndrome characterised by the early onset of specific cancers. Li-Fraumeni syndrome (LFS) is associated with germline mutations in the tumour suppressor gene, TP53. This study reports the first cases of molecularly confirmed LFS germline mutations in sub-Saharan Africa. Three black African patients, all with LFS-associated cancers, were seen through the Clinical and Counselling Section of the Division of Human Genetics at the National Health Laboratory Service and University of the Witwatersrand in Johannesburg, South Africa, during 2011-2012. All three patients (two were related) were recruited into this research study. Sequence analysis of the coding region of the TP53 gene identified a Class IV (likely pathogenic) variant, c.326T > C (p.Phe109Ser), in the two related patients, and a known pathogenic mutation, c.1010G > A (p.Arg337His), also referred to as the Brazilian founder mutation, in the other patient. A confirmed diagnosis in these patients will assist in tailored medical management (it is recommended that individuals carrying a germline TP53 mutation avoid radiotherapy as this might cause secondary radiotherapy-induced malignancies) and in addition, genetic testing of at-risk family members can be offered. Very little is known and documented on LFS in African individuals. Despite the small number of patients in this study, the results support the need for diagnostic genetic testing for LFS in South Africa.

Abstract IA02: Modeling sarcoma susceptibility: The Li-Fraumeni syndrome paradigm

Abstract The original description of Li-Fraumeni syndrome (LFS) 1969 was generated from the ascertainment of medical and death records of over 600 children with rhabdomyosarcoma. Although the clinical definition of LFS has evolved over the decades, the occurrence of sarcoma in at least one affected TP53 gene mutation carrier is common to many families. However, the genotype:cancer phenotype association of sarcomas in mutation carriers remains poorly understood. This lecture will review some of the phenotypic characterizations of sarcomas in LFS and explore recent exciting advances that suggest a role for various genetic/genomic and epigenetic modifiers of the underlying germline TP53 mutation in defining these clinical phenotypes. The challenges and opportunities to enhance early tumor detection and modify disease risk will also be discussed. Citation Format: David Malkin. Modeling sarcoma susceptibility: The Li-Fraumeni syndrome paradigm [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA02.

Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark.

IntroductionTP53 mutation carrier (Li-Fraumeni Syndrome, LFS) cohort studies often suffer from lack of extensive pedigree exploration.MethodsWe performed a nation-wide exploration of TP53 mutation carrier families identified through all clinical genetics departments in Denmark. Pedigrees were expanded and verified using unique national person identification, cancer, cause of death, pathology, and church registries.ResultsWe identified 30 confirmed, six obligate and 14 assumed carriers in 15 families harboring 14 different mutations, including five novel and three de novo germline mutations. All but two (96%) developed cancer by age 54 years [mean debut age; 29.1 y., median 33.0 y., n = 26 (17F, 9M), range 1–54 y]]. Cancer was the primary cause of all deaths [average age at death; 34.5 years]. Two tumors were identified through registry data alone. Two independent families harbored novel c.80delC mutations shown to be related through an ancestor born in 1907. This exhaustive national collection yielded markedly fewer TP53 mutation carriers than the 300–1,100 expected based on estimated background population frequencies.ConclusionGermline TP53 mutations in Denmark are likely to be drastically underdiagnosed despite their severe phenotype. Following recent advances in surveillance options of LFS patients, lack of pre-symptomatic testing may lead to the mismanagement of some individuals.

Revisiting tumor patterns and penetrance in germline TP53 mutation carriers: temporal phases of Li-Fraumeni syndrome.

Germline pathogenic TP53 mutation may predispose to multiple cancers but penetrance and cancer patterns remain incompletely documented. We have analyzed international agency for research on cancer TP53 database to reevaluate age and variant-dependent tumor patterns. Genome-wide studies suggest that germline variants are more frequent than estimated prevalence of Li-Fraumeni syndrome (LFS), suggesting that many carriers of potentially pathogenic mutations may not develop the syndrome. Carriers of a germline TP53 mutation who are detected in a clinical context have a penetrance of 80% at age 70. Penetrance varies according to age, sex and mutation type. Temporal tumor patterns show distinct phases, with childhood phase (0-15 years, 22% of all cancers) characterized by adrenal cortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma and medulloblastoma; early adulthood phase (16-50 years, 51%) including breast cancer, osteosarcoma, soft tissue sarcomas, leukemia, astrocytoma and glioblastoma, colorectal and lung cancer; late adulthood phase (51-80 years, 27%) including pancreatic and prostate cancer. Germline pathogenic variants in TP53 gene have different consequences according to cell, tissue, context and age. The occurrence of frequent variants in patients with no criteria suggestive of LFS calls for attention in predicting individual risk and highlights the need of additional predictors for assigning carriers to appropriate surveillance programs.

MA 06.08 Lung Cancer Patients with Germline Mutation: A Retrospective Study

Genetic testing for alterations of oncogenic driver genes has become essential and standard in clinical practice. Germline mutations predisposing to lung cancer are rare, but there have been reports regarding germline mutations in EGFR, HER2, BRCA2, CDKN2A, BAP1, SFTPA2, and PARK2. Next generation sequencing is being introduced to clinical practice of lung cancer, enabling investigation of multiple oncogenic driver genes simultaneously. In addition, liquid biopsy, which analyzes cell free DNA in blood, increases the opportunity to detect germline mutations in lung cancer patients. We examined the frequency and characteristics of lung cancer patients with germline mutations. Between February 2012 and January 2017, 3,869 patients with a diagnosis of lung cancer were seen by Division of Medical Oncology in Ohio State University. Of these, seven were found to have germline mutations. The patient characteristics and treatment outcomes were retrospectively investigated. Table 1 shows characteristics and treatment outcomes of the seven lung cancer patients with germline mutations. Median age was 50 (range, 34-72). Three had BRCA2 germline mutations, two had germline TP53 mutations (of which one patient also had a PARK2 mutation), one had a BRCA1 mutation, and one had an EGFR mutation. Testing for other oncogenic drivers were done in five patients, and interestingly, four patients had oncogenic driver mutations. The frequency of detecting germline mutations in lung cancer patients has been increasing in recent years, but is often unrecognized by providers. In our series, one patient was found to have a germline mutation by Foundation ONE, and another was found to have a germline mutation by Foundation ACT. Introduction of next generation sequencing technology and liquid biopsies to clinical practice can raise the probability of detecting germline mutations in lung cancer patients. Clinicians should be alert to the potential existence and importance of germline mutations in their lung cancer patients.

Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome

BackgroundDevelopment of tumours such as adrenocortical carcinomas (ACC), choroid plexus tumours (CPT) or female breast cancers before age 31 or multiple primary cancers belonging to the Li-Fraumeni (LFS) spectrum is,...

Genomic analysis of the origins and evolution of multicentric diffuse lower-grade gliomas

Rare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution. In this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions. One patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second. Each tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Identification of Clinical and Biologic Correlates Associated With Outcome in Children With Adrenocortical Tumors Without Germline TP53 Mutations: A St Jude Adrenocortical Tumor Registry and Children's Oncology Group Study.

Purpose The clinical features, pathogenesis, and outcomes in children with adrenocortical tumors (ACTs) without germline TP53 mutations have not been systematically studied. Herein, we describe these correlates and analyze their association with outcome. Patients and Methods Genomic DNA was analyzed for TP53, CTNNB1, CDKN1C, ATRX, and chromosome 11p15 abnormalities. β-catenin expression and Ki-67 labeling index (LI) were evaluated by immunostaining. Primary end points were progression-free (PFS) and overall survival. Results Median age of 42 girls and 18 boys was 3.3 years (range, 0.25 to 21.7 years). Complete resection (stages I and II) was achieved in 32 patients, and 28 patients had stage III or IV disease. Constitutional abnormalities of chromosome 11p15 occurred in nine of 40 patients, with six patients not showing phenotype of Beckwith-Wiedemann syndrome. Three-year PFS and overall survival for all patients were 71.4% and 80.5%, respectively. In single-predictor Cox regression analysis, age, disease stage, tumor weight, somatic TP53 mutations, and Ki-67 LI were associated with prognosis. Ki-67 LI and age remained significantly associated with PFS after adjusting for stage and tumor weight. Three-year PFS for 27 patients with Ki-67 LI ≥ 15% was 48.5% compared with 96.2% for 29 patients with Ki-67 LI < 15% (log-rank P = .002), and the rate of relapse increased by 24% with each 1-year increase in age at diagnosis (hazard ratio, 1.24; P = .0057). Conclusion Clinicopathologic features and outcomes of children with ACTs without germline TP53 mutations overlapped those reported for children with germline TP53 mutations. Our findings highlight the central role of genetic or epigenetic alterations on chromosome 11p15 in pediatric ACTs. Ki-67 LI is a strong prognostic indicator and should be investigated to improve the histologic classification of pediatric ACTs.