Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting ...in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype–phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants.
This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975–2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468.
Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9–26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9–13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% 95% CI 19·6–30·5 vs 50·4% 43·5–56·5 by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence.
This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals.
Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.
Li-Fraumeni syndrome (LFS), linked to heterozygous germline pathogenic/likely pathogenic variants in TP53, confers exceptionally high cancer risk, including core cancers (sarcoma, breast, ...adrenocortical, and brain cancer) among many other cancer types.
Colorectal cancer (CRC) is most common after the core and hematologic cancers, accounting for ∼2.8% of diagnoses. Stomach and esophageal cancers constitute another 1.3% (TP53 Database; R20, July 2019: https://tp53.isb-cgc.org).
.
IMPORTANCE: Knowledge about the prevalence and tumor types of CDKN2A-related melanoma-astrocytoma syndrome (MAS) is limited and could improve disease recognition. OBJECTIVE: To estimate the ...prevalence and describe the tumor types of MAS. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study analyzed all available MAS cases from medical centers in the US (2 sites) and Europe (2 sites) and from biomedical population genomic databases (UK Biobank United Kingdom, Geisinger MyCode US) between January 1, 1976, and December 31, 2020. Patients with MAS with CDKN2A germline pathogenic variants and 1 or more neural tumors were included. Data were analyzed from June 1, 2022, to January 31, 2023. MAIN OUTCOMES AND MEASURES: Disease prevalence and tumor frequency. RESULTS: Prevalence of MAS ranged from 1 in 170 503 (n = 1 case; 95% CI, 1:30 098-1:965 887) in Geisinger MyCode (n = 170 503; mean SD age, 58.9 19.1 years; 60.6% women; 96.2% White) to 1 in 39 149 (n = 12 cases; 95% CI, 1:22 396-1:68 434) in UK Biobank (n = 469 789; mean SD age, 70.0 8.0 years; 54.2% women; 94.8% White). Among UK Biobank patients with MAS (n = 12) identified using an unbiased genomic ascertainment approach, brain neoplasms (4 of 12, 33%; 1 glioblastoma, 1 gliosarcoma, 1 astrocytoma, 1 unspecified type) and schwannomas (3 of 12, 25%) were the most common malignant and benign neural tumors, while cutaneous melanoma (2 of 12, 17%) and head and neck squamous cell carcinoma (2 of 12, 17%) were the most common nonneural malignant neoplasms. In a separate case series of 14 patients with MAS from the US and Europe, brain neoplasms (4 of 14, 29%; 2 glioblastomas, 2 unspecified type) and malignant peripheral nerve sheath tumor (2 of 14, 14%) were the most common neural cancers, while cutaneous melanoma (4 of 14, 29%) and sarcomas (2 of 14, 14%; 1 liposarcoma, 1 unspecified type) were the most common nonneural cancers. Cutaneous neurofibromas (7 of 14, 50%) and schwannomas (2 of 14, 14%) were also common. In 1 US family, a father and son with MAS had clinical diagnoses of neurofibromatosis type 1 (NF1). Genetic testing of the son detected a pathogenic CDKN2A splicing variant (c.151-1G>C) and was negative for NF1 genetic alterations. In UK Biobank, 2 in 150 (1.3%) individuals with clinical NF1 diagnoses had likely pathogenic variants in CDKN2A, including 1 individual with no detected variants in the NF1 gene. CONCLUSIONS AND RELEVANCE: This cohort study estimates the prevalence and describes the tumors of MAS. Additional studies are needed in genetically diverse populations to further define population prevalence and disease phenotypes.
Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification are essential for reliable diagnosis of ...DICER1-related tumor predisposition and the identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for DICER1 germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP) to create DICER1-specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known pathogenic/likely pathogenic (P/LP) variants, 12 known benign/likely benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.
Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. ...The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants were conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB after removing related individuals and heterozygotes who had ever developed a hematologic cancer due to the potential confounding impact of clonal hematopoiesis. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.
Genome-first analysis of cohorts with linked clinical data demonstrates that the prevalence estimates of pathogenic germline TP53 variants is approximately 1:3,000 in health care-based cohorts and 1:10,000 in a predominantly older, healthy cohort. These findings highlight the importance of carefully assessing the impact of database-specific selection biases on these estimates.
Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well characterized in children with a ...pathogenic DICER1 (HGNC ID:17098) variant. Here, the prevalence, penetrance, and phenotype of pathogenic germline DICER1 variants in adults were investigated in 2 population-scale cohorts.
Variant pathogenicity was classified using published DICER1 ClinGen criteria in the UK Biobank (469,787 exomes; unrelated: 437,663) and Geisinger (170,503 exomes; unrelated: 109,789) cohorts. In the UK Biobank cohort, cancer diagnoses in the EHR, cancer, and death registry were queried. For the Geisinger cohort, the Geisinger Cancer Registry and EHR were queried.
In the UK Biobank, there were 46 unique pathogenic DICER1 variants in 57 individuals (1:8242; 95% CI: 1:6362-1:10,677). In Geisinger, there were 16 unique pathogenic DICER1 variants (including 1 microdeletion) in 21 individuals (1:8119; 95% CI: 1:5310-1:12,412). Cohorts were well powered to find larger effect sizes for common cancers. Cancers were not significantly enriched in DICER1 heterozygotes; however, there was a ∼4-fold increased risk for thyroid disease in both cohorts. There were multiple ICD10 codes enriched >2-fold in both cohorts.
Estimates of pathogenic germline DICER1 prevalence, thyroid disease penetrance, and cancer phenotype from genomically ascertained adults are determined in 2 large cohorts.
Germline pathogenic loss-of-function (pLOF) variants in
are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). ...The most common
pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of
-related cancers and cascade testing of family members. However, some patients with
-associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense
RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no
pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.
Few studies have evaluated the relationship between CDKN2A germline pathogenic variants (GPV), transcript (p16/p14ARF) alteration, and cancer risk.
Standardized incidence ratios (SIRs) comparing ...cancer risk with the general population were calculated for 385 CDKN2A GPV carriers from 2 large cohorts (259 United States and 126 Swedish individuals) using Poisson regression; statistical significance was defined as P less than .002 (Bonferroni correction). Cumulative incidence is reported for melanoma and nonmelanoma cancer.
Incidence was increased for melanoma (SIR = 159.8, 95% confidence interval CI = 132.1 to 193.2), pancreatic cancer (SIR = 24.1, 95% CI = 14.7 to 39.4), head and neck squamous cell carcinoma (SIR = 16.2, 95% CI = 9.5 to 27.6), and lung cancer (SIR = 5.6, 95% CI = 3.4 to 9.1) in GPV carriers. Similar associations were observed with p16 alteration. Combined p16 and p14ARF alteration was associated with increased incidence of esophageal cancer (SIR = 16.7, 95% CI = 5.7 to 48.9) and malignant peripheral nerve sheath tumor (SIR = 113.0, 95% CI = 16.4 to 780.9), although cancer events were limited (n < 5 for each malignancy). Cumulative incidence at age 70 years for melanoma and nonmelanoma cancer was 68.3% (95% CI = 68.0% to 68.6%) and 35.2% (95% CI = 34.9% to 35.6%), respectively. A total 89% of smoking-related cancers (lung, head and neck squamous cell carcinoma, pancreatic, esophageal) occurred in ever smokers.
These findings highlight the impact of p16 and p14ARF alteration on cancer risk. Smoking was an important risk factor for smoking-related cancers in our study.
