Coverage Policy Manual
Policy #: 2014013
Category: Laboratory
Initiated: June 2014
Last Review: June 2018
  Genetic Test: Li-Fraumeni Syndrome

Description:
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several different types of tumors. The syndrome is caused by germline mutations in the TP53 gene.
 
Background
LFS is a cancer predisposition syndrome associated a high lifetime cumulative risk of cancer and a tendency for multiple cancers in affected individuals. The syndrome was originally described in 1969 by 2 physician-scientists, Frederick P. Li and Joseph F. Fraumeni, based on a retrospective analysis of families with aggressive soft tissue sarcomas in young siblings and their biologically related cousins (Sorrell, 2013).
 
The tumor types that are most closely associated with LFS include soft tissue sarcomas, premenopausal breast cancer, brain tumors, and adrenal cortical carcinoma (Schneider, 1993). These core cancers account for approximately 70% to 80% of all LFS-related tumors. There is less agreement about the noncore cancers, which account for the remaining 30% of malignancies in LFS and include a wide variety of gastrointestinal tract, genitourinary tract, lung, skin and thyroid cancers and leukemias and lymphomas (Schneider, 1993).
 
Individuals with LFS are at increased risk of developing multiple primary tumors, with subsequent malignancies not all being clearly related to the treatment of the previous neoplasms. The risk of developing a second tumor has been estimated at 57% and the risk of a third malignancy, 38% (Schneider, 1993). Individuals with LFS are at increased risk of both bone and soft tissue sarcomas. Sarcomas of various histologies account for 25% of the cancers reported in people with LFS, with the most commonly reported sarcomas in an international database being rhabdomyosarcoma before age 5 years and osteosarcoma at any age (Ognjanovic, 2012). Women with LFS are at greatly increased risk of developing premenopausal breast cancer, with the median age of diagnosis being 33 years of age (Schneider, 1993).  Male breast cancer has rarely been reported in LFS families (Schneider, 1993). Many different types of brain tumors have been described in LFS, including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas (Schneider, 1993). The median age of onset of LFS-related brain tumors is 16 years of age. Individuals with LFS are at increased risk of developing adrenal cortical carcinoma (ACC). In adults, in 1 series, it was estimated that 6% of individuals diagnosed with ACC after age 18 years have a germline TP53 mutation (Raymond, 2013).
 
Data from M.D. Anderson Cancer Center’s long-term clinical studies of LFS showed that the risk of developing soft tissue sarcomas is greatest before the age of 10, brain cancer appears to occur early in childhood with a smaller peak in risk in the fourth to fifth decade of life, risk for osteosarcoma is highest during adolescence, and breast cancer risk among females with LFS starts to increase significantly around age 20 and continues into older adulthood (Hwang, 2003).
 
Clinical Diagnosis
The diagnosis of LFS is based on an evolving set of clinical classification criteria, established using salient aspects of family history and tumor-related characteristics (Sorrell, 2013). The first formal set of criteria, the classic LFS criteria, were developed in 1988, and are the most stringent criteria used to make a clinical diagnosis of LFS (Sorrell, 2013).  
 
Classic LFS is defined by the presence of all of the following criteria:
    •  A proband with a sarcoma before 45 years of age
    • A first-degree relative with any cancer before 45 years of age
    • A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age (Schneider, 1993).  
 
Chompret et al developed criteria which were shown to have the highest positive predictive value, and which, when combined with the classic LFS criteria, provide the highest sensitivity for identifying individuals with LFS (Chompret, 2001). The Chompret criteria were updated in 2009 to assist in identifying families with milder phenotypes (Gonzalez, 2009). The Chompret criteria will also identify individuals with de novo TP53 mutations, whereas the classic LFS criteria require a family history.
 
Chompret Criteria
    • Proband with tumor belonging to LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least 1 first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
    • Proband with multiple tumors (except multiple breast tumors), 2 of which belong to LFS tumor spectrum and the first of which occurred before age 46 years; OR
    • Patient with adrenocortical carcinoma (ACC) or choroid plexus tumor, irrespective of family history
 
National Comprehensive Cancer Network (NCCN) guidelines recommend TP53 analysis for individuals who meet classic LFS criteria, Chompret criteria, or who have been diagnosed with early-onset breast cancer (age of diagnosis ≤35 years).
 
Molecular Diagnosis
LFS is associated with germline mutations in the TP53 gene (chromosome 17p13.1), which encodes for a ubiquitous transcription factor that is responsible for a complex set of regulatory functions that promote DNA repair and tumor suppression. TP53 is the only gene in which mutations are known to cause LFS, and no other inherited phenotypes are associated specifically with germline mutations involving TP53  (Schneider, 1993).
 
LFS is a highly penetrant cancer syndrome, with the risks for cancer being ~50% by age 30 years, and 90% by age 60 years (Schneider, 1993). LFS is inherited in an autosomal dominant manner. De novo germline TP53 mutations (no mutation is identified in either biologic parent) are estimated to be 7% to 20%.
 
Approximately 95% of mutations detected in TP53 gene are sequence variants (small intragenic deletions/insertions and missense, nonsense, and splice site mutations). Large deletion/duplications not readily detected by sequence analysis accounts for approximately 1% of the mutations detected (Schneider, 1993).
 
Certain genotype-phenotype correlations have been reported in families with LFS and TP53 mutations. Genotype-phenotype correlations in LFS are predictive of the age of onset of tumor, level of risk of developing tumor, and outcome in patients with TP53 germline mutations (Sorrell, 2013; Schneider, 1993).
 
Management
 
Treatment
The evaluation for cancer in an individual diagnosed with LFS should be based on personal medical history and, to some degree, the specific pattern of cancer in the family. Women with LFS who develop breast cancer are encouraged to consider bilateral mastectomies to reduce the risk of developing a second primary breast cancer and to avoid exposure to radiation therapy. Preventive measures may include prophylactic mastectomy in women, and in all patients with a TP53 mutation, avoidance of radiation therapy, as there is some evidence to suggest that TP53 mutations confer an increased sensitivity to ionizing radiation and the possibility of radiation-induced malignancies.
 
Surveillance
LFS confers a high risk of multiple different types of cancer, which poses challenges for establishing a comprehensive screening regimen, and many of the cancers associated with LFS do not lend themselves to early detection.
 
There is no international consensus on the appropriate clinical surveillance strategy in individuals with LFS, (Mai, 2012) but, in general, the strategy includes physical examination, colonoscopy and breast imaging. Other protocols that are being evaluated include additional imaging techniques and biochemical assessment.
 
NCCN has consensus-based screening guidelines.
 
Regulatory Status
No U.S. Food and Drug Administration (FDA)-cleared molecular diagnostic tests were found. Thus, molecular evaluation is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
 
Coding
CPT code 81405 includes the following testing for Li-Fraumeni syndrome:
 
TP53 (tumor protein 53) (eg, Li-Fraumeni syndrome, tumor samples), full gene sequence or targeted sequence analysis of >5 exons
 
Duplication/deletion analysis for TP53 would be reported with the unlisted molecular pathology procedure code (81479).
 

Policy/
Coverage:
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for TP53 mutations meets member benefit certificate primary coverage criteria to confirm a diagnosis of Li-Fraumeni syndrome under the following conditions:
 
    • The patient has undergone genetic counseling (96040 or S0265),
 
AND
 
    • Meets either the classic or the Chompret clinical diagnostic criteria for Li-Fraumeni syndrome (See diagnostic criteria below), or
    • Has early-onset breast cancer (age of diagnosis ≤35 years), or
    • Is a first degree relative of the proband positive for TP53 mutation.
 
Diagnostic criteria for LFS:
 
Classic LFS
 
        • A proband with a sarcoma before 45 years of age AND  
        • A first-degree relative with any cancer before 45 years of age AND  
        • A first- or second-degree relative with any cancer before 45 years of age or a sarcoma at any age  
 
Chompret criteria
 
        • Proband with tumor belonging to LFS tumor spectrum (eg, soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least 1 first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR  
        • Proband with multiple tumors (except multiple breast tumors), 2 of which belong to LFS tumor spectrum and first of which occurred before age 46 years; OR  
        • Patient with adrenocortical carcinoma (ACC) or choroid plexus tumor, irrespective of family history  
 
Note: The optimal strategy for confirming a TP53 mutation in a proband would be:
1) sequencing of the entire TP53 coding region (exons 2-11), which detects about 95% of TP53 mutations in patients with LFS (81405). If sequencing is negative, then:
2) deletion/duplication analysis, which detects large deletions/duplications (81479). These types of mutations account for less than 1 percent of mutations in individuals meeting classic LFS criteria.
Deletion/duplication analysis (81479) will be covered only if sequencing of the entire TP53 coding region (81405) is negative.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for a germline TP53 mutation for all other indications does not meet member benefit certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, genetic testing for a germline TP53 mutation is considered not medically necessary for all other indications.
 

Rationale:
Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
 
According to a large reference laboratory, analytic sensitivity and specificity for polymerase chain reaction sequencing for LFS TP53 testing and deletions/duplications testing by multiplex ligation-dependent probe amplification is greater than 95% (ARUP, 2014).  
 
The order of testing to optimize yield would be:
1) sequencing of the entire TP53 coding region (exons 2-11), which detects about 95% of TP53 mutations in patients with LFS. Examples of types of mutations detected by sequence analysis include small deletions/duplications, and missense, nonsense and splice site mutations; most are missense mutations
2) deletion/duplication analysis, which detects large deletions/duplications involving the coding region, exon 1, or promoter; these types of deletions/duplications are not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. These types of mutations account for less than 1 percent of mutations found in individuals with LFS.
 
Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
Approximately 80% of families with features of LFS will have an identifiable TP53 mutation (Schneider, 1993). Families that have no identifiable TP53 mutation but share clinical features of LFS are more likely to have a different hereditary cancer syndrome (eg hereditary breast-ovarian cancer syndrome) (Schneider, 1993).  
 
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
The clinical utility of genetic testing can be considered in the following clinical situations: 1) individuals with suspected LFS, and 2) family members of individuals with LFS. These situations will be discussed separately next.
 
Individuals with suspected LFS. The clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. Direct evidence for the clinical utility of genetic testing in these patients, describing how a molecular diagnosis of LFS changed patient management, is limited. However, for patients who are diagnosed with LFS by identifying a TP53 mutation, the medical management focuses on increased cancer surveillance to detect tumors at the earliest, most treatable stages.
 
Villani et al conducted a prospective, observational study of members of 8 LFS families who were asymptomatic TP53 carriers (Villani, 2011). The participants either chose to undergo or to not undergo surveillance. Surveillance included biochemical and imaging studies, which included ultrasounds, brain magnetic resonance imaging (MRI) scans and rapid total body MRI scans. The primary outcome measure was detection of new cancers and the secondary outcome measure was overall survival. Of 33 mutation carriers that were identified, 18 underwent surveillance. The surveillance protocol detected 10 asymptomatic tumors in 7 patients, which included premalignant or low grade tumors (3 low-grade gliomas, a benign thyroid tumor, 1 myelodysplastic syndrome), and small, high-grade tumors (2 choroid plexus carcinomas, 2 adrenocortical carcinomas, 1 sarcoma). The 9 solid tumors that were detected were completely resected, and the patients were in complete remission. After a median follow-up of 24 months, all of the patients who had undergone surveillance were alive. In the nonsurveillance group, 12 high-grade, high-stage tumors developed in 10 patients, of which 2 were alive at the end of follow-up (p=0·04 for comparison of survival in the surveillance group). Three-year overall survival in the surveillance group was 100% and 21% in the nonsurveillance group (p=0·0155).
 
Family members. When a TP53 mutation has been identified in a proband, testing of at-risk relatives can identify those who also have the mutation and have LFS. These individuals need initial evaluation and ongoing surveillance.
 
Conclusions. Direct evidence of the clinical utility of TP53 testing is limited. However, the clinical utility of genetic testing for TP53 mutations is that genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of LFS and in at-risk family members. Management changes include increased surveillance and possible prophylactic measures for the cancers that are associated with this syndrome.
 
Summary
Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with the development of several different types of tumors. The syndrome is caused by germline mutations in the TP53 gene.
 
Analytic validity of TP53 mutation testing is high, and almost all of these mutations can be identified by sequence analysis; a far smaller number of mutations can be detected by deletion/duplication analysis.
 
The clinical validity of TP53 mutation testing is high in that a mutation can be identified in up to 80% of patients who meet the clinical criteria for a diagnosis of LFS.
 
The clinical utility of genetic testing for a TP53 mutation is high in that confirming a diagnosis in a patient with clinical criteria of LFS will lead to changes in clinical management by increasing surveillance to detect cancers known to be associated with LFS at an early and treatable stage, or to address possible prophylactic measures. Most cases of LFS are inherited, and testing of at-risk relatives will identify those who should also undergo increased cancer surveillance.
 
Practice Guidelines and Position Statements
National Comprehensive Cancer Network guidelines (v.1.2014) recommend the following for LFS management:
 
Breast cancer risk, women:
 
    • Breast awareness starting at age 18 years.
    • Clinical breast exam every 6-12 months, starting at age 20-25 years or 5-10 years before the earliest known breast cancer in the family.
    • Breast screening:
        • Age 20-29 years, annual breast MRI screening (preferred) or mammogram if MRI is unavailable or individualized based on earliest age of onset in family.
        • Age >30-75 years, annual mammogram, and breast MRI screening.
        • Age >75 years, management considered on an individual basis.
        • Discuss risk-reducing mastectomy and counsel regarding degree of protection and cancer risk, and reconstruction options.
        • Address psychosocial, social, and quality-of-life aspects of risk-reducing mastectomy.
 
Other cancer risks:
    • Annual comprehensive physical exam with high index of suspicion for the cancers associated with LFS.
    • Consider colonoscopy every 2-5 years starting no later than 25 years of age.
    • Therapeutic radiation therapy for cancer treatment should be avoided when possible.
    • Discuss limitations of screening for many cancers associated with LFS, educate regarding signs and symptoms of cancer, and base additional surveillance on individual family history.
 
For relatives:
    • Advise about possible inherited cancer risk to relatives, options for risk assessment, and management.
    • Recommend genetic counseling and consideration of genetic testing for at-risk relatives.
 
 
U.S. Preventive Services Task Force (USPSTF) Guidelines
No USPSTF guidelines for Li-Fraumeni syndrome testing have been identified.
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
There is a lack of published evidence on analytic validity of testing for TP53 mutations. It is expected that analytic validity will be high when testing is performed according to optimal laboratory standards. The website of 1 large laboratory claims analytic validity of greater than 95% but empirical, peer-reviewed data is not available.
 
Cohorts of individuals with adrenocortical carcinoma, which is diagnostic of LFS by the Chompret criteria, have been published (Petitjean, 2007; Wagner, 1994; Wasserman, 2015). In 1 study, 88 consecutive patients with adrenocortical carcinoma were evaluated.14 Direct sequencing of exons 2 through 11 together with multiplex ligation-dependent probe amplification was used to identify mutations. For the entire population, 50% of individuals had a pathogenic mutation detected. The detection rate was dependent on age, with 58% of individuals younger than 12 years of age having a mutation compared with 25% of individuals between ages 12 and 20.
 
There is a small amount of evidence on the clinical validity of testing for TP53 mutations. In patients who meet clinical criteria for LFS, the clinical sensitivity has been reported to range between 50% and 80%. The largest amount of evidence is on patients with adrenocortical carcinoma, which represents a subset of all patients with LFS. No evidence was identified on the clinical specificity of testing.
 
Diagnostic Testing in Individuals With Suspected LFS
Direct evidence for the clinical utility of genetic testing to confirm a diagnosis of LFS is lacking. An indirect chain of evidence can provide evidence of clinical utility if all the links in the chain of evidence are intact.
 
The elements contributing to the indirect chain of evidence are derived from evidence review 2.04.91 (general approach to genetic testing). The following series of questions represent the indirect chain of evidence for diagnostic testing to confirm a diagnosis of LFS.
 
Are there some individuals in which the diagnosis of LFS is uncertain following standard clinical workup without genetic testing?
 
Yes. There are standardized diagnostic criteria based on personal, clinical and family history. However, there are limitations to these methods of diagnosis. A detailed family history may not be complete or may not be available in many instances. There are different diagnostic instruments that use different criteria, and they may be used alone or in combination with each other. The population identified as having LFS will differ depending on the way the instruments are used. In addition, the available instruments do not have high overall accuracy. Therefore, there may be considerable uncertainty about the diagnosis using clinical criteria alone.
 
Can genetic testing make the diagnosis of LFS with certainty in patients with an uncertain clinical diagnosis?
 
Yes, in some patients. A positive genetic test will confirm the diagnosis of LFS with high certainty in individuals who meet clinical criteria. As a result, patients with a positive genetic test will have a high certainty for the diagnosis of LFS, whereas the diagnosis by clinical criteria alone has a high false positive rate of up to 50%.
 
Does establishment of a definitive diagnosis of LFS lead to management changes?
 
Yes. In the majority of cases, treatment and management will be unaffected by genetic testing, as individuals with a negative genetic test are likely to be treated as presumed LFS. However, there are some situations in which genetic testing may impact management. A positive test will facilitate the work-up for cancer susceptibility syndromes when multiple conditions are considered. Knowledge of mutation status may also assist in decision-making for prophylactic mastectomy by providing more definitive risk estimates.
 
Do the management changes result in improved health outcomes?
 
Yes. Outcomes are improved when a definitive diagnosis is made by avoiding the need for further testing to determine whether a cancer susceptibility syndrome is present. Better estimation of risk for breast cancer improves the capacity for informed decision-making regarding prophylactic mastectomy.
 
Testing Asymptomatic Individuals to Determine Future Risk of LFS
There is limited direct evidence on the clinical utility of genetic testing in this population. An indirect chain of evidence can provide evidence of clinical utility if all the links in the chain of evidence are intact. The elements contributing to the indirect chain of evidence are derived from evidence review 2.04.91 (general approach to genetic testing). The following series of questions represent the indirect chain of evidence for testing asymptomatic individuals to determine future risk of disease.
 
In summary the evidence of clinical utility of TP53 testing is limited. One observational study reported improved survival for screened patients. However, this study is limited by the observational design that included self-selection into screening protocols, likely resulting in selection bias. An indirect chain of evidence can demonstrate clinical utility of genetic testing for TP53 mutations. For diagnosis, a positive genetic test will increase the certainty of LFS, facilitate the overall workup for cancer susceptibility syndromes, and assist in decision-making for prophylactic mastectomy. For asymptomatic family members who have a close relative with a pathogenic mutation, genetic testing can confirm or exclude the presence of a mutation, and direct future screening interventions that are likely to improve outcomes.
 
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.

CPT/HCPCS:
81405MOLECULAR PATHOLOGY PROCEDURE LEVEL 6
81479Unlisted molecular pathology procedure
96040Medical genetics and genetic counseling services, each 30 minutes face-to-face with patient/family
S0265Genetic counseling, under physician supervision, each 15 minutes

References: Schneider K, Zelley K, Nichols KE et al.(1993) Li-Fraumeni Syndrome. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle (WA)1993.

ARUP Laboratories. Website available online at: http://ltd.aruplab.com/Tests/Pub/2009302. Last accessed April 2014.

Bouaoun L, Sonkin D, Ardin M, et al.(2016) Variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum Mutat. Sep 2016;37(9):865-876. PMID 27328919

Bougeard G, Renaux-Petel M, Flaman JM, et al.(2015) Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol. Jul 20 2015;33(21):2345-2352. PMID 26014290

Chompret A, Abel A, Stoppa-Lyonnet D et al.(2001) Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 2001; 38(1):43-7.

Gonzalez KD, Noltner KA, Buzin CH et al.(2009) Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009; 27(8):1250-6.

Hwang SJ, Lozano G, Amos CI et al.(2003) Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet 2003; 72(4):975-83.

Mai PL, Malkin D, Garber JE et al.(2012) Li-Fraumeni syndrome: report of a clinical research workshop and creation of a research consortium. Cancer Genet 2012; 205(10):479-87.

Ognjanovic S, Olivier M, Bergemann TL et al.(2012) Sarcomas in TP53 germline mutation carriers: a review of the IARC TP53 database. Cancer 2012; 118(5):1387-96.

Petitjean A, Mathe E, Kato S, et al.(2007) Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat. Jun 2007;28(6):622-629. PMID 17311302

Raymond VM, Else T, Everett JN et al.(2013) Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. J Clin Endocrinol Metab 2013; 98(1):E119-25.

Singh AD, Medina CA, Singh N, et al.(2016) Fine-needle aspiration biopsy of uveal melanoma: outcomes and complications. Br J Ophthalmol. Apr 2016;100(4):456-462. PMID 26231747

Sorrell AD, Espenschied CR, Culver JO et al.(2013) Tumor protein p53 (TP53) testing and Li-Fraumeni syndrome : current status of clinical applications and future directions. Mol Diagn Ther 2013; 17(1):31-47.

Villani A, Tabori U, Schiffman J et al.(2011) Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011; 12(6):559-67.

Wagner J, Portwine C, Rabin K, et al.(1994) High frequency of germline p53 mutations in childhood adrenocortical cancer. J Natl Cancer Inst. Nov 16 1994;86(22):1707-1710. PMID 7966399

Wasserman JD, Novokmet A, Eichler-Jonsson C, et al.(2015) Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. J Clin Oncol. Feb 20 2015;33(6):602-609. PMID 25584008


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