Anthem Blue Cross California Genetic Testing for TP53 Mutations Form

Subject:

Description

This document addresses genetic testing for TP53 mutations.

The TP53 gene (also known as p53) located on chromosome 17 is a tumor suppressor gene. The protein product of the TP53 gene binds to cellular DNA and is involved in the control of the cell cycle and apoptosis (programmed cell death).

Note: For additional information on genetic testing for malignant conditions, please refer to:

• CG-GENE-13 Genetic Testing for Inherited Diseases
• CG-GENE-14 Gene Mutation Testing for Cancer Susceptibility and Management
• CG-GENE-15 Genetic Testing for Lynch Syndrome, Familial Adenomatous Polyposis (FAP), Attenuated FAP and MYH-associated Polyposis
• CG-GENE-16 BRCA Genetic Testing
• GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels, and Molecular Profiling

Clinical Indications

Medically Necessary:

Germline testing for cancer susceptibility

1. TP53 gene mutation testing for Li-Fraumeni syndrome (LFS) is considered medically necessary when any one of criteria A through H and all of criteria I are met:
   1. The individual has a family history of known TP53 mutation; or
   2. The individual was diagnosed with sarcoma prior to age 45 years; and
      1. Has a first-degree relative who was diagnosed with cancer prior to age 45 years; and
      2. Has an additional first- or second-degree relative on the same side of the family who was diagnosed with cancer prior to age 45 years, or sarcoma at any age; or
   3. The individual was diagnosed with a tumor from the LFS tumor spectrum (for example, soft tissue sarcoma, osteosarcoma, brain tumor, breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) prior to age 46 years; and
      1. Has at least one first-or second-degree relative with any of the above LFS spectrum tumors (other than breast cancer, if the proband has breast cancer) diagnosed prior to the age of 56 years or with multiple primaries at any age; or
   4. The individual was diagnosed with multiple tumors (except multiple breast tumors), two of which belong to LFS tumor spectrum, with the initial cancer occurring prior to age 46 years; or
   5. The individual was diagnosed with adrenocortical carcinoma, choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype at any age, regardless of family history; or
   6. The individual was diagnosed with early onset breast cancer at age 30 years or younger; or
   7. The individual has a personal or family history of pediatric hypodiploid acute lymphoblastic leukemia; or
   8. The individual’s somatic tumor testing has identified a TP53 variant and both of the following criteria are met:
      1. Personal and family history suggest a germline mutation; and
      2. The results of germline testing are likely to be used to guide further medical management of the individual;
         and
   9. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
2. Prenatal or preimplantation genetic testing is considered medically necessary to establish a diagnosis of LFS in the offspring of individuals with known TP53 genetic mutation, and genetic counseling, which encompasses all of the following components, has been performed:
   1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
   2. Education about inheritance, genetic testing, disease management, prevention and resources; and
   3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
   4. Counseling for the psychological aspects of genetic testing.

Somatic tumor testing

TP53 gene mutation testing is considered medically necessary for individuals diagnosed with chronic lymphocytic leukemia or hypodiploid acute lymphocytic leukemia to identify those who would benefit from treatment with chemotherapy.

Not Medically Necessary:

TP53 gene mutation testing is considered not medically necessary in individuals not meeting the criteria above.

Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

When services are Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed.

Discussion/General Information

Genetic testing for TP53 mutations may be carried out using a variety of technologies, including but not limited to direct sequencing and analysis as well as multiplex ligation-dependent probe amplification (MLPA). TP53 gene testing may be performed for the purpose of diagnosis, risk assessment, and/or disease management.

Li-Fraumeni syndrome (LFS)

LFS is a rare, autosomal dominant cancer predisposition syndrome which often manifests at a young age. Individuals with LFS have an estimated 60% chance of malignancy by age 45 and a 95% chance by age 70. LFS is diagnosed in individuals meeting established clinical criteria or in those who have a germline mutation in TP53 regardless of family cancer history. At least 70% of individuals diagnosed clinically have an identifiable germline mutation in TP53, and somatic mutations of the TP53 gene are found in approximately 50% of all tumors. Acquired TP53 mutations are observed in numerous tumors; however, no other inherited phenotypes are associated specifically with germline mutations involving TP53.

Once a TP53 mutation has been identified in a family, testing of at-risk relatives can identify those family members who also have the familial mutation. Management for individuals with LFS may include increased surveillance for the development of cancer. For individuals with LFS, breast MRIs instead of mammograms may be recommended as a means to reduce radiation exposure. Prophylactic mastectomy rather than lumpectomy may be recommended as a preventive measure in individuals with a germline TP53 mutation. Individuals with germline TP53 mutations are cautioned to avoid known carcinogens including excessive sun exposure, tobacco use, occupational exposures and excessive alcohol use.

Germline testing for cancer susceptibility

Two forms of LFS have been identified: classic LFS and Li-Fraumeni-like syndrome (LFLS). Several criteria sets have been developed over the years to identify individuals with classic LFS or LFLS. Individuals with classic LFS meet the following criteria: a diagnosis of a sarcoma was made before age 45 years; a first-degree relative was diagnosed with any cancer prior to age 45 years; and an additional first- or second-degree relative was diagnosed with any form of cancer prior to age 45 years or diagnosed with sarcoma at any age (Li, 1988). Individuals with LFLS fulfill a portion, but not all, of the above criteria. The Birch criteria and the Eeles criteria are less stringent than the criteria for LFS and were developed to identify individuals with LFLS. The Chompret criteria was developed to update the criteria to account for different clinical presentations associated with germline TP53 mutations (Birch, 1994; Chompret, 2001; Eeles, 1995). Bougeard and colleagues (2015) noted the 3 clinical situations which might suggest the presence of LFS:

1. Familial presentation [a proband with an LFS tumor (breast cancer, STS, osteosarcoma, CNS tumor, ACC, leukemia, bronchoalveolar lung cancer) under 46 years and one first- or second-degree relative with an LFS tumor under age 56 years or with multiple tumors],
2. Multiple primary tumors (two of which belong to the narrow LFS spectrum, the first being developed before age 46 years) or
3. Rare cancers [ACC or choroid plexus carcinoma (CPC) irrespective of the family history].

The importance of the role of TP53 in tumor suppression is illustrated by the fact that the majority of individuals fulfilling the criteria for classic LFS (and a smaller proportion of individuals fulfilling the Chompret criteria) carry germline variants in the TP53 gene.

Multiple studies have been published demonstrating the clinical validity of genetic testing for LFS in childhood and adult cancer (Birch, 2001; Bougeard, 2008; Chompret, 2000; Hwang, 2003; Mai, 2016). At this time, the TP53 mutations are considered high penetrance and is the only gene which has unequivocally been shown to be associated in LFS (Bougeard, 2015). LFS syndrome management involves more frequent monitoring, which begins at an earlier age compared to the general population (NCCN, V3.2023). The clinical utility of TP53 mutation testing in individuals with a high-risk personal or family history suggestive LFS has been established (Asdahl, 2017; Ballinger, 2015; Gonzalez, 2009; Kratz, 2017; Villani, 2011).

Somatic tumor testing

Hypodiploid acute lymphocytic leukemia (ALL)

ALL is a rapidly progressing type of cancer that originates in the lymphocytes of the bone marrow. Because ALL cells typically invade the blood fairly quickly, they can metastasize to other parts of the body, including but not limited to the lymph nodes, liver, spleen, central nervous system (brain and spinal cord), and testicles. If not treated promptly, the proliferation of leukemia cells can cause bone marrow failure and death due to anemia, hemorrhage, and/or infection within a few months.

Contemporary therapy for ALL generally involves the administration of various cytotoxic chemotherapeutic agents in several phases over several years. Treatment is curative in more than 90% of children. However, relapse of ALL occurs in up to 20% of children and even more frequently in adults and is often refractory to further chemotherapy. For this reason, relapsed ALL is a leading cause of childhood cancer death (Comeaux, 2017).

Although TP53 mutations are one of the most frequently observed somatic alterations in cancer, and are also common in acute myeloid leukemia, they are relatively uncommon in ALL. In cases involving ALL, TP53 is frequently mutated in two settings: (1) relapsed and (2) low-hypodiploid ALL. Hypodiploid ALL encompasses up to 5% of childhood ALL cases “and is stratified according to the severity of aneuploidy; with several stereotyped patterns of chromosomal loss identified: near haploidy (24–31 chromosomes), low hypodiploidy (32–39 chromosomes), and high hypodiploidy (40–44 chromosomes)” (Comeaux, 2017). Each of these patterns of chromosomal loss is characterized by distinct genetic mutations which are not commonly found in other forms of ALL, one of the most prominent being TP53 mutations in low-hypodiploid ALL. It has been noted that the frequency of TP53 mutations/deletions increase with age and that individuals harboring a hypodiploid ALL have a high risk of treatment failure. Research suggests the presence of TP53 mutations/deletions is a valuable prognostic parameter for individuals with ALL and may be used as a tool to identify which individuals would benefit from chemotherapy treatment (Comeaux, 2017; Holmfeldt, 2013; Stengal, 2014).

A TP53 mutation is identified in 91.2% of low-hypodiploid ALL. In the pediatric population, almost half of the TP53 mutations are identified in nontumor compartments. This finding suggests the mutations are inherited or acquired as de novo in the germline or hematopoietic compartments, and the individual has a predisposition to LFS cancers (Saifi, 2023). TP53 testing is appropriate in individuals with ALL to both aid in developing appropriate treatment plans, and as a means to identify individuals with LFS syndrome which would guide future surveillance plans.

The TP53 alteration seems to be an essential component of the pathogenesis of low-hypodiploid ALL, with approximately 50% of tumors showing somatic TP53 mutations and many of the remaining cases acquiring other genetic or epigenetic alterations that negatively affect TP53 function (Bloom, 2020). Based on the published data and specialty consensus input, TP53 gene mutation testing may be considered appropriate for individuals diagnosed with hypodiploid acute lymphocytic leukemia in order to identify those who would benefit from treatment with chemotherapy and as a prognostic factor (Bloom, 2020; Comeaux, 2017; Hof, 2011; Swaminathan, 2019) .

Chronic Lymphocytic Leukemia (CLL)

CLL is a chronic, slowly developing form of leukemia which is characterized by the progressive accumulation of incompetent leukemic cells in the peripheral blood, lymphoid tissues and bone marrow. CLL represents approximately 1.1% of all new cancer cases in the U.S. with approximately 18,740 new cases being diagnosed and an estimated 4490 individuals dying of the disease in 2023 (NCI, 2023). In contrast to some other forms of leukemia, CLL can progress slowly causing few, if any, problems in the initial stages. CLL may be identified during routine physical exams or may be diagnosed at the time of a symptomatic individual seeking treatment. The majority of affected individuals do not require treatment at the time of diagnosis. The average time from diagnosis to first treatment is 4 to 5 years (Jain, 2015). Family members of individuals with CLL have a 6-to-9-fold increased risk of developing the disease (Eichhorst, 2015; NCCN, V3.2023; SEER, 2016).

Multiple factors have been identified which provide prognostic information for CLL. Del(17p) and a mutation of TP53 are considered useful markers to provide prognostic information beyond clinical staging. Individuals with a detectable del(17p) or a mutation of TP53 have the poorest outcomes, such as poorer response rates, a shorter duration of response to treatment and a median OS of 7 years (Chauffaille, 2020; Gonzalez, 2011; NCI, 2023; Stilgenbauer, 2014; Zen, 2010).

The NCCN (V3. 2023) recommends that all individuals diagnosed with CLL undergo TP53 sequencing prior to the initiation of treatment to direct the selection of appropriate therapy (2A recommendation). Studies have demonstrated that TP53 mutation is an independent marker of poor prognosis in individuals with CLL. Genetic testing as a prognostic factor is starting to play a role in therapeutic selection. Current guidelines recommend using TP53 mutation status as a tool to identify the most appropriate regimen for symptomatic CLL individuals requiring treatment.

Germline Testing in the presence of a somatic tumor TP53 mutation

Somatic mutations in the TP53 gene are present in up to 50% of tumors, including relapsed or refractory CLL (Chauffaille, 2020; Schneider, 2019). The NCCN CPG (V3.2023) notes that somatic TP53 pathogenic/likely pathogenic mutations in the absence of germline pathogenic/likely pathogenic mutations stating:

Somatic TP53 variants frequently confound germline testing results. Late post-zygotic aberrant clonal expansions (ACEs) containing a pathogenic TP53 variant, limited to hematologic compartment or to a tumor, may be detected in the blood or saliva through germline testing, particularly using NGS technology. The phenomenon of ACE is well described and is most often due to CHIP, which can be demonstrated in healthy populations at increasing frequency with increasing age. This finding has important clinical implications regarding the potential application of unwarranted clinical intervention.

Yamamoto and colleagues (2020) evaluated the relationship between TP53 mutations identified through next-generation sequencing (NGS) somatic tumor testing and germline testing. Individuals with advanced cancer underwent NGS somatic tumor testing. A total of 61.9% (120/194) of the population were found to have a pathogenic/likely pathogen mutation in one of several genes, including TP53, PTEN, BRCA1 and BRCA2, with TP53 mutation being the most common variant found. The results of germline testing were available for 30 individuals with somatic TP53 mutations. No cases of a TP53 germline mutation were located. The authors summarized that unless individuals have a relevant medical or family history, the significance of germline testing following positive somatic tumor testing appears to be low in daily clinical practice.

Genetic Counseling

According to the National Society of Genetic Counselors (NSGC, 2006), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease. This process typically includes the guidance of a specially trained professional who:

(1) Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
(2) Provides education about inheritance, genetic testing, disease management, prevention and resources; and
(3) Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
(4) Provides counseling for the psychological aspects of genetic testing

Definitions

Acute lymphocytic leukemia (also known as acute lymphoblastic leukemia; ALL): A fast growing type of cancer that originates in the lymphocytes (white blood cells) in the bone marrow.

Chronic lymphocytic leukemia: A type of cancer in which the bone marrow produces abnormal leukocytes (white blood cells).

Germ cell: An ovum or a sperm cell or one of its precursors.

Germline mutation: Any detectable and heritable change in the lineage of germ cells. Mutations in these cells are transmitted to offspring, while, on the other hand, somatic mutations are not inherited.

Leukemia: A type of cancer affecting the blood and bone marrow.

Penetrance: The probability of a clinical condition occurring when a particular genotype is present.

Proband: The affected individual who serves as the starting point for the genetic study of a family.

Somatic cells: Cells that make up the body of an organism with the exception of germ cells.

References

Peer Reviewed Publications:

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7. Bloom M, Maciaszek JL, Clark ME, et al. Recent advances in genetic predisposition to pediatric acute lymphoblastic leukemia. Expert Rev Hematol. 2020; 13(1):55-70.
8. Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni Syndrome from TP53 mutation carriers. J Clin Oncol. 2015; 33(21):2345-2352.
9. Bougeard G, Sesboue R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008; 45(8):535-538.
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24. Hof J, Krentz S, van Schewick C, et al. Mutations and deletions of the TP53 gene predict nonresponse to treatment and poor outcome in first relapse of childhood acute lymphoblastic leukemia. J Clin Oncol. 2011; 29(23):3185-3193.
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26. Hwang SJ, Lozano G, Amos CI, Strong LC. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003; 72(4):975-983.
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29. Kratz CP, Achatz MI, Brugières L, et al. Cancer screening recommendations for individuals with Li-Fraumeni syndrome. Clin Cancer Res. 2017; 23(11):e38-e45.
30. Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988; 48(18):5358-5362.
31. Lin PH, Kuo WH, Huang AC, et al. Multiple gene sequencing for risk assessment in patients with early-onset or familial breast cancer. Oncotarget. 2016; 7(7):8310-8320.
32. Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016; 122(23):3673-3681.
33. Masciari S, Van den Abbeele AD, Diller LR, et al. F18-fluorodeoxyglucose-positron emission tomography/computed tomography screening in Li-Fraumeni syndrome. JAMA. 2008; 299(11):1315-1319.
34. Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res. 2010; 70(12):4795-4800.
35. Prochazkova K, Foretova L, Sedlacek Z. A rare tumor and an ethical dilemma in a family with a germline TP53 mutation. Cancer Genet Cytogenet. 2008; 180(1):65-69.
36. Saiki R, Ogawa S. Adult low-hypodiploid acute lymphoblastic leukemia evolves from tp53-mutated clonal hematopoiesis. Blood Cancer Discov. 2023; 4(2):102-105.
37. Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni Syndrome. 1999 Jan 19 [Updated 2019 Nov 21]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1311/pdf/Bookshelf_NBK1311.pdf. Accessed on October 17, 2023.
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39. Stengel A, Schnittger S, Weissmann S, et al. TP53 mutations occur in 15.7% of ALL and are associated with MYC-rearrangement, low hypodiploidy, and a poor prognosis. Blood. 2014; 124(2):251-258.
40. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014; 123(21):3247-3254.
41. Swaminathan M, Bannon SA, Routbort M, et al. Hematologic malignancies and Li-Fraumeni syndrome. Cold Spring Harb Mol Case Stud. 2019; 5(1):a003210.
42. Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009; 27(26):e108-109.
43. Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol. 2011; 12(6):559-567.
44. Yamamoto Y, Kanai M, Kou T, et al. Clinical significance of TP53 variants as possible secondary findings in tumor-only next-generation sequencing. J Hum Genet. 2020; 65(2):125-132.
45. Zenz T, Eichhorst B, Busch R, et al. TP53 mutation and survival in chronic lymphocytic leukemia. J Clin Oncol. 2010; 28(29):4473-4479.

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Board of Genetic Counselors. Practice-Based Competencies for Genetic Counselors. Available at: Forms & Resources - ACGC | Accreditation Council for Genetic Counseling (gceducation.org). Accessed on October 17, 2023.
2. American College of Obstetricians and Gynecologists (ACOG). Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION, Number 793. Obstet Gynecol. 2019; 134(6):e143-e149.
3. Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26 Suppl 5:v78-84.
4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008; 111(12):5446-556.
5. Hampel H, Bennett RL, Buchanan A, et al; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1):70-87.
6. Lancaster JM, Powell CB, Chen LM, Richardson DL; SGO Clinical Practice Committee. Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer women with germline mutations in the cancer susceptibility genes, BRCA1 or BRCA2, associated with hereditary predispositions. Gynecol Oncol. 2015; 136(1):3-7.
7. National Library of Medicine (NLM). Genetics Home Reference: Li-Fraumeni syndrome. Reviewed June 1, 2020. Available at: http://ghr.nlm.nih.gov/condition/li-fraumeni-syndrome. Accessed on October 17, 2023.
8. National Society of Genetic Counselors' Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns. 2006; 5(2):77-83.
9. NCCN Clinical Practice Guidelines in Oncology™. ^© 2023 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org.index.asp. Accessed on October 4, 2023:
   • Acute Lymphoblastic Leukemia. V2.2023. Revised July 28, 2023.
   • Acute Myeloid Leukemia.V5.2023. Revised October 3, 2023.
   • Breast Cancer Risk Reduction. V1.2023. Revised October 12, 2022.
   • Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. V3.2023. Revised June 12, 2023.
   • Gastric Cancer. V2.2023. Revised August 29, 2023.
   • Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. V2.2024. Revised September 27, 2023.
   • Genetic/Familial High-Risk Assessment: Colorectal. V1.2023. Revised May 30, 2023.
   • Myelodysplastic Syndromes. V1.2023. Revised September 12, 2022.
   • Pediatric Acute Lymphoblastic Leukemia. V1.2024. Revised August 17, 2023.
10. SEER Cancer Statistics Factsheets: Chronic Lymphocytic Leukemia. National Cancer Institute. Bethesda, MD. Available at: http://seer.cancer.gov/statfacts/html/clyl.html. Accessed on October 17, 2023.

Websites for Additional Information

1. American Cancer Society. What is chronic lymphocytic leukemia? Last revised: May 10, 2018. Available at: http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-what-is-cll. Accessed on October 17, 2023.
2. Li-Fraumeni Syndrome (LFSA) Association. Criteria for LFS - Li-Fraumeni Syndrome Association. Available at: https://www.lfsassociation.org/what-is-lfs/lfs-critieria/. Accessed on October 17, 2023.
3. National Cancer Institute. Cancer Statistics. Available at: https://seer.cancer.gov/statfacts/. Accessed on October 17, 2023.
4. National Cancer Institute. Chronic Lymphocytic Leukemia Treatment. Updated August 26, 2022. Available at: https://www.cancer.gov/types/leukemia/patient/cll-treatment-pdq. Accessed on October 17, 2023.
5. U.S. National Library of Medicine. Medline Plus. TP53 Gene. Last reviewed: February 1, 2020. Available at: https://medlineplus.gov/genetics/gene/tp53/#conditions. Accessed on October 17, 2023.

Index

Li-Fraumeni
Low-hypodiploid Acute Lymphocytic (Lymphoblastic) Leukemia
TP53 (tp53)

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History

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