bims-lifras 2024-03-03 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–03–03
eight papers selected by
Joanna Zawacka, Karolinska Institutet

Hematologic malignancies in Li-Fraumeni syndrome: A case report.
Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.
Clinically-relevant Germline Variants in Children with Non-Medullary Thyroid Cancer.
Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions.
Germline variants in patients developing second malignant neoplasms after therapy for pediatric acute lymphoblastic leukemia-a case-control study.
First report of familial mixed phenotype acute leukemia: shared clinical characteristics, Philadelphia translocation, and germline variants.
Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.
Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Am J Med Genet A. 2024 Feb 27. e63573

Hematologic malignancies in Li-Fraumeni syndrome: A case report.

Bethany Bundrant, Yoheved Gerstein, Banu Arun, Courtney D DiNardo.

  Li-Fraumeni syndrome (LFS) is a rare syndrome characterized by an increased lifetime risk of cancer development in multiple organ systems, typically caused by de novo or inherited germline pathogenic variants in the tumor suppressor TP53 gene. LFS is more classically associated with solid tumors; however, it is also associated with hematologic malignancies such as therapy-related acute myeloid leukemia (AML). We present the case of a female patient with a strong family and personal history of cancer who presented to our institution with therapy-related AML with next-generation sequencing showing a pathogenic TP53 mutation. She received several lines of systemic therapy and underwent stem cell transplant using her adult daughter as a haploidentical donor after achieving minimal residual disease (MRD). Her posttransplant bone marrow evaluations demonstrated persistence of the same pathogenic TP53 mutation despite ongoing clinical remission with full donor engraftment and negative MRD. Genetic testing was performed which confirmed the germline origin of the TP53 pathogenic variant in the patient. The patient's adult donor daughter was also identified to have the same pathogenic variant in TP53 consistent with LFS. The presented case highlights the need for increased awareness of LFS in the adult hematologic community, particularly for patients undergoing evaluation for stem cell transplant.

Keywords:  Li-Fraumeni syndrome; TP53 mutation; stem cell transplant; therapy-related acute myeloid leukemia

DOI:  https://doi.org/10.1002/ajmg.a.63573
JCO Precis Oncol. 2024 Feb;8 e2300453

Cancer Risks Associated With TP53 Pathogenic Variants: Maximum Likelihood Analysis of Extended Pedigrees for Diagnosis of First Cancers Beyond the Li-Fraumeni Syndrome Spectrum.

kConFab Investigators

PURPOSE: Establishing accurate age-related penetrance figures for the broad range of cancer types that occur in individuals harboring a pathogenic germline variant in the TP53 gene is essential to determine the most effective clinical management strategies. These figures also permit optimal use of cosegregation data for classification of TP53 variants of unknown significance. Penetrance estimation can easily be affected by bias from ascertainment criteria, an issue not commonly addressed by previous studies.
MATERIALS AND METHODS: We performed a maximum likelihood penetrance estimation using full pedigree data from a multicenter study of 146 TP53-positive families, incorporating adjustment for the effect of ascertainment and population-specific background cancer risks. The analysis included pedigrees from Australia, Spain, and United States, with phenotypic information for 4,028 individuals.
RESULTS: Core Li-Fraumeni syndrome (LFS) cancers (breast cancer, adrenocortical carcinoma, brain cancer, osteosarcoma, and soft tissue sarcoma) had the highest hazard ratios of all cancers analyzed in this study. The analysis also detected a significantly increased lifetime risk for a range of cancers not previously formally associated with TP53 pathogenic variant status, including colorectal, gastric, lung, pancreatic, and ovarian cancers. The cumulative risk of any cancer type by age 50 years was 92.4% (95% CI, 82.2 to 98.3) for females and 59.7% (95% CI, 39.9 to 81.3) for males. Females had a 63.3% (95% CI, 35.6 to 90.1) cumulative risk of developing breast cancer by age 50 years.
CONCLUSION: The results from maximum likelihood analysis confirm the known high lifetime risk for the core LFS-associated cancer types providing new risk estimates and indicate significantly increased lifetime risks for several additional cancer types. Accurate cancer risk estimates will help refine clinical recommendations for TP53 pathogenic variant carriers and improve TP53 variant classification.

DOI: https://doi.org/10.1200/PO.23.00453
J Clin Endocrinol Metab. 2024 Feb 28. pii: dgae107. [Epub ahead of print]

Clinically-relevant Germline Variants in Children with Non-Medullary Thyroid Cancer.

Dutch Pediatric Thyroid cancer consortium

   CONTEXT: The underlying genetic cause of non-medullary thyroid cancer (NMTC) in children is often unknown, hampering both predictive testing of family members and preventive clinical management.
OBJECTIVE: Our objectives were to investigated the potential heritability in the largest childhood NMTC cohort that has been genotyped to date.
DESIGN: Nationwide retrospective cohort study.
SETTING: Tertiary referral centers.
PATIENTS: In total, 97 patients diagnosed with pediatric NMTC between 1970-2020 were included in this study.
INTERVENTION: Germline whole genome sequencing (WGS).
MAIN OUTCOME: The main outcome measures were mutation detection yield in 1) clinically-relevant tumor predisposition genes, and 2) genes previously associated with NMTC.
RESULTS: In total, 13 of 97 patients (13%) carried a germline (likely) pathogenic (P/LP) variant in a well-known tumor predisposition gene: APC (n=1), BRCA2 (n=2), CHEK2 (n=4), DICER1 (n=4), HOXB13 (n=1), , and MITF (n=1). In addition, one patient was diagnosed with Pendred syndrome (SLC26A4) and nine variants of high interest were found in other NMTC candidate susceptibility genes.
CONCLUSION: The reported prevalence (13%) of germline variants in well-known tumor predisposing genes and the added value of a revised personal-/family history and histology led us to recommend genetic counseling for all childhood NMTC patients.The detected tumor predisposition syndromes are associated with a risk for second cancers which necessitates additional surveillance of the index patients and pre-symptomatic genetic testing of at risk family members.

Keywords:  Genetics; Heritability; Non-Medullary Thyroid Cancer; Pediatrics

DOI:  https://doi.org/10.1210/clinem/dgae107
Cancer Discov. 2024 Mar 01. 14(3): 396-405

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions.

Cesar Cobaleda, Lucy A Godley, Kim E Nichols, Marcin W Wlodarski, Isidro Sanchez-Garcia.

SUMMARY: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

DOI: https://doi.org/10.1158/2159-8290.CD-23-1091
Leukemia. 2024 Feb 27.

Germline variants in patients developing second malignant neoplasms after therapy for pediatric acute lymphoblastic leukemia-a case-control study.

Stefanie V Junk, Alisa Förster, Gunnar Schmidt, Martin Zimmermann, Birthe Fedders, Bernd Haermeyer, Anke K Bergmann, Anja Möricke, Gunnar Cario, Bernd Auber, Martin Schrappe, Christian P Kratz, Martin Stanulla.

DOI: https://doi.org/10.1038/s41375-024-02173-2
Int J Hematol. 2024 Feb 29.

First report of familial mixed phenotype acute leukemia: shared clinical characteristics, Philadelphia translocation, and germline variants.

Yuka Shiozawa, Shinya Fujita, Yasuhito Nannya, Seishi Ogawa, Naho Nomura, Toru Kiguchi, Nobuo Sezaki, Himari Kudo, Takaaki Toyama.

  While our understanding of the molecular basis of mixed phenotype acute leukemia (MPAL) has progressed over the decades, our knowledge is limited and the prognosis remains poor. Investigating cases of familial leukemia can provide insights into the role of genetic and environmental factors in leukemogenesis. Although familial cases and associated mutations have been identified in some leukemias, familial occurrence of MPAL has never been reported. Here, we report the first cases of MPAL in a family. A 68-year-old woman was diagnosed with MPAL and received haploidentical stem cell transplantation from her 44-year-old son. In four years, the son himself developed MPAL. Both cases exhibited similar characteristics such as biphenotypic leukemia with B/myeloid cell antigens, Philadelphia translocation (BCR-ABL1 mutation), and response to acute lymphoblastic leukemia-type chemotherapy. These similarities suggest the presence of hereditary factors contributing to the development of MPAL. Targeted sequencing identified shared germline variants in these cases; however, in silico analyses did not strongly support their pathogenicity. Intriguingly, when the son developed MPAL, the mother did not develop donor-derived leukemia and remained in remission. Our cases provide valuable insights to guide future research on familial MPAL.

Keywords:  Familial occurrence; Germline variants; Mixed phenotype acute leukemia; Philadelphia translocation; Shared clinical characteristics

DOI:  https://doi.org/10.1007/s12185-024-03724-0
Pancreas. 2024 Feb 26.

Familial Intraductal Papillary Mucinous Neoplasm Associated With the Germline MSH6 Missense Variant and Progression of Pancreatic cancer.

Koji Tezuka, Mitsunori Yamakawa, Ryoko Murakami, Ichiro Hirai, Ryo Toya, Akihiko Suzuki, Hiroshi Kawamura, Yuki Miyano, Hidenori Sato, Fuyuhiko Motoi.

OBJECTIVES: Intraductal papillary mucinous neoplasm (IPMN) in individuals with at least one first-degree relative with IPMN is defined as familial IPMN. However, few studies have reported on familial IPMN, its clinical characteristics, or the associated genetic factors.
MATERIALS AND METHODS: We report the case of a 58-year-old woman with multifocal IPMN and a mural nodule in the pancreatic body. The patient underwent a distal pancreatectomy and developed pancreatic head cancer 1 year and 6 months postoperatively. The patient had a family history of multifocal IPMN in her father. Therefore, a genetic predisposition to IPMN and pancreatic cancer was suspected. The patient was analyzed for germline variants, and the resected IPMN was subjected to immunohistochemical and somatic variant analyses.
RESULTS: Next-generation sequencing revealed a heterozygous germline missense variant in exon 5 of MSH6 (c.3197A>G; Tyr1066Cys). The pathogenicity of this variant of uncertain significance was suspected based on multiple in silico analyses, and the same MSH6 variant was identified in the patient's father's colonic adenoma. The mural nodule in the pancreatic body was pathologically diagnosed as a high-grade IPMN with ossification and somatic KRAS and PIK3CA variants.
CONCLUSIONS: This case revealed a possible genetic factor for familial IPMN development and presented interesting clinicopathological findings.

DOI: https://doi.org/10.1097/MPA.0000000000002313
Am J Hum Genet. 2024 Feb 21. pii: S0002-9297(24)00034-X. [Epub ahead of print]

Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Chunling Hu, Huaizhi Huang, Jie Na, Carolyn Lumby, Mohamed Abozaid, Megan A Holdren, Tara J Rao, Rachid Karam, Tina Pesaran, Jamie D Weyandt, Christen M Csuy, Christina A Seelaus, Colin C Young, Kelly Fulk, Zahra Heidari, Paulo Cilas Morais Lyra, Ronan E Couch, Benjamin Persons, Eric C Polley, Rohan D Gnanaolivu, Nicholas J Boddicker, Alvaro N A Monteiro, Siddhartha Yadav, Susan M Domchek, Marcy E Richardson, Fergus J Couch.

  Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay. Of these, 137 were functionally abnormal, 313 were functionally normal, and 12 demonstrated intermediate function. Comparisons with other functional studies of BRCA2 missense variants yielded strong correlations. Sequence-based in silico prediction models had high sensitivity, but limited specificity, relative to the homology-directed repair assay. Combining the functional results with clinical and genetic data in an American College of Medical Genetics (ACMG)/Association for Molecular Pathology (AMP)-like variant classification framework from a clinical testing laboratory, after excluding known splicing variants and functionally intermediate variants, classified 431 of 442 (97.5%) missense variants (129 as pathogenic/likely pathogenic and 302 as benign/likely benign). Functionally abnormal variants classified as pathogenic by ACMG/AMP rules were associated with a slightly lower risk of breast cancer (odds ratio [OR] 5.15, 95% confidence interval [CI] 3.43-7.83) than BRCA2 DBD protein truncating variants (OR 8.56, 95% CI 6.03-12.36). Overall, functional studies of BRCA2 variants using validated assays substantially improved the variant classification yield from ACMG/AMP models and are expected to improve clinical management of many individuals found to harbor germline BRCA2 missense VUS.

Keywords:  BRCA2; HDR; VUS; cancer; predisposition genes; variant classification

DOI:  https://doi.org/10.1016/j.ajhg.2024.02.002