bims-lifras 2023-07-16 papers

Cureus. 2023 Jun;15(6): e40025

Identification of a TP53 Mutation in a Patient With Li-Fraumeni Syndrome and Not Meeting the Revised Chompret Criteria: A Case Report.

Monika Iwasaki, Clara So, Torahiko Jinta.

Li-Fraumeni syndrome (LFS) is a rare familial disorder caused by germline TP53 mutations. Despite the establishment of the revised Chompret criteria to guide genetic testing for TP53, identifying LFS in patients who do not satisfy these criteria remains a challenge. Herein, we present the case of a 50-year-old woman with a history of breast, lung, colorectal, and tongue cancers who did not satisfy the revised Chompret criteria. However, genetic testing ultimately revealed a TP53 mutation, leading to the diagnosis of LFS. Although her family history did not satisfy the classic LFS criteria, she had a TP53 core tumor before the age of 46 years. This case highlights the importance of considering LFS in patients with a history of multiple cancers and suggests that genetic testing should be considered even in patients who do not satisfy the revised Chompret criteria.

Keywords: braca1; brca2; breast cancer; chompret criteria; her2-positive; heritable tp53-related cancer syndrome; li-fraumeni syndrome; lung cancer; multiple cancer; tp53

DOI: https://doi.org/10.7759/cureus.40025

Cancer Prev Res (Phila). 2023 Jul 05. pii: CAPR-23-0011. [Epub ahead of print]

Rates of intervention and cancer detection on initial versus subsequent whole body MRI screening in Li-Fraumeni Syndrome.

Laura At Kagami, Yun K Du, Conrad J Fernandes, Anh N Le, Madeline Good, Melani M Duvall, Sarah E Baldino, Jacquelyn Powers, Kristin Zelley, Lisa J States, Manoj C Mathew, Bryson W Katona, Suzanne P MacFarland, Kara N Maxwell.

Li-Fraumeni Syndrome (LFS) is a hereditary cancer predisposition syndrome with up to 90% lifetime cancer risk. Cancer screening, including annual whole-body MRI (WBMRI), is recommended due to known survival advantage, with cancer detection rate of 7% on initial screening. Intervention and cancer detection rates on subsequent screenings are unknown. Clinical data for pediatric and adult LFS patients (n=182) were reviewed, including instances of WBMRI screening and interventions based on screening results. For each WBMRI screening, interventions including biopsy and secondary imaging, as well as rate of cancer diagnosis, were analyzed comparing initial versus subsequent WBMRI. Of the total cohort (n=182), we identified 68 adult patients and 50 pediatric patients who had undergone at least two WBMRI screenings, with a mean of 3.8+1.9 (adults) and 4.0+2.1 (pediatric) screenings. Findings on initial screening led to an imaging or invasive intervention in 38% of adults and 20% of children. On follow up, overall intervention rates were lower for adults (19%, p=0.0026) and stable for children (19%, p=NS). Thirteen cancers were detected overall (7% of adult and 14% of pediatric scans), on both initial (pediatric: 4%, adult: 3%) and subsequent (pediatric: 10%, adult: 6%) screenings. Rates of intervention after WBMRI screening decreased significantly in adults between first and subsequent exams and remained stable in pediatric patients. Cancer detection rates were similar on screening (3-4% initial, 6-10% subsequent) for both children and adults. These findings provide important data for counseling LFS patients about screening outcomes.

DOI: https://doi.org/10.1158/1940-6207.CAPR-23-0011

Blood Adv. 2023 Jul 14. pii: bloodadvances.2023009742. [Epub ahead of print]

Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome.

Germline predisposition in acute myeloid leukemia (AML) has gained importance in recent years due to a non-negligible frequency and impact on management of patients and their relatives. Risk alleles for AML development may be present in patients without a clinical suspicion of hereditary hematologic malignancy syndrome. In this study we investigated the presence of germline variants (GV) in 288 genes related to cancer predisposition in 47 patients with available paired tumor-normal material, namely bone marrow stroma cells (BMSC, n=29), post-remission bone marrow (PRBM, n=17) and saliva (n=1). These patients correspond to two broad AML categories with heterogeneous genetic background (AML myelodysplasia-related and AML defined by differentiation) and none of them had phenotypic abnormalities, previous history of cytopenia nor strong cancer aggregation. We found 11 pathogenic or likely pathogenic variants, six affecting genes related to autosomal dominant cancer predisposition syndromes (ATM, DDX41 and CHEK2) and 5 related to autosomal recessive bone marrow failure syndromes (FANCA, FANCM, SBDS, DNAJC21 and CSF3R). We did not find differences in clinical characteristics nor outcome between GV carriers vs non-carriers. Further studies in unselected AML cohorts are needed to determine GV incidence and penetrance and, in particular, to clarify the role of ATM nonsense mutations in AML predisposition.

DOI: https://doi.org/10.1182/bloodadvances.2023009742

Front Oncol. 2023 ;13 1153082

Biallelic disruption of DDX41 activity is associated with distinct genomic and immunophenotypic hallmarks in acute leukemia.

Anne Tierens, Elizabeth Kagotho, Satoru Shinriki, Andrew Seto, Adam C Smith, Melanie Care, Dawn Maze, Hassan Sibai, Karen W Yee, Andre C Schuh, Dennis Dong Hwan Kim, Vikas Gupta, Mark D Minden, Hirotaka Matsui, José-Mario Capo-Chichi.

Introduction: Inherited DDX41 mutations cause familial predisposition to hematologic malignancies including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), with the majority of DDX41 mutated MDS/AMLs described to date harboring germline DDX41 and co-occurring somatic DDX41 variants. DDX41-AMLs were shown to share distinguishing clinical features such as a late AML onset and an indolent disease associated with a favorable outcome. However, genotype-phenotype correlation in DDX41-MDS/AMLs remain poorly understood.
Methods: Here, we studied the genetic profile, bone marrow morphology and immunophenotype of 51 patients with DDX41 mutations. We further assessed the functional impact of ten previously uncharacterized DDX41 variants of uncertain significance.
Results: Our results demonstrate that MDS/AML cases harboring two DDX41 variants share specific clinicopathologic hallmarks that are not seen in other patients with monoallelic DDX41 related hematologic malignancies. We further showed that the features seen in these individuals with two DDX41 variants were concordant with biallelic DDX41 disruption.
Discussion: Here, we expand on previous clinicopathologic findings on DDX41 mutated hematologic malignancies. Functional analyses conducted in this study unraveled previously uncharacterized DDX41 alleles and further illustrate the implication of biallelic disruption in the pathophysiology of this distinct AML entity.

Keywords: DDX41 mutations; acute leukemia; biallelic; clinical pathology; myelodysplastic syndrome

DOI: https://doi.org/10.3389/fonc.2023.1153082

Cancer Res Commun. 2023 Jul;3(7): 1200-1211

The African-centric P47S Variant of TP53 Confers Immune Dysregulation and Impaired Response to Immune Checkpoint Inhibition.

David C Stieg, Joshua L D Parris, Tyler Hong Loong Yang, Gauri Mirji, Sarah Kim Reiser, Nivitha Murali, Madison Werts, Thibaut Barnoud, David Y Lu, Rahul Shinde, Maureen E Murphy, Daniel T Claiborne.

The tumor suppressor TP53 is the most frequently mutated gene in cancer and is mutationally inactivated in 50% of sporadic tumors. Inactivating mutations in TP53 also occur in Li Fraumeni syndrome (LFS). In addition to germline mutations in TP53 in LFS that completely inactivate this protein, there are many more germline mutant forms of TP53 in human populations that partially inactivate this protein: we call these partially inactivating mutations "hypomorphs." One of these hypomorphs is a SNP that exists in 6%-10% of Africans and 1%-2% of African Americans, which changes proline at amino acid 47 to serine (Pro47Ser; P47S). We previously showed that the P47S variant of p53 is intrinsically impaired for tumor suppressor function, and that this SNP is associated with increased cancer risk in mice and humans. Here we show that this SNP also influences the tumor microenvironment, and the immune microenvironment profile in P47S mice is more protumorigenic. At basal levels, P47S mice show impaired memory T-cell formation and function, along with increased anti-inflammatory (so-called "M2") macrophages. We show that in tumor-bearing P47S mice, there is an increase in immunosuppressive myeloid-derived suppressor cells and decreased numbers of activated dendritic cells, macrophages, and B cells, along with evidence for increased T-cell exhaustion in the tumor microenvironment. Finally, we show that P47S mice demonstrate an incomplete response to anti-PD-L1 therapy. Our combined data suggest that the African-centric P47S variant leads to both intrinsic and extrinsic defects in tumor suppression.
Significance: Findings presented here show that the P47S variant of TP53 influences the immune microenvironment, and the immune response to cancer. This is the first time that a naturally occurring genetic variant of TP53 has been shown to negatively impact the immune microenvironment and the response to immunotherapy.

DOI: https://doi.org/10.1158/2767-9764.CRC-23-0149

Leuk Res. 2023 Jun 19. pii: S0145-2126(23)00609-4. [Epub ahead of print]132 107344

Germline predisposition to clonal hematopoiesis.

Jie Liu, Afaf E G Osman, Kelly Bolton, Lucy A Godley.

We now recognize that with aging, hematopoietic stem and progenitor cells (HSPCs) acquire mutations that confer a fitness advantage and clonally expand in a process now termed clonal hematopoiesis (CH). Because CH predisposes to a variety of health problems, including cancers, cardiovascular diseases, and inflammatory conditions, there is intense interest in the inherited alleles associated with the development of CH. DNA variants near TERT, SMC4, KPNA4, IL12A, CD164, and ATM confer the strongest associations. In this review, we discuss our current state of knowledge regarding germline predisposition to CH.

DOI: https://doi.org/10.1016/j.leukres.2023.107344