bims-lifras 2022-04-17 papers

Front Oncol. 2022 ;12 849004

Case Report: A Novel Pathomechanism in PEComa by the Loss of Heterozygosity of TP53.

Henriett Butz, József Lövey, Márton Szentkereszty, Anikó Bozsik, Erika Tóth, Attila Patócs.

Since the introduction of next-generation sequencing, the frequency of germline pathogenic TP53 variants and the number of cases with unusual clinical presentations have been increasing. This has led to the expansion of the classical Li-Fraumeni syndrome concept to a wider cancer predisposition syndrome designated as the Li-Fraumeni spectrum. Here, we present a case with a malignant, metastatic perivascular epithelioid cell tumor (PEComa) of the thigh muscle and a sinonasal carcinoma harboring a novel TP53 germline splice mutation (NM_000546.5:c.97-2A>C). The classical presentation of LFS in the long-since deceased mother and the presence of a germline TP53 variant in the proband suggested a possible familial TP53-related condition. Complex pathological, molecular, and clinical genetic analyses (whole exome sequencing of germline variants, multigene panel sequencing of tumor DNA, Sanger validation, an in vitro functional test on splicing effect, 3D protein modeling, p53 immunohistochemistry, and pedigree analysis) were performed. The in vitro characterization of the splice mutation supported the pathogenic effect that resulted in exon skipping. A locus-specific loss of heterozygosity in the PEComa but not in the sinonasal carcinoma was identified, suggesting the causative role of the splice mutation in the PEComa pathogenesis, because we excluded known pathogenetic pathways characteristic to PEComas (TSC1/2, TFE3, RAD51B). However, the second hit affecting TP53 in the molecular pathogenesis of the sinonasal carcinoma was not identified. Although PEComa has been reported previously in two patients with Li-Fraumeni syndrome, to the best of our knowledge, this is the first report suggesting a relationship between the aberrant TP53 variant and PEComa.

Keywords: Li-Fraumeni; Li-Fraumeni spectrum; Li–Fraumeni syndrome; PEComa; TP53; germline mutation; heritable TP53-related cancer syndrome; p53

DOI: https://doi.org/10.3389/fonc.2022.849004

Mol Syndromol. 2022 Feb;13(2): 123-131

Genetic Characterization of Hereditary Cancer Syndromes Based on Targeted Next-Generation Sequencing.

Pelin Ercoskun, Cigdem Yuce Kahraman, Guller Ozkan, Abdulgani Tatar.

A hereditary cancer syndrome is a genetic predisposition to cancer caused by a germline mutation in cancer-related genes. Identifying the disease-causing variant is important for both the patient and relatives at risk in cancer families because this could be a guide in treatment and secondary cancer prevention. In this study, hereditary cancer panel harboring cancer-related genes was performed on MiSeq Illumina NGS system from peripheral blood samples. Sequencing files were fed into a cloud-based data analysis pipeline. Reportable variants were classified according to the American College of Medical Genetics and Genomics guidelines. Three hundred five individuals were included in the study. Different pathogenic/likely pathogenic variants were detected in 75 individuals. The majority of these variants were in the MUTYH, BRCA2, and CHEK2 genes. Nine novel pathogenic/likely pathogenic variants were identified in BRCA1, BRCA2, GALNT12, ATM, MLH1, MSH2, APC, and KIT genes. We obtained interesting and novel variants which could be related to hereditary cancer, and this study confirmed that NGS is an indispensable method for the risk assessment in cancer families.

Keywords: Familial cancer; Hereditary cancer syndrome; Li-Fraumeni syndrome; Lynch syndrome; Next-generation sequencing

DOI: https://doi.org/10.1159/000518927

Jpn J Clin Oncol. 2022 Apr 12. pii: hyac046. [Epub ahead of print]

Present status of germline findings in precision medicine for Japanese cancer patients: issues in the current system.

Satomi Higashigawa, Hiroyuki Matsubayashi, Yoshimi Kiyozumi, Nobuhiro Kado, Seiichiro Nishimura, Takuma Oishi, Takashi Sugino, Kunihiro Fushiki, Hiromichi Shirasu, Hirofumi Yasui, Nobuaki Mamesaya, Naomi Fukuzaki, Kana Kunitomo, Yasue Horiuchi, Hirotsugu Kenmotsu, Masakuni Serizawa.

OBJECTIVE: Since 2019, precision cancer medicine has been covered by national insurance in Japan; however, to date, germline findings have not been fully reported. The aim of this study was to evaluate the current status and raise a problem of germline finding analysis and disclosure in Japanese precision cancer medicine.
METHODS: Germline findings of 52 genes were examined in 296 cases with advanced cancer by a case series study.
RESULTS: Six (2.0%) cases were examined by the Oncoguide™ NCC Oncopanel with germline testing, but no germline findings were reported. The remaining 290 (98.0%) cases were analyzed by FoundationOne® CDx (tumor-only testing), which recognized 404 pathogenic variants; those of BRCA1/2 were recognized in 16 (5.5%) tumors. Our institutional algorithm suggested 39 candidate germline findings in 34 cases, while the public algorithm listed at least 91 candidate germline findings. Four germline findings had been previously identified (BRCA1: 3 and ATM: 1). Nine of 30 cases with candidate germline findings excluding these known germline findings refused or deferred germline testing. Only 4 of 16 cases that received counseling underwent germline testing, and those 4 revealed 3 germline findings (BRCA2, CDK4 and RAD51C); in total, 8 (2.7%) germline findings were revealed. Reasons for refusing genetic counseling and/or germline testing included extra hospital visits, added expense for germline testing due to limited national insurance coverage, poor patient physical condition and no known family members associated with the possible germline finding.
CONCLUSIONS: In current Japanese precision cancer medicine, only a small fraction of the patients undergoes germline testing and demonstrated germline finding. The current results suggested a need for earlier indications for precision cancer medicine, broader insurance coverage and more efficient germline finding prediction algorithms, to increase the number of germline testings and to improve the following managements.

Keywords: cancer-gene panel testing; comprehensive genomic profiling; germline finding; hereditary cancer; national health insurance; precision medicine

DOI: https://doi.org/10.1093/jjco/hyac046

Hum Mutat. 2022 Apr 14.

Feasibility and limitations of cultured skin fibroblasts for germline genetic testing in hematologic disorders.

Lia DeRoin, Marcela Cavalcante de Andrade Silva, Kristin Petras, Kelly Arndt, Nathaniel Phillips, Pankhuri Wanjari, Hari Prasanna Subramanian, David Montes, James McElherne, Megan Theissen, Renee Briese, Soma Das, Lucy A Godley, Jeremy Segal, Daniela Del Gaudio, Carrie Fitzpatrick, Jane E Churpek.

To avoid acquired variants found in the blood, cultured skin fibroblasts are a recommended DNA source for germline genetic testing in patients with hematologic disorders, but data are lacking regarding practicality and limitations. We conducted a retrospective cohort study of 350 subjects with hematologic disorders who underwent skin fibroblast culture for germline genetic testing. We analyzed next-generation sequencing data from the targeted capture of 144 inherited cancer and bonemarrow failure genes to identify variants at heterozygous and subclonal variant allele frequencies. Sixteen (5%) biopsies failed to culture. Culture failure was more likely in samples with delays in culture initiation (OR = 4.3; p < 0.01) or a pathogenic variant in a telomere gene (OR = 42.6; p < 0.01). Median culture time was 28 days (IQR 22-29 days). Culture time was longer for subjects with prior allogeneic stem cell transplantation (+10.7%; p = 0.02) and shorter in subjects with a heterozygous pathogenic variant (-11.9%; p < 0.01), larger biopsy size (-10.6%; p < 0.01), or lymphoid malignancy (-8.4%; p < 0.01). Subclonal variants were identified in 10 (4%) and confirmed in five (56%) of eight with alternate samples available. Subclonal and discordant variants illustrate that germline testing from cultured skin fibroblasts requires phenotypic correlation and, in rare cases, follow-up studies for optimal interpretation.

Keywords: germline genetics; inherited; leukemia; lymphoma; myelodysplastic syndrome; skin fibroblasts

DOI: https://doi.org/10.1002/humu.24374

Cancers (Basel). 2022 Mar 23. pii: 1621. [Epub ahead of print]14(7):

Inhibiting the Priming for Cancer in Li-Fraumeni Syndrome.

Pan Pantziarka, Sarah Blagden.

The concept of the pre-cancerous niche applies the 'seed and soil' theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS.

Keywords: Li-Fraumeni Syndrome; TP53; cancer pre-disposition; drug re-purposing; pre-cancer niche

DOI: https://doi.org/10.3390/cancers14071621

Oral Oncol. 2022 Apr 12. pii: S1368-8375(22)00148-8. [Epub ahead of print]128 105859

Interaction analysis between germline genetic variants and somatic mutations in head and neck cancer.

Guanying Feng, Hongjie Feng, Yibo Qi, Tianxiao Wang, Nan Ni, Jia Wu, Hua Yuan.

OBJECTIVES: To evaluate interactions between germline genetic variants and somatic mutations in head and neck cancer (HNC).
METHODS: The region enrichment analysis was performed to evaluate the enrichment of cancer driver genes (CDGs) in susceptibility regions. The pathway enrichment analysis was performed to identify common pathways of cancer driver genes and susceptibility genes. The association analysis was performed to evaluate the relationships between germline variants and somatic mutations. Stratified analysis was performed based on HPV status.
RESULTS: A total of 18 risk SNPs, 149 cancer susceptibility genes (CSGs), and 211 CDGs were included. Enrichment analysis revealed that CDGs were significantly enriched in susceptibility regions (P = 0.048) and CSGs were significantly enriched in CDGs (P = 0.006). The CSGs and CDGs were commonly enriched in seven pathways. The rs1229984 was associated with truncation mutation within five pathways (P = 0.0026). The rs1453414 was associated with somatic mutations in RBM15 (P = 0.0012). The rs310518 was significantly associated with signature 15, and rs259919 was significantly associated with signature 6. The HPV status significantly influenced the association between risk SNPs and somatic mutations, copy number values, and mutation signatures.
CONCLUSION: These results provide novel insights for germline-somatic interactions in HNC, which will enhance the understanding of the molecular mechanisms of germline variants with somatic mutations in HNC.

Keywords: Association analysis; Enrichment analysis; Germline genetic variant; Head and neck cancer; Interaction; Somatic mutation

DOI: https://doi.org/10.1016/j.oraloncology.2022.105859