bims-lifras 2024-06-23 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2024–06–23
nine papers selected by
Joanna Zawacka, Karolinska Institutet

Molecular insights into TP53 mutation (p. Arg267Trp) and its connection to Choroid Plexus Carcinomas and Li-Fraumeni Syndrome.
Landscape of potential germline pathogenic variants in select cancer susceptibility genes in patients with adult-type ovarian granulosa cell tumors.
BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management.
Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer.
Hereditary Cancer Clinics Improve Adherence to NCCN Germline Testing Guidelines for Pancreatic Cancer.
Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer.
Mutational characteristics and clinical outcomes for lung adenocarcinoma with EGFR germline mutations.
Management and Clinical Outcomes of Breast Cancer in Women Diagnosed with Hereditary Cancer Syndromes in a Clinic-Based Sample from Colombia.
Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

Genes Genomics. 2024 Jun 19.

Molecular insights into TP53 mutation (p. Arg267Trp) and its connection to Choroid Plexus Carcinomas and Li-Fraumeni Syndrome.

Zainularifeen Abduljaleel.

   BACKGROUND: Choroid plexus carcinomas (CPCs) are rare malignant tumors primarily affecting pediatric patients and often co-occur with Li-Fraumeni Syndrome (LFS), an inherited predisposition to early-onset malignancies in multiple organ systems. LFS is closely linked to TP53 mutations, with germline TP53 gene mutations present in approximately 75% of Li-Fraumeni syndrome families and 25% of Li-Fraumeni-like syndrome families. Individuals with TP53 mutations also have an elevated probability of carrying mutations in BRCA1 and BRCA2 genes.
OBJECTIVE: To investigate the structural and functional implications of the TP53: 799C > T, p. (Arg267Trp) missense mutation, initially identified in a Saudi family, and understand its impact on TP53 functionality and related intermolecular interactions.
METHODS: Computational analyses were conducted to examine the structural modifications resulting from the TP53: 799C > T, p. (Arg267Trp) mutation. These analyses focused on the mutation's impact on hydrogen bonding, ionic interactions, and the specific interaction with Cell Cycle and Apoptosis Regulator 2 (CCAR2), as annotated in UniProt.
RESULTS: The study revealed that the native Arg267 residue is critical for a salt bridge interaction with glutamic acid at position 258. The mutation-induced charge alteration has the potential to disrupt this ionic bonding. Additionally, the mutation is located within an amino acid region crucial for interaction with CCAR2. The altered properties of the amino acid within this domain may affect its functionality and disrupt this interaction, thereby impacting the regulation of catalytic enzyme activity.
CONCLUSIONS: Our findings highlight the intricate intermolecular interactions governing TP53 functionality. The TP53: 799C > T, p. (Arg267Trp) mutation causes structural modifications that potentially disrupt critical ionic bonds and protein interactions, offering valuable insights for the development of targeted mutants with distinct functional attributes. These insights could inform therapeutic strategies for conditions associated with TP53 mutations.

Keywords:  Computational Structural Analysis; Genetic Variants; Hereditary Cancer Syndrome; Rare Genetic Disorder; Tumor Suppressor Gene

DOI:  https://doi.org/10.1007/s13258-024-01531-9
Cancer Med. 2024 Jun;13(12): e7340

Landscape of potential germline pathogenic variants in select cancer susceptibility genes in patients with adult-type ovarian granulosa cell tumors.

Rebekah M Summey, Erica Gornstein, Brennan Decker, Kali C Dougherty, Janet S Rader, Elizabeth Hopp.

   OBJECTIVE: The objective of this study was to assess the frequency of potential germline pathogenic variants that may contribute to risk of development of adult granulosa cell tumors (AGCT) given the paucity of germline testing guidelines for these patients.
METHODS: This was a retrospective cross-sectional study analyzing comprehensive genomic profiling (CGP) results of AGCT with the FOXL2 p.C134W mutation submitted to Foundation Medicine between 2012 and 2022. Cases with a potential germline pathogenic variant were identified by filtering single nucleotide variants and short indels by variant allele frequency (VAF) and presence in ClinVar for select cancer susceptibility genes. Odds ratios for AGCT risk were calculated compared to a healthy population.
RESULTS: Prior to analysis, 595 patients were screened and 516 with a somatic FOXL2 p.C134W mutation were included. Potential germline pathogenic variants in a DNA repair-related gene (ATM, BRCA1, BRCA2, CHEK2, PALB2, PMS2, RAD51C, or RAD51D) were found in 6.6% of FOXL2-mutated AGCT. Potential germline pathogenic CHEK2 variants were found in 3.5% (18/516) of AGCT patients, a rate that was 2.8-fold higher than Genome Aggregation Database non-cancer subjects (95% CI 1.8-4.6, p < 0.001). The founder variants p.I157T (38.9%, 7/18) and p.T367fs*15 (c.1100delC; 27.8%, 5/18) were most commonly observed. CHEK2 VAF indicated frequent loss of the wildtype copy of the gene.
CONCLUSIONS: These results support ongoing utilization of genomic tumor profiling and confirmatory germline testing for potential germline pathogenic variants. Further prospective investigation into the biology of germline variants in this population is warranted.

Keywords:  cancer genetics; cancer prevention; cancer risk factors; clinical cancer research

DOI:  https://doi.org/10.1002/cam4.7340
Int J Mol Sci. 2024 Jun 06. pii: 6274. [Epub ahead of print]25(11):

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management.

Vuthy Ea, Claudine Berthozat, Hélène Dreyfus, Clémentine Legrand, Estelle Rousselet, Magalie Peysselon, Laura Baudet, Guillaume Martinez, Charles Coutton, Marie Bidart.

  For patients with hereditary breast and ovarian cancer, the probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes is rare. Using targeted next-generation sequencing (NGS), we investigated a 49-year-old Caucasian woman who developed a highly aggressive breast tumor. Our analyses identified an intragenic germline heterozygous duplication in BRCA1 with an additional likely PV in the TP53 gene. The BRCA1 variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints were characterized at the nucleotide level (c.135-2578_442-1104dup). mRNA extracted from lymphocytes was amplified by RT-PCR and then Sanger sequenced, revealing a tandem duplication r.135_441dup; p.(Gln148Ilefs*20). This duplication results in the synthesis of a truncated and, most likely, nonfunctional protein. Following functional studies, the TP53 exon 5 c.472C > T; p.(Arg158Cys) missense variant was classified as likely pathogenic by the Li-Fraumeni Syndrome (LFS) working group. This type of unexpected association will be increasingly identified in the future, with the switch from targeted BRCA sequencing to hereditary breast and ovarian cancer (HBOC) panel sequencing, raising the question of how these patients should be managed. It is therefore important to record and investigate these rare double-heterozygous genotypes.

Keywords:  double heterozygotes; exon duplication; genetic counseling; hereditary breast and ovarian cancer syndrome (HBOC); multi-gene panel testing

DOI:  https://doi.org/10.3390/ijms25116274
Lancet Respir Med. 2024 Jun 14. pii: S2213-2600(24)00124-3. [Epub ahead of print]

Biological and therapeutic implications of the cancer-related germline mutation landscape in lung cancer.

Emmanouil Panagiotou, Ioannis A Vathiotis, Periklis Makrythanasis, Fred Hirsch, Triparna Sen, Konstantinos Syrigos.

Although smoking is the primary cause of lung cancer, only about 15% of lifelong smokers develop the disease. Moreover, a substantial proportion of lung cancer cases occur in never-smokers, highlighting the potential role of inherited genetic factors in the cause of lung cancer. Lung cancer is significantly more common among those with a positive family history, especially for early-onset disease. Therefore, the presence of pathogenic germline variants might act synergistically with environmental factors. The incorporation of next-generation sequencing in routine clinical practice has led to the identification of cancer-predisposing mutations in an increasing proportion of patients with lung cancer. This Review summarises the landscape of germline susceptibility in lung cancer and highlights the importance of germline testing in patients diagnosed with the disease, which has the potential to identify individuals at risk, with implications for tailored therapeutic approaches and successful prevention through genetic counselling and screening.

DOI: https://doi.org/10.1016/S2213-2600(24)00124-3
J Natl Compr Canc Netw. 2024 Jun 18. 1-7

Hereditary Cancer Clinics Improve Adherence to NCCN Germline Testing Guidelines for Pancreatic Cancer.

Claudia Rosso, Naomie Devico Marciano, Deepika Nathan, Wen-Pin Chen, Christine E McLaren, Kathryn E Osann, Pamela L Flodman, May T Cho, Fa-Chyi Lee, Farshid Dayyani, Jason A Zell, Jennifer B Valerin.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC).
METHODS: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses.
RESULTS: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]).
CONCLUSIONS: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

Keywords:  NCCN guidelines; genetic counseling; germline mutation; hereditary cancer clinic; pancreatic cancer

DOI:  https://doi.org/10.6004/jnccn.2023.7333
Breast Cancer Res Treat. 2024 Jun 15.

Pedigree analysis exploring the inconsistency between diverse phenotypes and testing criteria for germline TP53 mutations in Chinese women with breast cancer.

Xin Huang, Chang Chen, Yan Lin, Changjun Wang, Xingtong Zhou, Ying Xu, Qiang Sun, Yidong Zhou.

   PURPOSE: In the present study, we addressed the inconsistency between the testing criteria and diverse phenotypes for germline TP53 mutation in patients with breast cancer in the Chinese population.
METHOD: We proposed a new added item (synchronous or metachronous bilateral breast cancer) as one of the testing criteria (aimed at high-penetrance breast cancer susceptibility genes) and applied it for determining TP53 germline mutation status in 420 female patients with breast cancer using multigene panel-based next-generation sequencing, Sanger sequencing, and mass spectrometry.
RESULTS: We found that 1.4% of patients carried a pathogenic or likely pathogenic germline TP53 mutation. Compared with BRCA mutation carriers (8.0%) and non-carriers (7.1%), TP53 mutation carriers (33.3%) developed breast cancer earlier. The majority of TP53 mutation carriers (66.7%) developed breast cancer after age 30 and had bilateral breast cancer (33.3%). Pedigree investigation of four TP53 carriers and a patient with a TP53 variant of unknown significance revealed that neither of their parents harbored the same mutations as the probands, indicating that the mutations might occur de novo.
CONCLUSION: Our study revealed distinguishing features of TP53 carriers among Chinese women with breast cancer, which is inconsistent with the currently used testing criteria; therefore, the newly proposed testing criteria may be more appropriate.

Keywords:   TP53 mutation; Breast cancer; De novo mutation; Mosaic mutation; Pedigree analysis; Phenotype

DOI:  https://doi.org/10.1007/s10549-024-07341-7
J Thorac Oncol. 2024 Jun 10. pii: S1556-0864(24)00614-2. [Epub ahead of print]

Mutational characteristics and clinical outcomes for lung adenocarcinoma with EGFR germline mutations.

Kelsey Pan, Jennifer Owens, Yasir Elamin, Charles Lu, Mark Routbort, Jianjun Zhang, Frank Fossella, Marcelo V Negrao, Mehmet Altan, Jenny Pozadzides, Ferdinandos Skoulidis, Anne Tsao, Tina Cascone, John V Heymach, Edwin Ostrin, Xiuning Le.

   BACKGROUND: Germline mutations driving lung cancer have been infrequently reported in literature, with EGFR T790M being a known germline mutation identified in 1% of NSCLC. Typically, a somatic EGFR mutation is acquired to develop lung adenocarcinoma. Osimertinib has become standard-of-care treatment for EGFR T790M-positive lung cancer.
METHODS: We perform a retrospective analysis through the Lung Cancer Moon Shot GEMINI database at the UT MD Anderson Cancer Center. Of the patients that underwent cfDNA analysis, germline mutations were identified by those with high variant allelic fraction (VAF) approximating 50%, followed by further confirmation on genetic testing.
RESULTS: We identified 22 patients with germline EGFR mutations, with the majority harboring an EGFR T790M mutation (95.5%) and EGFR L858R somatic mutation (50%). Notably, most patients were female (86.4%), non-smokers (81.8%), Caucasian (86.4%), have family history of lung cancer (59.1%), and stage IV at diagnosis (72.7%). A distinct radiographic pattern of small multifocal ground-glass pulmonary nodules was observed in the majority of our cohort (72.7%). Among the 18 with advanced-stage NSCLC, 12 (66.7%) were treated with first-line osimertinib, demonstrating a median PFS of 16.9 months (95% CI; 6.3-NR). Others were treated with first-line afatinib (11.1%) or chemotherapy (22.2%). Among the 17 patients treated with osimertinib (in first or second-line), mPFS was 20.4 months (95% CI; 6.3-NR) and mOS was 82.0 months (95% CI; 28.4-NR).
CONCLUSION: Based on our institutional cohort, NSCLC driven by EGFR germline mutations occur more frequently in non-smoking, Caucasian females with multi-focal pulmonary nodules radiographically. Osimertinib for advanced germline EGFR-mutated NSCLC renders similar PFS compared to somatic T790M EGFR-mutated NSCLC.

Keywords:  EGFR; NSCLC; germline

DOI:  https://doi.org/10.1016/j.jtho.2024.06.004
Cancers (Basel). 2024 May 26. pii: 2020. [Epub ahead of print]16(11):

Management and Clinical Outcomes of Breast Cancer in Women Diagnosed with Hereditary Cancer Syndromes in a Clinic-Based Sample from Colombia.

María Carolina Sanabria-Salas, Ana Pedroza-Duran, Sandra E Díaz-Casas, Marcela Nuñez Lemus, Carlos F Grillo-Ardila, Ximena Briceño-Morales, Mauricio García-Mora, Javier Ángel-Aristizábal, Iván Fernando Mariño Lozano, Raúl Alexis Suarez Rodríguez, Luis Hernán Guzmán Abisaab.

  This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs.

Keywords:  bilateral risk-reducing mastectomy; breast neoplasms; genetic predisposition to disease; hereditary breast and ovarian cancer syndrome; prevention; survival

DOI:  https://doi.org/10.3390/cancers16112020
Breast Cancer Res Treat. 2024 Jun 20.

Characteristics of Chinese breast cancer patients with double heterozygosity for BRCA1 and BRCA2 germline pathogenic variants.

Song Wen, Meng Zhang, Jiuan Chen, Li Hu, Jie Sun, Lu Yao, Ye Xu, Juan Zhang, Yuntao Xie.

   PURPOSE: Despite of very rare, breast cancer patients with double heterozygosity (DH) variants in BRCA1 and BRCA2 genes have been identified in other ethnic groups and seem to be associated with distinctive phenotypes. However, little is known about the frequency and clinical characteristics of Chinese breast cancer patients with BRCA1/2 DH variants.
METHODS: Four hundred and eleven unrelated patients with BRCA1 or BRCA2 pathogenic variants (PVs) were identified in a large series of unselected breast cancer patients. Another two siblings with metachronous bilateral breast cancer were referred for genetic counseling, after which BRCA1/2 DH variants were detected.
RESULTS: Four unrelated breast cancer patients with BRCA1/2 DH were identified in the cohort of 411 patients with BRCA1 or BRCA2 PVs, the frequency of BRCA1/2 DH was 0.97%. In total, six BRCA1/2 DH patients from five families were found in this study. In two families, the hereditary pattern of DH was speculated to have originated from both sides of the family. BRCA1/2 DH patients were more likely to have a family history of breast cancer than patients with a BRCA1 (100% vs. 29.2%, P = 0.004) or BRCA2 (100% vs. 29.6%, P = 0.004) single PV. BRCA1/2 DH patients were more likely to be triple-negative breast tumors than patients with single BRCA2 PVs (66.7% vs. 14.1%, P = 0.020), which was comparable to the findings in patients with single BRCA1 PVs (66.7% vs. 56.9%, P = 1.00).
CONCLUSION: Chinese patients with BRCA1/2 DH exhibit a high percentage of family history of breast cancer. The tumor pathological features of BRCA1/2 DH carriers are similar to those of BRCA1 PV carriers.

Keywords:   BRCA1 ; BRCA2 ; Double heterozygosity; Hereditary breast cancer

DOI:  https://doi.org/10.1007/s10549-024-07409-4