bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–05–29
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. TP53 Pathogenic Variants in Early-Onset Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and Li-Fraumeni-like Syndromes.
  2. Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer.
  3. Germline mutations in Chinese ovarian cancer with or without breast cancer.
  4. PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina.
  5. Clinician-Reported Impact of Germline Multigene Panel Testing on Cancer Risk Management Recommendations.
  6. Cancer Risk C (CR-C), a functional genomics test is a sensitive and rapid test for germline mismatch repair deficiency.
  1. Biomolecules. 2022 Apr 27. pii: 640. [Epub ahead of print]12(5):
    TP53 Pathogenic Variants in Early-Onset Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and Li-Fraumeni-like Syndromes.
    Paula Francinete Faustino da Silva, Rebeca Mota Goveia, Thaís Bomfim Teixeira, Bruno Faulin Gamba, Aliny Pereira de Lima, Sílvia Regina Rogatto, Elisângela de Paula Silveira-Lacerda.
      TP53 gene mutation is the most common genetic alteration in human malignant tumors and is mainly responsible for Li-Fraumeni syndrome. Among the several cancers related to this syndrome, breast cancer (BC) is the most common. The TP53 p.R337H germline pathogenic variant is highly prevalent in Brazil's South and Southeast regions, accounting for 0.3% of the general population. We investigated the prevalence of TP53 germline pathogenic variants in a cohort of 83 BC patients from the Midwest Brazilian region. All patients met the clinical criteria for hereditary breast and ovarian cancer syndrome (HBOC) and were negative for BRCA1 and BRCA2 mutations. Moreover, 40 index patients fulfilled HBOC and the Li-Fraumeni-like (LFL) syndromes criteria. The samples were tested using next generation sequencing for TP53. Three patients harbored TP53 missense pathogenic variants (p.Arg248Gln, p.Arg337His, and p.Arg337Cys), confirmed by Sanger sequencing. One (1.2%) patient showed a large TP53 deletion (exons 2-11), which was also confirmed. The p.R337H variant was detected in only one patient. In conclusion, four (4.8%) early-onset breast cancer patients fulfilling the HBOC and LFL syndromes presented TP53 pathogenic variants, confirming the relevance of genetic tests in this group of patients. In contrast to other Brazilian regions, TP53 p.R337H variant appeared with low prevalence.
    Keywords:  Li-Fraumeni syndrome; TP53; breast cancer; cancer predisposition
    DOI:  https://doi.org/10.3390/biom12050640
  2. Biomedicines. 2022 Apr 26. pii: 1004. [Epub ahead of print]10(5):
    Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer.
    Yaxuan Liu, Hafdis T Helgadottir, Pedram Kharaziha, Jungmin Choi, Francesc López-Giráldez, Shrikant M Mane, Veronica Höiom, Carl Christofer Juhlin, Catharina Larsson, Svetlana Bajalica-Lagercrantz.
      Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5-10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17-35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families.
    Keywords:  bioinformatics; germline variants; hereditary breast cancer; whole-exome sequencing
    DOI:  https://doi.org/10.3390/biomedicines10051004
  3. Mol Genet Genomic Med. 2022 May 24. e1940
    Germline mutations in Chinese ovarian cancer with or without breast cancer.
    Ava Kwong, Cecilia Yuen Sze Ho, Vivian Yvonne Shin, Chun Hang Au, Wing Pan Luk, Ling Hiu Fung, Tsun-Leung Chan, Karen Kar Loen Chan, Hextan Yuen Sheung Ngan, Edmond Shiu Kwan Ma.
       BACKGROUND: Ovarian and breast cancers are known to have significant genetic components. Considering the differences in the mutation spectrum across ethnicity, it is important to identify hereditary breast and ovarian cancer (HBOC) genes mutation in Chinese for clinical management.
    METHODS: Two cohorts of 451 patients with ovarian cancer only (OV) and 93 patients with both breast and ovarian (BROV) cancers were initially screened for BRCA1, BRCA2, TP53, and PTEN. 109 OV and 43 BROV patients with extensive clinical risk and were being tested negative, were then further characterized by 30-gene panel analysis.
    RESULTS: Pathogenic BRCA1/2 variants were identified in 45 OV patients and 33 BROV patients, giving a prevalence of 10% and 35.5%, respectively. After the extended screening, mutations in other HBOC genes were identified in an additional 12.8% (14/109) of the OV cohort and 14% (6/43) in the BROV cohort. The most commonly mutated genes in the OV cohort were MSH2 (4.6%) while in the BROV cohort were MSH2 (4.7%) and PALB2 (4.7%). With this extended multigene testing strategy, pathogenic mutations were detected in 12.8% of OV patients (BRCAs: 10%; additional genes: 12.8%) and 40.9% (BRCAs: 35.5%; additional genes: 14%) of BROV patients.
    CONCLUSION: Extended characterization of the contributions of HBOC genes to OV and BROV patients has significant impacts on further management in patients and their families, expanding the screening net for more asymptomatic individuals.
    Keywords:  Chinese; germline mutation; hereditary breast and ovarian cancer
    DOI:  https://doi.org/10.1002/mgg3.1940
  4. Breast Cancer Res Treat. 2022 May 24.
    PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina.
    Ariana Gonzalez, Franco Del Greco, Laura Vargas-Roig, Bianca Brun, Gonzalo Tabares, Alejandra Mampel, Cecilia Montes, Claudia Martin, Marcela Lopez, Norma Rossi, Luisina Bruno, Carolina Ponce, Patricia Quaglio, Alvaro Yanzi, Santiago Acevedo, Lilia Lugo, Paula Lopez Breccia, Silvia Avila, Silvina Sisterna, María Soledad Del Castillo, Martín Vazquez, Lina M Nuñez.
       PURPOSE: PALB2 variants have been scarcely described in Argentinian and Latin-American reports. In this study, we describe molecular and clinical characteristics of PALB2 mutations found in multi-gene panels (MP) from breast-ovarian cancer (BOC) families in different institutions from Argentina.
    METHODS: We retrospectively identified PALB2 pathogenic (PV) and likely pathogenic (LPV) variants from a cohort of 1905 MP results, provided by one local lab (Heritas) and SITHER (Hereditary Tumor Information System) public database. All patients met hereditary BOC clinical criteria for testing, according to current guidelines.
    RESULTS: The frequency of PALB2 mutations is 2.78% (53/1905). Forty-eight (90.5%) are PV and five (9.5%) are LPV. Most of the 18 different mutations (89%) are nonsense and frameshift types and 2 variants are novel. One high-rate recurrent PV (Y551*) is present in 43% (23/53) of the unrelated index cases. From the 53 affected carriers, 94% have BC diagnosis with 14% of bilateral cases. BC phenotype is mainly invasive ductal (78%) with 62% of hormone-receptor positive and 22% of triple negative tumors. Self-reported ethnic background of the cohort is West European (66%) and native Latin-American (20%) which is representative of Buenos Aires and other big urban areas of the country.
    CONCLUSION: This is the first report describing molecular and clinical characteristics of PALB2 carriers in Argentina. Frequency of PALB2 PV in Argentinian HBOC families is higher than in other reported populations. Y551* is a recurrent mutation that seems to be responsible for almost 50% of PALB2 cases.
    Keywords:  Argentina; Breast-ovarian cancer; Germline mutations; Multi-gene panel; PALB2; Recurrent mutation
    DOI:  https://doi.org/10.1007/s10549-022-06620-5
  5. JNCI Cancer Spectr. 2022 Mar 02. pii: pkac002. [Epub ahead of print]6(2):
    Clinician-Reported Impact of Germline Multigene Panel Testing on Cancer Risk Management Recommendations.
    Carolyn Horton, Kirsten Blanco, Min-Tzu Lo, Virginia Speare, Holly LaDuca, Jill S Dolinsky, Allison W Kurian.
       BACKGROUND: With increased adoption of multi-gene panel testing (MGPT) for hereditary cancer, management guidelines now include a wider range of predisposition genes. Yet little is known about whether MGPT results prompt changes to clinicians' risk management recommendations and whether those recommendations adhere to guidelines.
    METHODS: We assessed cancer risk management recommendations made by clinicians ordering MGPT for hereditary cancer at a diagnostic laboratory using an internet-based survey. We received paired pre- and posttest responses for 2172 patients (response rate = 14.3%). Unpaired posttest responses were received in 168 additional patients with positive results. All tests were 2-sided.
    RESULTS: Clinicians reported a change in risk management recommendations for 76.6% of patients who tested positive for a pathogenic or likely pathogenic variant, with changes to surveillance being most common (71.1%), followed by surgical (33.6%), chemoprevention (15.1%), and clinical trial (9.4%) recommendations. Clinicians recommended risk-reducing interventions more often for patients with pathogenic variants in high-risk than moderate-risk genes (P < .001), whereas surveillance recommendations were similar for high-risk and moderate-risk genes. Guideline adherence was high for surveillance (86.3%) and surgical (79.6%) recommendations. Changes to risk management recommendations occurred in 8.8% and 7.6% of patients with uncertain and negative results, respectively.
    CONCLUSIONS: Clinicians report frequent changes to cancer risk management recommendations based on positive results in both high-risk and moderate-risk genes. Reported introduction of interventions in patients with inconclusive and negative results is rare and adherence to practice guidelines is high in patients with positive results, suggesting a low probability of harm resulting from MGPT.
    DOI:  https://doi.org/10.1093/jncics/pkac002
  6. Genet Med. 2022 May 25. pii: S1098-3600(22)00758-4. [Epub ahead of print]
    Cancer Risk C (CR-C), a functional genomics test is a sensitive and rapid test for germline mismatch repair deficiency.
    Ishraq Alim, Johnny Loke, Sarah Yam, Allyson S Templeton, Polly Newcomb, Noralane M Lindor, Rish K Pai, Mark A Jenkins, Daniel D Buchanan, Steven Gallinger, Susan Klugman, Harry Ostrer.
       PURPOSE: Heritable pathogenic variants in the DNA mismatch repair (MMR) pathway cause Lynch syndrome, a condition that significantly increases risk of colorectal and other cancers. At least half of individuals tested using gene panel sequencing have a variant of uncertain significance or no variant identified leading to no diagnosis. To fill this diagnostic gap, we developed Cancer Risk C (CR-C), a flow variant assay test.
    METHODS: In response to treatment with an alkylating agent, individual assays of the nuclear translocation of MLH1, MSH2, BARD1, PMS2, and BRCA2 proteins and the nuclear phosphorylation of the ATM and ATR proteins distinguished pathogenic/likely pathogenic (P/LP) from benign/likely benign variants in MMR genes.
    RESULTS: A risk classification score based on MLH1, MSH2, and ATR assays was 100% sensitive and 98% specific. Causality of MMR P/LP variants was shown through gene editing and rescue. In individuals with suspected Lynch syndrome but no P/LP, CR-C identified most (73%) as having germline MMR defects. Direct comparison of CR-C on matched blood samples and lymphoblastoid cell lines yielded comparable results (r2 > 0.9).
    CONCLUSION: For identifying germline MMR defects, CR-C provides augmentation to traditional panel sequencing through greater accuracy, shorter turnaround time (48 hours), and performance on blood with minimal sample handling.
    Keywords:  Colorectal cancer; Functional genomics; Genetic testing; Lynch syndrome; Variant of uncertain significance
    DOI:  https://doi.org/10.1016/j.gim.2022.05.003
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