bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2023–07–30
six papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. A Novel Variant in the TP53 Gene Causing Li-Fraumeni Syndrome.
  2. Germline whole genome sequencing in adults with multiple primary tumors.
  3. Germline mutations in 12 genes and risk of ovarian cancer in three population-based cohorts.
  4. Prevalence and significance of DDX41 gene variants in the general population.
  5. Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility.
  6. Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.
  1. Children (Basel). 2023 Jun 30. pii: 1150. [Epub ahead of print]10(7):
    A Novel Variant in the TP53 Gene Causing Li-Fraumeni Syndrome.
    Dimitrios T Papadimitriou, Constantine A Stratakis, Antonis Kattamis, Stavros Glentis, Constantine Dimitrakakis, George P Spyridis, Panagiotis Christopoulos, George Mastorakos, Nikolaos F Vlahos, Nicoletta Iacovidou.
      Li-Fraumeni syndrome (LFS) is an autosomal dominant hereditary cancer syndrome associated with germline pathogenic variants in the tumor protein p53 (TP53) gene and elevated risk of a broad range of early-onset malignancies. Patients with LFS are at risk of a second and third primary tumor. A 15-month-old girl consulted for clitoromegaly and pubic hair. Adrenal ultrasound detected a large left adrenal tumor. Left total adrenalectomy confirmed adrenocortical carcinoma. Family history revealed multiple highly malignant neoplasms at an early age across five generations, and a genetic dominant trait seemed probable. Whole-genome sequencing was performed. Multiple members of the family were found positive for a novel likely pathogenic variant (c. 892delGinsTTT, p. Glu298PhefsX48, NM_000546.6) in the TP53 gene, causing the loss of normal protein function through non-sense-mediated mRNA decay. According to the PSV1 supporting criteria and the Auto PVS1 online tool this frameshift variant: hg19/17-7577045-TC-TAAA:NM_000546.6 has a very strong, definitive clinical validity for LFS with autosomal dominant inheritance. Proper guidance resulted in timely diagnosis of a second tumor (primary osteosarcoma) in the index case and in the early detection of breast and cervical cancer in her young mother. Patients with cancer predisposition syndromes like LFS require close multidisciplinary cancer surveillance and appropriate referral to expert centers.
    Keywords:  Li–Fraumeni syndrome; TP53 gene; adrenocortical tumor; breast cancer; cervical cancer; osteosarcoma
    DOI:  https://doi.org/10.3390/children10071150
  2. Fam Cancer. 2023 Jul 22.
    Germline whole genome sequencing in adults with multiple primary tumors.
    Yiming Wang, Qiliang Ding, Stephenie Prokopec, Kirsten M Farncombe, Jeffrey Bruce, Selina Casalino, Jeanna McCuaig, Marta Szybowska, Kalene van Engelen, Jordan Lerner-Ellis, Trevor J Pugh, Raymond H Kim.
      Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored. Here, we report our germline sequencing results from WGS in 9 patients with MPTs who had non-informative multigene panel testing. Following germline WGS, sequence (agnostic or 735 selected genes) and copy number variant (CNV) analysis was performed according to the American College of Medical Genetics (ACMG) standards and guidelines for interpreting sequence variants and reporting CNVs. In this cohort, WGS, as a second-tier test, did not identify additional pathogenic or likely pathogenic variants in cancer predisposition genes. Although we identified a CHEK2 likely pathogenic variant and a MUTYH pathogenic variant, both were previously identified in the multigene panels and were not explanatory for the presented type of tumors. CNV analysis also failed to identify any pathogenic or likely pathogenic variants in cancer predisposition genes. In summary, after multigene panel testing, WGS did not reveal any additional pathogenic variants in patients with MPTs. Our study, based on a small cohort of patients with MPT, suggests that germline gene panel testing may be sufficient to investigate these cases. Future studies with larger sample sizes may further elucidate the additional utility of WGS in MPTs.
    Keywords:  Cancer predisposition genes; Multigene panel; Multiple primary tumors; Whole genome sequencing
    DOI:  https://doi.org/10.1007/s10689-023-00343-2
  3. Cancer Epidemiol Biomarkers Prev. 2023 Jul 26. pii: EPI-23-0041. [Epub ahead of print]
    Germline mutations in 12 genes and risk of ovarian cancer in three population-based cohorts.
    Joanne Kotsopoulos, Cassandra A Hathaway, Steven A Narod, Lauren R Teras, Alpa V Patel, Chunling Hu, Siddhartha Yadav, Fergus J Couch, Shelley S Tworoger.
       BACKGROUND: With the widespread use of multigene panel genetic testing, population-based studies are necessary to accurately assess penetrance in unselected individuals. We evaluated the prevalence of germline pathogenic or likely pathogenic variants (mutations) in 12 cancer-predisposition genes and associations with ovarian cancer risk in three population-based prospective studies (Nurses' Health Study [NHS], NHSII, Cancer Prevention Study II).
    METHODS: We included women with epithelial ovarian or peritoneal cancer (n=776) and controls who were alive and had at least one intact ovary at the time of the matched case diagnosis (n=1,509). Germline DNA was sequenced for mutations in 12 genes. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for ovarian cancer risk by mutation status.
    RESULTS: The mutation frequency across all 12 genes was 11.2% in cases and 3.3% in controls (P<0.0001). BRCA1 and BRCA2 were the most frequently mutated (3.5% and 3.8% of cases and 0.3% and 0.5% of controls, respectively) and were associated with increased ovarian cancer risk (OR, BRCA1=12.38; 95%CI=4.72-32.45; OR, BRCA2=9.18; 95%CI=3.98-21.15). Mutation frequencies for the other genes were ≤1.0% and only PALB2 was significantly associated with risk (OR=5.79; 95%CI=1.09-30.83). There was no difference in survival for women with a BRCA germline mutation versus no mutation.
    CONCLUSIONS: Further research is needed to better understand the role of other mutations in ovarian cancer among unselected populations.
    IMPACT: Our data support guidelines for germline genetic testing for BRCA1 and BRCA2 among women diagnosed with epithelial ovarian cancer; testing for PALB2 may be warranted.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-23-0041
  4. Blood. 2023 Jul 28. pii: blood.2023020209. [Epub ahead of print]
    Prevalence and significance of DDX41 gene variants in the general population.
    Sruthi Cheloor Kovilakam, Muxin Gu, William G Dunn, Ludovica Marando, Clea Barcena, Serena Nik-Zainal, Irina Mohorianu, Siddhartha Kar, Margarete Alice Fabre, Pedro M Quiros, George S Vassiliou.
      Germline variants in the DDX41 gene have been linked to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) development. However, the risks associated with different variants remain unknown, as do the basis of their leukemogenic properties, impact on steady-state hematopoiesis and links to other cancers. Here, we investigate the frequency and significance of DDX41 variants in 454,792 United Kingdom Biobank (UKB) participants and identify 452 unique non-synonymous DNA variants in 3,538 (1/129) individuals. Many were novel and prevalence of most varied markedly by ancestry. Amongst the 1059 individuals with germline pathogenic variants (DDX41-GPV) 34 developed MDS/AML (odds ratio 12.3 versus non-carriers). Of these 7/218 had start-loss, 22/584 truncating and 5/257 missense (odds ratios: 12.9, 15.1 and 7.5 respectively). Using multivariate regression, we found significant associations of DDX41-GPV with MDS, AML and "family history of leukemia", but not lymphoma, myeloproliferative neoplasms or other cancers. We also report that DDX41-GPV carriers do not have an increased prevalence of clonal hematopoiesis (CH). In fact, CH was significantly more common prior to sporadic versus DDX41-mutant MDS/AML, revealing distinct evolutionary paths. Furthermore, somatic mutation rates did not differ between sporadic and DDX41-mutant AML genomes, ruling out genomic instability as a driver of the latter. Finally, we found that higher mean red cell volume and somatic DDX41 mutations in blood DNA identify DDX41-GPV carriers at increased MDS/AML risk. Collectively, our findings give new insights into the prevalence and cognate risks associated with DDX41 variants, as well as the clonal evolution and early detection of DDX41-mutant MDS/AML.
    DOI:  https://doi.org/10.1182/blood.2023020209
  5. Biomedicines. 2023 Jul 22. pii: 2062. [Epub ahead of print]11(7):
    Heterozygous Pathogenic Nonsense Variant in the ATM Gene in a Family with Unusually High Gastric Cancer Susceptibility.
    Daniele Guadagnolo, Gioia Mastromoro, Enrica Marchionni, Aldo Germani, Fabio Libi, Soha Sadeghi, Camilla Savio, Simona Petrucci, Laura De Marchis, Maria Piane, Antonio Pizzuti.
      Germline pathogenic variants (PVs) in the Ataxia Telangiectasia mutated (ATM) gene (MIM* 607585) increase the risk for breast, pancreatic, gastric, and prostatic cancer and, to a reduced extent, ovarian and colon cancer and melanoma, with moderate penetrance and variable expressivity. We describe a family presenting early-onset gastric cancer and harboring a heterozygous pathogenic ATM variant. The proband had gastric cancer (age 45) and reported a sister deceased due to diffuse gastric cancer (age 30) and another sister who developed diffuse gastric cancer (age 52) and ovarian serous cancer. Next generation sequencing for cancer susceptibility genes (APC, ATM, BRD1, BRIP1, CDH1, CDK4, CDKN2A, CHEK2, EPCAM, MLH1, MRE11, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, PTEN, RAD50, RAD51C, RAD51D, RECQL1, SMAD4, STK11, and TP53) was performed. Molecular analysis identified the truncating c.5944C>T, p.(Gln1982*) variant in the ATM (NM_000051.3; NP_000042.3) in the proband. The variant had segregated in the living affected sister and in the unaffected daughter of the deceased affected sister. Familial early-onset gastric cancer is an unusual presentation for ATM-related malignancies. Individual variants may result in different specific risks. Genotype-phenotype correlations are challenging given the low penetrance and variable expressivity. Careful family history assessments are pivotal for prevention planning and are strengthened by the availability of molecular diagnoses.
    Keywords:  ATM; cancer susceptibility; gastric cancer
    DOI:  https://doi.org/10.3390/biomedicines11072062
  6. Int J Mol Sci. 2023 Jul 18. pii: 11570. [Epub ahead of print]24(14):
    Combined Tumor-Based BRCA1/2 and TP53 Mutation Testing in Ovarian Cancer.
    Edith Borcoman, Elizabeth Santana Dos Santos, Catherine Genestie, Patricia Pautier, Ludovic Lacroix, Sandrine M Caputo, Odile Cabaret, Marine Guillaud-Bataille, Judith Michels, Aurelie Auguste, Alexandra Leary, Etienne Rouleau.
      Somatic/germline BRCA1/2 mutations (m)/(likely) pathogenic variants (PV) (s/gBRCAm) remain the best predictive biomarker for PARP inhibitor efficacy. As >95% of high-grade serous ovarian cancers (HGSOC) have a somatic TP53m, combined tumor-based BRCA1/2 (tBRCA) and TP53 mutation testing (tBRCA/TP53m) may improve the quality of results in somatic BRCAm identification and interpretation of the 'second hit' event, i.e., loss of heterozygosity (LOH). A total of 237 patients with HGSOC underwent tBRCA/TP53m testing. The ratio of allelic fractions (AFs) for tBRCA/TP53m was calculated to estimate the proportion of cells carrying BRCAm and to infer LOH. Among the 142/237 gBRCA results, 16.2% demonstrated a pathogenic/deleterious variant (DEL) gBRCA1/2m. Among the 195 contributive tumor samples, 43 DEL of tBRCAm (22.1%) were identified (23 gBRCAm and 20 sBRCAm) with LOH identified in 37/41 conclusive samples. The median AF of TP53m was 0.52 (0.01-0.93), confirming huge variability in tumor cellularity. Initially, three samples were considered as wild type with <10% cellularity. However, additional testing detected a very low AF (<0.05) in both BRCA1/2m and TP53m, thus reidentifying them as sBRCA1/2m. Combined tBRCA/TP53m testing is rapid, sensitive, and identifies somatic and germline BRCA1/2m. AF TP53m is essential for interpreting sBRCA1/2m in low-cellularity samples and provides indirect evidence for LOH as the 'second hit' of BRCA1/2-related tumorigenesis.
    Keywords:  BRCA1/2 tumoral testing; TP53m; allelic frequency; high-grade serous ovarian cancers; loss of heterozygosity; ovarian cancer
    DOI:  https://doi.org/10.3390/ijms241411570
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