bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒12‒27
nine papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Cells. 2020 12 12. pii: E2675. [Epub ahead of print]9(12):
    Stolarova L, Kleiblova P, Janatova M, Soukupova J, Zemankova P, Macurek L, Kleibl Z.
      Germline alterations in many genes coding for proteins regulating DNA repair and DNA damage response (DDR) to DNA double-strand breaks (DDSB) have been recognized as pathogenic factors in hereditary cancer predisposition. The ATM-CHEK2-p53 axis has been documented as a backbone for DDR and hypothesized as a barrier against cancer initiation. However, although CHK2 kinase coded by the CHEK2 gene expedites the DDR signal, its function in activation of p53-dependent cell cycle arrest is dispensable. CHEK2 mutations rank among the most frequent germline alterations revealed by germline genetic testing for various hereditary cancer predispositions, but their interpretation is not trivial. From the perspective of interpretation of germline CHEK2 variants, we review the current knowledge related to the structure of the CHEK2 gene, the function of CHK2 kinase, and the clinical significance of CHEK2 germline mutations in patients with hereditary breast, prostate, kidney, thyroid, and colon cancers.
    Keywords:  CHEK2; CHK2; KAP1; WIP1; breast cancer; checkpoint kinase 2; colorectal cancer; germline mutation; hereditary cancer; prostate cancer; renal cancer; thyroid cancer
    DOI:  https://doi.org/10.3390/cells9122675
  2. Pathol Res Pract. 2020 Dec 04. pii: S0344-0338(20)32164-6. [Epub ahead of print]217 153309
    Kumari N, Singh RK, Mishra SK, L R, Mohindra S, Krishnani N.
      BACKGROUND: Ampullary cancer may occur as a component of hereditary cancer syndromes. Mutations in inherited cancer susceptibility genes play a therapeutic role and its knowledge in ampullary cancer is lacking.METHODS: Thirty-seven cases of ampullary carcinoma were subjected to tumor-normal whole exome sequencing with mean coverage of 100X (blood) and 200X (tumor). Data were analyzed and correlated with intestinal and pancreatobiliary differentiation.
    RESULTS: There were 22 intestinal, 13 pancreatobiliary and 2 cases of mixed differentiation. One hundred and forty-three germline variations with at least >1 pathogenic germline variants (PGVs) across 83 genes were found in 36 of 37 patients. Twelve genes (14.5 %) showed >3, 20 genes (24.1 %) showed two and 51 genes (61.4 %) showed one PGVs. Intestinal differentiation showed higher PGVs (117 variants, 73 genes) than pancreatobiliary differentiation (85 variants, 62 genes). PGVs in ERCC5, MEN1, MSH3, CHEK1, TP53, APC, FANCA, ERBB2, BRCA1, BRCA2, RTEL1, HNF1A and PTCH1 were seen in >50 % of cases. Nine genes harbored somatic second hits in 14 cases. PGVs in DNA damage-repair, homologous recombination repair, TP53 transcriptional regulation, DNA double stranded breaks, cell cycle and nucleotide excision repair genes were seen in all cases of intestinal and pancreatobiliary differentiation, while DNA mismatch repair genes were found in 81.8 % of intestinal and 84.6 % of pancreatobiliary cancers. Functional pathway analysis showed that DNA damage-repair, double stranded break repair, mismatch repair, homologous recombination repair and TP53 transcriptional regulation genes were altered in both while nucleotide-excision repair was significantly mutated in intestinal type and cell-cycle genes in pancreatobiliary type (p < 0.05).
    CONCLUSION: This study reports spectrum of PGVs in intestinal and pancreatobiliary differentiation of ampullary carcinoma at higher frequency through whole exome sequencing. PGVs were most frequently found in DNA repair genes. Detecting PGVs through tumor-normal sequencing may identify therapeutically actionable and double-hit mutations that can guide towards appropriate management.
    Keywords:  Ampullary carcinoma; Germline; Intestinal; Pancreatobiliary; Whole exome
    DOI:  https://doi.org/10.1016/j.prp.2020.153309
  3. Hered Cancer Clin Pract. 2020 Dec 20. 18(1): 25
    Rashid MU, Muhammad N, Khan FA, Shehzad U, Naeemi H, Malkani N, Hamann U.
      BACKGROUND: The RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan.METHODS: Comprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines.
    RESULTS: One novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls.
    CONCLUSIONS: Our data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.
    Keywords:  Breast cancer; Germline variants; Pakistan; RECQL
    DOI:  https://doi.org/10.1186/s13053-020-00159-6
  4. J Cancer Res Ther. 2020 Oct-Dec;16(6):16(6): 1524-1527
    Iwasaki T, Mizumoto M, Numajiri H, Oshiro Y, Suzuki R, Moritani K, Eguchi M, Ishii E, Sakurai H.
      Li-Fraumeni syndrome (LFS) is a genetic disease that is hypersensitive to radiotherapy. Proton therapy (PT) was strongly recommended for pediatric and radiation-sensitive tumors. However, there is little information on PT for LFS. The patient was a 7-year-old girl with LFS who was diagnosed with radiation-induced right shoulder blade osteosarcoma and left chest wall malignant fibrous histiocytoma. Both tumors were in the area that had previously been irradiated (36-45 Gy by photon radiotherapy). Sixty-six GyE in 30 fractions was planned for both tumors. We set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Cisplatin was used as simultaneous combination chemotherapy. Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was observed as Grade 1 dermatitis. The dermatitis became exacerbated 2 weeks after PT but subsequently improved with conservation treatment alone. Twenty-three months after PT, magnetic resonance imaging showed an increase in the tumor on the right shoulder. A histological examination was not conducted as the family declined, but secondary cancer was suggested rather than recurrent osteosarcoma, as the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after undergoing PT. Up to 23 months after PT, there were no signs of Grade 2 or more late toxicities. This represents the first reported case of PT for a patient with LF to treat radiation-induced secondary cancer.
    Keywords:  Li-Fraumeni syndrome; pediatric; proton radiotherapy; proton therapy; secondary cancer
    DOI:  https://doi.org/10.4103/jcrt.JCRT_449_19
  5. Mol Clin Oncol. 2021 Jan;14(1): 15
    Moscatello C, Di Nicola M, Veschi S, Di Gregorio P, Cianchetti E, Stuppia L, Battista P, Cama A, Curia MC, Aceto GM.
      The aetiology of breast and ovarian cancer (BC/OC) is multi-factorial. At present, the involvement of base excision repair (BER) glycosylases (MUTYH and OGG1) in BC/OC predisposition is controversial. The present study investigated whether germline mutation status and mRNA expression of two BER genes, MUTHY and OGG1, were correlated with BRCA1 in 59 patients with BC/OC and 50 matched population controls. In addition, to evaluate the relationship between MUTYH, OGG1 and BRCA1, their possible mutual modulation and correlation among mutational spectrum, gene expression and demographic characteristics were evaluated. The results identified 18 MUTYH and OGG1 variants, of which 4 were novel (2 MUTYH and 2 OGG1) in 44 of the 59 patients. In addition, two pathogenic mutations were identified: OGG1 p.Arg46Gln, detected in a patient with BC and a family history of cancer, and MUTYH p.Val234Gly in a patient with OC, also with a family history of cancer. A significant reduced transcript expression in MUTYH was observed (P=0.033) in cases, and in association with the presence of rare variants in the same gene (P=0.030). A significant correlation in the expression of the two BER genes was observed in cases (P=0.004), whereas OGG1 and BRCA1 was significantly correlated in cases (P=0.001) compared with controls (P=0.010). The results of the present study indicated that the relationship among mutational spectrum, gene expression and demographic characteristics may improve the genetic diagnosis and primary prevention of at-risk individuals belonging to families with reduced mRNA expression, regardless of mutation presence.
    Keywords:  BRCA1; MUTYH; OGG1; base excision repair; breast cancer; gene expression; mutation; ovarian cancer; oxidative stress; prevention
    DOI:  https://doi.org/10.3892/mco.2020.2177
  6. Cancers (Basel). 2020 Dec 17. pii: E3812. [Epub ahead of print]12(12):
    Bruggeman JW, Irie N, Lodder P, van Pelt AMM, Koster J, Hamer G.
      We have recently described a class of 756 genes that are widely expressed in cancers, but are normally restricted to adult germ cells, referred to as germ cell cancer genes (GC genes). We hypothesized that carcinogenesis involves the reactivation of biomolecular processes and regulatory mechanisms that, under normal circumstances, are restricted to germline development. This would imply that cancer cells share gene expression profiles with primordial germ cells (PGCs). We therefore compared the transcriptomes of human PGCs (hPGCs) and PGC-like cells (PGCLCs) with 17,382 samples from 54 healthy somatic tissues (GTEx) and 11,003 samples from 33 tumor types (TCGA), and identified 672 GC genes, expanding the known GC gene pool by 387 genes (51%). We found that GC genes are expressed in clusters that are often expressed in multiple tumor types. Moreover, the amount of GC gene expression correlates with poor survival in patients with lung adenocarcinoma. As GC genes specific to the embryonic germline are not expressed in any adult tissue, targeting these in cancer treatment may result in fewer side effects than targeting conventional cancer/testis (CT) or GC genes and may preserve fertility. We anticipate that our extended GC dataset enables improved understanding of tumor development and may provide multiple novel targets for cancer treatment development.
    Keywords:  cancer treatment development; cancer/testis genes (CT genes); fertility preservation; germ cell cancer genes (GC genes); germline; oncogenesis; primordial germ cells (PGCs)
    DOI:  https://doi.org/10.3390/cancers12123812
  7. Pigment Cell Melanoma Res. 2020 Dec 20.
    Pozzobon FC, Tell-Marti G, Calbet-Llopart N, Barreiro A, Espinosa N, Potrony M, Alejo B, Podlipnik S, Combalia M, Puig-Butillé JA, Carrera C, Malvehy J, Puig S.
      Nevus count is highly determined by inherited variants and has been associated with the origin of melanoma. De novo melanomas (DNMMs) are more prevalent in patients with a low nevus count and have distinctive dermoscopic features than nevus-associated melanomas. We evaluated the impact of 9 Single Nucleotide Polymorphisms (SNPs) of MTAP (rs10811629, rs2218220, rs7023329 and rs751173), PLA2G6 (rs132985 and rs2284063), IRF4 (rs12203592), and PAX3 (rs10180903 and rs7600206) genes associated with nevus count and melanoma susceptibility, and the MC1R variants on dermoscopic features of 371 melanomas from 310 patients. All MTAP variants associated with a low nevus count were associated with regression structures (peppering and mixed regression), blue-whitish veil, shiny white structures, and pigment network. SNPs of PLA2G6 (rs132985), PAX3 (rs7600206), and IRF4 (rs12203592) genes were also associated with either shiny white structures or mixed regression (all corrected p-values ≤ 0.06). Melanomas from red hair color MC1R variants carriers showed lower total dermoscopy score (p-value = 0.015) and less blotches than melanomas from non-carriers (p-value = 0.048). Our results provide evidence that germline variants protective for melanoma risk and/or associated with a low nevus count are associated with certain dermoscopic features, more characteristic of de novo and worse prognosis melanomas.
    Keywords:   MC1R ; dermatoscopy; dermoscopy; gene; germline variants; melanoma; nevus
    DOI:  https://doi.org/10.1111/pcmr.12954