bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒04‒19
nine papers selected by
Joanna Zawacka-Pankau



  1. Sci Adv. 2020 04;6(15): eaay3511
    Toufektchan E, Lejour V, Durand R, Giri N, Draskovic I, Bardot B, Laplante P, Jaber S, Alter BP, Londono-Vallejo JA, Savage SA, Toledo F.
      Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.
    DOI:  https://doi.org/10.1126/sciadv.aay3511
  2. Breast Cancer Res. 2020 Apr 15. 22(1): 36
    Van Marcke C, Helaers R, De Leener A, Merhi A, Schoonjans CA, Ambroise J, Galant C, Delrée P, Rothé F, Bar I, Khoury E, Brouillard P, Canon JL, Vuylsteke P, Machiels JP, Berlière M, Limaye N, Vikkula M, Duhoux FP.
      BACKGROUND: Multigene panels are routinely used to assess for predisposing germline mutations in families at high breast cancer risk. The number of variants of unknown significance thereby identified increases with the number of sequenced genes. We aimed to determine whether tumor sequencing can help refine the analysis of germline variants based on second somatic genetic events in the same gene.METHODS: Whole-exome sequencing (WES) was performed on whole blood DNA from 70 unrelated breast cancer patients referred for genetic testing and without a BRCA1, BRCA2, TP53, or CHEK2 mutation. Rare variants were retained in a list of 735 genes. WES was performed on matched tumor DNA to identify somatic second hits (copy number alterations (CNAs) or mutations) in the same genes. Distinct methods (among which immunohistochemistry, mutational signatures, homologous recombination deficiency, and tumor mutation burden analyses) were used to further study the role of the variants in tumor development, as appropriate.
    RESULTS: Sixty-eight patients (97%) carried at least one germline variant (4.7 ± 2.0 variants per patient). Of the 329 variants, 55 (17%) presented a second hit in paired tumor tissue. Of these, 53 were CNAs, resulting in tumor enrichment (28 variants) or depletion (25 variants) of the germline variant. Eleven patients received variant disclosure, with clinical measures for five of them. Seven variants in breast cancer-predisposing genes were considered not implicated in oncogenesis. One patient presented significant tumor enrichment of a germline variant in the oncogene ERBB2, in vitro expression of which caused downstream signaling pathway activation.
    CONCLUSION: Tumor sequencing is a powerful approach to refine variant interpretation in cancer-predisposing genes in high-risk breast cancer patients. In this series, the strategy provided clinically relevant information for 11 out of 70 patients (16%), adapted to the considered gene and the familial clinical phenotype.
    Keywords:  Breast cancer; Germline; Mutational signatures; Predisposition; Second hit; Variant of unknown significance
    DOI:  https://doi.org/10.1186/s13058-020-01273-y
  3. Cancers (Basel). 2020 Apr 13. pii: E956. [Epub ahead of print]12(4):
    Lhotova K, Stolarova L, Zemankova P, Vocka M, Janatova M, Borecka M, Cerna M, Jelinkova S, Kral J, Volkova Z, Urbanova M, Kleiblova P, Machackova E, Foretova L, Hazova J, Vasickova P, Lhota F, Koudova M, Cerna L, Tavandzis S, Indrakova J, Hruskova L, Kosarova M, Vrtel R, Stranecky V, Kmoch S, Zikan M, Macurek L, Kleibl Z, Soukupova J.
      Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO.
    Keywords:  cancer risk; mutation; next-generation sequencing; ovarian cancer; predisposition genes
    DOI:  https://doi.org/10.3390/cancers12040956
  4. Colomb Med (Cali). 2019 Sep 30. 50(3): 163-175
    Cifuentes-C L, Rivera-Herrera AL, Barreto G.
      Introduction: Breast cancer is the most common neoplasia of women from all over the world especially women from Colombia. 5%-10% of all cases are caused by hereditary factors, 25% of those cases have mutations in the BRCA1/BRCA2 genes.Objective: The purpose of this study was to identify the mutations associated with the risk of familial breast and/or ovarian cancer in a population of Colombian pacific.
    Methods: 58 high-risk breast and/or ovarian cancer families and 20 controls were screened for germline mutations in BRCA1 and BRCA2, by Single Strand Conformation Polymorphism (SSCP) and sequencing.
    Results: Four families (6.9%) were found to carry BRCA1 mutations and eight families (13.8%) had mutations in BRCA2. In BRCA1, we found three Variants of Uncertain Significance (VUS), of which we concluded, using in silico tools, that c.81-12C>G and c.3119G>A (p.Ser1040Asn) are probably deleterious, and c.3083G>A (p.Arg1028His) is probably neutral. In BRCA2, we found three variants of uncertain significance: two were previously described and one novel mutation. Using in silico analysis, we concluded that c.865A>G (p.Asn289Asp) and c.6427T>C (p.Ser2143Pro) are probably deleterious and c.125A>G (p.Tyr42Cys) is probably neutral. Only one of them has previously been reported in Colombia. We also identified 13 polymorphisms (4 in BRCA1 and 9 in BRCA2), two of them are associated with a moderate increase in breast cancer risk (BRCA2 c.1114A>C and c.8755-66T>C).
    Conclusion: According to our results, the Colombian pacific population presents diverse mutational spectrum for BRCA genes that differs from the findings in other regions in the country.
    Keywords:  BRCA1; BRCA2; Colombia; Germ-line mutations; Hereditary Breast and Ovarian Cancer Syndrome
    DOI:  https://doi.org/10.25100/cm.v50i3.2385
  5. Clin Orthop Relat Res. 2020 Mar 24.
    Min BJ, Kang YK, Chung YG, Seo ME, Chang KB, Joo MW.
      BACKGROUND: Schwannomatosis is a late-onset tumor predisposition syndrome associated with the development of many different types of malignancies. A relevant genetic mechanism can be explained by three mutational events. The first-hit mutation is a germline mutation, and the SMARCB1 mutation on chromosome 22 is the most well-known genetic abnormality in patients with schwannomatosis. LZTR1 is another major predisposing gene in 22q-related schwannomatosis that lacks SMARCB1 variants. Although these two variants account for the occurrence of most familiar schwannomatoses, the genetic causes of sporadic schwannomatosis for the most part remain unknown. Therefore, current molecular diagnostic criteria cannot completely explain the basis of this disease. The common genetic background between schwannomatosis and other related malignant tumors is also unclear. Moreover, it is not easy to explain various clinical manifestations by only two known mutations. QUESTION/PURPOSES: (1) Are there important sequences outside the SMARCB1 or LZTR1 region on chromosome 22 that might carry a first-hit mutational predisposition to sporadic schwannomatosis? Or are there alternative evolutionarily conserved loci that might carry a first-hit mutational predisposition? (2) Is the age of disease onset associated to such genetic variants?METHODS: This study was a retrospective chart review and prospective genetic study on patients with schwannomatosis who were treated surgically. The clinical criteria to diagnose schwannomatosis were as follows: (1) histologically proven non-vestibular schwannomas; (2) no evidence of vestibular schwannomas on 3-mm brain MRI. A total of 21 patients were treated between March 2006 and June 2015. Since nine patients did not visit the outpatient clinic during the recruitment period, we obtained blood samples from 12 patients with schwannomatosis for a genetic analysis. After two patients were excluded because of their family history of schwannomatosis, genetic analyses were finally performed on 10 patients. Then, those with NF2, SMARCB1 or LZTR1 variants were screened by whole exome sequencing. All 10 patients passed our screening strategy. There were eight men and two women, with a median (range) age of 43 years (24 to 66) at the time of diagnosis. To select candidate genes, common ethnic variants and frequent mutations in in-house exome sequencing data were removed to exclude the population-specific polymorphisms not found in other population and to generalize the findings. Frameshift, nonsense, and splice-site variants were deemed pathogenic. Missense variants were classified as potentially pathogenic, variants of uncertain significance, or benign using in silico (via computer simulation) prediction algorithms, Sorting Intolerant From Tolerant (SIFT), Polymorphism Phenotyping v2 (PolyPhen-2), and Combined Annotation Dependent Depletion (CADD). A variant was considered potentially pathogenic if two or more algorithms predicted the variant to be damaging and benign if none considered it damaging. Then, potentially pathogenic variants only in the genes associated with cancer-predisposition or DNA damage repair were classified as the pathogenic candidate variants of sporadic schwannomatosis. The predictions for pathogenic candidate variants were checked again on Clinical Interpretation of Genetic Variants (InterVar) based on the American College of Medical Genetics guidelines and validated against Mendelian clinically applicable pathogenicity scores (M-CAP scores).
    RESULTS: We detected 26 variants; 13 variants across 10 genes were predicted to be pathogenic and found in seven patients, two each in ARID1A, PTCH2, and NOTCH2 and one each in MSH6, ALPK2, MGMT, NOTCH1, CIC, TSC2, and CDKN2A. One frameshift deletion in PTCH2 met the criteria for pathogenic or likely pathogenic classification, as recommended by the American College of Medical Genetics guidelines. Six missense mutations were classified as possibly pathogenic variants based on M-CAP scores. Four predicted pathogenic missense variants were detected in DNA damage repair (DDR) genes. Three DDR genes were affected: ARID1A, MGMT, and MSH6. Among the nine predicted pathogenic mutations detected in known cancer-predisposing genes, one was a frameshift deletion and the others were missense mutations. Seven tumor suppressor genes were involved: PTCH2, ALPK2, CIC, NOTCH1, NOTCH2, TSC2, and CDKN2A. One patient with multiple pathogenic variants in two DDR genes, ARID1A and MSH6, received a schwannomatosis diagnosis at 33 years old. Each of the other patients who had single variants in the DDR gene received their diagnoses at 41 years of age. The age at diagnosis was 40 years or older in patients with variants in cancer-predisposing genes, except for one patient who had multiple variants in TSC2 and CDKN2A. The carrier of those variants received the diagnosis at 24 years old.
    CONCLUSIONS: This study identified first-hit candidate mutations predisposing patients to schwannomatosis that were not related to SMARCB1 or LZTR1 variations in a cohort of patients with sporadic schwannomatosis. Patients with sporadic schwannomatosis without SMARCB1 or LZTR1 genetic variation may have developed the disease because of genomic variants related to cancer initiation in areas other than chromosome 22. Seven of 10 patients had predicted pathogenic germline mutations in DDR and cancer predisposition genes. We detected multiple cancer-related mutations in each patient. The age at the time schwannomatosis was diagnosed might be associated with a combination of variants and characteristics of the genes containing the variants; however, we did not have enough patients to confirm this association.
    CLINICAL RELEVANCE: The germline mutations identified in this study and the ideas related to the age of disease onset may provide potential candidate variants for future research on sporadic schwannomatosis and help to revise the current clinical and molecular diagnostic criteria. Further in vivo and in vitro studies are needed for these variants.
    DOI:  https://doi.org/10.1097/CORR.0000000000001239
  6. Am J Surg Pathol. 2020 May;44(5): 649-656
    Leskela S, Romero I, Cristobal E, Pérez-Mies B, Rosa-Rosa JM, Gutierrez-Pecharroman A, Caniego-Casas T, Santón A, Ojeda B, López-Reig R, Palacios-Berraquero ML, García Á, Ibarra J, Hakim S, Guarch R, López-Guerrero JA, Poveda A, Palacios J.
      Mismatch repair deficiency (MMRD) is involved in the initiation of both hereditary and sporadic tumors. MMRD has been extensively studied in colorectal cancer and endometrial cancer, but not so in other tumors, such as ovarian carcinoma. We have determined the expression of mismatch repair proteins in a large cohort of 502 early-stage epithelial ovarian carcinoma entailing all the 5 main subtypes: high-grade serous carcinoma, endometrioid ovarian carcinoma (EOC), clear cell carcinoma (CCC), mucinous carcinoma, and low-grade serous carcinoma. We studied the association of MMRD with clinicopathologic and immunohistochemical features, including tumor-infiltrating lymphocytes in EOC, the histologic type in which MMRD is most frequent. In addition, MLH1 promoter methylation status and massive parallel sequencing were used to evaluate the proportion of sporadic and Lynch syndrome-associated tumors, and the most frequently mutated genes in MMRD EOCs. MMRD occurred only in endometriosis-associated histologic types, and it was much more frequent in EOC (18%) than in CCC (2%). The most frequent immunohistochemical pattern was loss of MLH1/PMS2, and in this group, 80% of the cases were sporadic and secondary to MLH1 promoter hypermethylation. The presence of somatic mutations in mismatch repair genes was the other mechanism of MMRD in sporadic tumors. In this series, the minimum estimated frequency of Lynch syndrome was 35% and it was due to germline mutations in MLH1, MSH2, and MSH6. ARID1A, PTEN, KTM2B, and PIK3CA were the most common mutated genes in this series. Interestingly, possible actionable mutations in ERRB2 were found in 5 tumors, but no TP53 mutations were detected. MMRD was associated with younger age and increased tumor-infiltrating lymphocytes. Universal screening in EOC and mixed EOC/CCC is recommended for the high frequency of MMRD detected; however, for CCC, additional clinical and pathologic criteria should be evaluated to help select cases for analysis.
    DOI:  https://doi.org/10.1097/PAS.0000000000001432
  7. Eur J Breast Health. 2020 Apr;16(2): 106-109
    Sheehan M, Heald B, Yanda C, Kelly ED, Grobmyer S, Eng C, Kalady M, Pederson H.
      Objective: Lynch syndrome is an inherited genetic disorder associated with a predisposition to early-onset colorectal and endometrial cancers, but breast cancer risk in these patients is debated. The aim of this study is to evaluate breast cancer rates in a cohort of Lynch syndrome patients, as well as to identify women who may be eligible for additional breast cancer specific genetic testing or enhanced breast surveillance (contrast-enhanced magnetic resonance imaging (MRI) screening).Materials and Methods: Using a hereditary colorectal cancer registry at a single academic institution for identification of patients with Lynch syndrome, a retrospective chart review was performed of 188 women with DNA mismatch repair (MMR) mutations. The Tyrer-Cuzick model was used to estimate breast cancer risk in patients without breast cancer.
    Results: The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years. Additionally, 7.5% of unaffected women had an estimated lifetime risk of breast cancer greater than 20%. 46/188 (24.4%) of patients were eligible for breast specific genetic testing.
    Conclusion: Our analysis suggests that Lynch syndrome patients with PMS2 mutations may be at higher risk of developing breast cancer. Additionally, the personal and family history of cancer suggests crossover in eligibility for breast specific genetic testing in a significant number of patients (16.5-24.4%). Also, many women are eligible for enhanced breast surveillance (7.5%) which would otherwise not be offered.
    Keywords:  Breast neoplasms; cancer screening; colorectal cancer hereditary nonpolyposis
    DOI:  https://doi.org/10.5152/ejbh.2020.5198
  8. Nature. 2020 Apr;580(7803): 396-401
    Waszak SM, Robinson GW, Gudenas BL, Smith KS, Forget A, Kojic M, Garcia-Lopez J, Hadley J, Hamilton KV, Indersie E, Buchhalter I, Kerssemakers J, Jäger N, Sharma T, Rausch T, Kool M, Sturm D, Jones DTW, Vasilyeva A, Tatevossian RG, Neale G, Lombard B, Loew D, Nakitandwe J, Rusch M, Bowers DC, Bendel A, Partap S, Chintagumpala M, Crawford J, Gottardo NG, Smith A, Dufour C, Rutkowski S, Eggen T, Wesenberg F, Kjaerheim K, Feychting M, Lannering B, Schüz J, Johansen C, Andersen TV, Röösli M, Kuehni CE, Grotzer M, Remke M, Puget S, Pajtler KW, Milde T, Witt O, Ryzhova M, Korshunov A, Orr BA, Ellison DW, Brugieres L, Lichter P, Nichols KE, Gajjar A, Wainwright BJ, Ayrault O, Korbel JO, Northcott PA, Pfister SM.
      Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children1,2, and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma3. Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHHα subtype4 and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U34) position5,6. Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems7-9. Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
    DOI:  https://doi.org/10.1038/s41586-020-2164-5
  9. J Cancer Res Clin Oncol. 2020 Apr 13.
    Vitiello GAF, de Sousa Pereira N, Amarante MK, Banin-Hirata BK, Campos CZ, de Oliveira KB, Losi-Guembarovski R, Watanabe MAE.
      PURPOSE: APOBEC3A and APOBEC3B cytidine deaminases have been implicated in the pathogenesis of multiple cancers, including breast cancer (BC). A germline deletion linking APOBEC3A and APOBEC3B loci (A3A/B) has been associated with higher APOBEC-mediated mutational burden, but its association with BC risk have been controversial. Therefore, this study investigated the association between A3A/B and BC susceptibility and clinical presentation in a Brazilian cohort.METHODS: A3A/B deletion was evaluated through allele-specific PCR in 341 BC patients and 397 women without familial or personal history of neoplasia from Brazil and associations with susceptibility to BC subtypes were tested through age-adjusted logistic models while correlations with clinicopathological parameters were tested using Kendall's tests.
    RESULTS: No association was found between A3A/B and BC susceptibility; however, in Luminal-A BCs, it was positively correlated with tumor size (Tau-c = 0.125) and Ki67 (Tau-c = 0.116) and negatively correlated with lymph node metastasis (LNM) (Tau-c = - 0.162). The negative association between A3A/B with LNM in Luminal-A BCs remained significant even after adjusting for tumor size and Ki67 in logistic models (OR = 0.22; p = 0.008).
    CONCLUSION: These results show that although A3A/B may not modify BC susceptibility in Brazilian population, it may affect clinicopathological features in BC subtypes, promoting tumor cell proliferation while being negatively associated with LNM in Luminal-A BCs.
    Keywords:  APOBEC deaminases; Breast neoplasm; Copy-number variations; Prognosis; Susceptibility
    DOI:  https://doi.org/10.1007/s00432-020-03208-8