bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒02‒07
sixteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Gastroenterology. 2021 Jan 29. pii: S0016-5085(21)00326-7. [Epub ahead of print]
    Golan T, O'Kane GM, Denroche RE, Raitses-Gurevich M, Grant RC, Holter S, Wang Y, Zhang A, Jang GH, Stossel C, Atias D, Halperin S, Berger R, Glick Y, Patrick Park JY, Cuggia A, Williamson L, Wong HL, Schaeffer DF, Renouf DJ, Borgida A, Dodd A, Wilson JM, Fischer SE, Notta F, Knox JJ, Zogopoulos G, Gallinger S.
      BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline(g) alterations in BRCA1, BRCA2 and PALB2.METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included: 1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; 2) substitution base signature 3 (SBS3); 3) HRDetect; and, 4) Structural Variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status.
    RESULTS: Biallelic tumour inactivation of gBRCA or PALB2 was evident in 43/49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumour classifiers suggested that 7-10% of PDAC that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared to BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC. However in advanced disease the GIS (p=0.02), SBS3 (p=0.03) and HRDetect score (p=0.005) were predictive of platinum response and superior survival. PVs in gATM (n=6) or gCHEK2 (n=2) did not result in HRD-PDAC by any of the classifiers. In four patients, BRCA2 reversion mutations associated with platinum resistance.
    CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7-10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.
    DOI:  https://doi.org/10.1053/j.gastro.2021.01.220
  2. Mol Oncol. 2021 Feb 03.
    Andrés-Zayas C, Suárez-González J, Rodríguez-Macías G, Dorado N, Osorio S, Font P, Carbonell D, Chicano M, Muñiz P, Bastos M, Kwon M, Díez-Martín JL, Buño I, Martínez-Laperche C.
      Myeloid neoplasms with germline predisposition (MNGP) are likely to be more common than currently appreciated. Many of the genes involved in MNGP are also recurrently mutated in sporadic myeloid neoplasms (MN). Therefore, routine analysis of gene panels by NGS provides an effective approach to detect germline variants with clinical significance in patients with hematological malignancies. Gene panel sequencing was performed in 88 consecutive and 5 non-consecutive patients with MN diagnosis. Disease causing germline mutations in CEBPα, ASXL1, TP53, MPL, GATA2, DDX41 and ETV6 genes were identified in nine patients. Six out of the nine patients with germline variants had a strong family history. These patients presented great heterogeneity in the age of diagnosis and phenotypic characteristics. In our study, there were families in which all the affected members presented the same subtype of disease, whereas members of other families presented various disease phenotypes. This intra-familiar heterogeneity suggests that the acquisition of particular somatic variants may drive the evolution of the disease. This approach enabled high-throughput detection of MNGP in patients with MN diagnosis, which is of great relevance for both the patients themselves as well as for the asymptomatic mutation carriers within the family. It is crucial to make a proper diagnosis of these patients to provide them with the most suitable treatment, follow-up and genetic counseling.
    Keywords:  family history; genetic counseling; hereditary cancer; myeloid neoplasms with germline predisposition; next generation sequencing
    DOI:  https://doi.org/10.1002/1878-0261.12921
  3. PLoS One. 2021 ;16(1): e0245362
    Boujemaa M, Hamdi Y, Mejri N, Romdhane L, Ghedira K, Bouaziz H, El Benna H, Labidi S, Dallali H, Jaidane O, Ben Nasr S, Haddaoui A, Rahal K, Abdelhak S, Boussen H, Boubaker MS.
      Hereditary breast cancer accounts for 5-10% of all breast cancer cases. So far, known genetic risk factors account for only 50% of the breast cancer genetic component and almost a quarter of hereditary cases are carriers of pathogenic mutations in BRCA1/2 genes. Hence, the genetic basis for a significant fraction of familial cases remains unsolved. This missing heritability may be explained in part by Copy Number Variations (CNVs). We herein aimed to evaluate the contribution of CNVs to hereditary breast cancer in Tunisia. Whole exome sequencing was performed for 9 BRCA negative cases with a strong family history of breast cancer and 10 matched controls. CNVs were called using the ExomeDepth R-package and investigated by pathway analysis and web-based bioinformatic tools. Overall, 483 CNVs have been identified in breast cancer patients. Rare CNVs affecting cancer genes were detected, of special interest were those disrupting APC2, POU5F1, DOCK8, KANSL1, TMTC3 and the mismatch repair gene PMS2. In addition, common CNVs known to be associated with breast cancer risk have also been identified including CNVs on APOBECA/B, UGT2B17 and GSTT1 genes. Whereas those disrupting SULT1A1 and UGT2B15 seem to correlate with good clinical response to tamoxifen. Our study revealed new insights regarding CNVs and breast cancer risk in the Tunisian population. These findings suggest that rare and common CNVs may contribute to disease susceptibility. Those affecting mismatch repair genes are of interest and require additional attention since it may help to select candidates for immunotherapy leading to better outcomes.
    DOI:  https://doi.org/10.1371/journal.pone.0245362
  4. Curr Oncol. 2021 Feb 01. 28(1): 757-766
    Rittberg R, Harlos C, Rothenmund H, Das A, Tabori U, Sinha N, Singh H, Chodirker B, Kim CA.
      Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessive hereditary cancer syndrome due to biallelic germline mutation involving one of the four DNA mismatch repair genes. Here we present a case of a young female with CMMRD, homozygous for the c.2002A>G mutation in the PMS2 gene. She developed an early stage adenocarcinoma of the colon at the age of 14. Surveillance MRI of the brain at age 18 resulted in the detection of an asymptomatic brain cancer. On resection, this was diagnosed as an anaplastic astrocytoma. Due to emerging literature suggesting benefit of immunotherapy in this patient population, she was treated with adjuvant dual immune checkpoint inhibition, avoiding radiation. The patient remains stable with no evidence of progression 20 months after resection. The patient's clinical course, as well as the rational for considering adjuvant immunotherapy in patients with CMMRD are discussed in this report.
    Keywords:  CMMRD; adjuvant therapy; checkpoint inhibitors; constitutional mismatch repair deficiency; immunotherapy; screening; surveillance; tumor mutational burden
    DOI:  https://doi.org/10.3390/curroncol28010074
  5. Breast Cancer Res Treat. 2021 Feb 04.
    Grill S, Yahiaoui-Doktor M, Basrai M, Struck J, Schulte J, Berling-Ernst A, Engel C, Ullrich M, Lammert J, Bischoff SC, Schmidt T, Niederberger U, Chronas D, Rhiem K, Schmutzler R, Halle M, Kiechle M.
      BACKGROUND: Germline BRCA1/2 mutation carriers (gBMC) face increased cancer risks that are modulated via non-genetic lifestyle factors whose underlying molecular mechanisms are unknown. The peptides Neurotensin (NT) and Enkephalin (ENK)-involved in tumorigenesis and obesity-related diseases-are of interest. We wanted to know whether these biomarkers differ between gBMC and women from the general population and what effect a 1-year lifestyle-intervention has in gBMC.METHODS: The stable precursor fragments pro-NT and pro-ENK were measured at study entry (SE), after 3 and 12 months for 68 women from LIBRE-1 (a controlled lifestyle-intervention feasibility trial for gBMC involving structured endurance training and the Mediterranean Diet). The SE values were compared with a cohort of the general population including female subjects with and without previous cancer disease, non-suggestive for hereditary breast and ovarian cancer (OMA-reference). For LIBRE-1, we analysed the association between the intervention-related change in the two biomarkers and certain lifestyle factors.
    RESULTS: At SE, gBMC had a higher median pro-NT than OMA-reference (in the subgroups with previous cancer 117 vs. 91 pmol/L, p = 0.002). Non-diseased gBMC had lower median pro-ENK levels when compared to the non-diseased reference group. VO2peak and pro-NT 1-year change in LIBRE-1 were inversely correlated (r = - 0.435; CI - 0.653 to - 0.151; p = 0.004). Pro-ENK correlated positively with VO2peak at SE (r = 0.323; CI 0.061-0.544; p = 0.017). Regression analyses showed an inverse association of 1-year changes for pro-NT and Omega-6/Omega-3 (Estimate: - 37.9, p = 0.097/0.080) in multivariate analysis.
    CONCLUSION: Our results give first indications for lifestyle-related modification particularly of pro-NT in gBMC.
    Keywords:  BRCA1/2 mutation carriers; Breast cancer; Cardiopulmonary fitness; Lifestyle intervention; Nutrition; Physical activity
    DOI:  https://doi.org/10.1007/s10549-020-06070-x
  6. Cancers (Basel). 2021 Jan 26. pii: 459. [Epub ahead of print]13(3):
    Eikenboom EL, van Doorn HC, Dinjens WNM, Dubbink HJ, Geurts-Giele WRR, Spaander MCW, Tops CMJ, Wagner A, Goverde A.
      Lynch syndrome (LS) is caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, predisposing female carriers for endometrial cancer (EC) and ovarian cancer (OC). Since gynecological LS surveillance guidelines are based on little evidence, we assessed its outcomes. Data regarding gynecological tumors, surveillance, and (risk-reducing) surgery were collected from female LS carriers diagnosed in our center since 1993. Of 505 female carriers, 104 had a gynecological malignancy prior to genetic LS diagnosis. Of 264 carriers eligible for gynecological management, 164 carriers gave informed consent and had available surveillance data: 38 MLH1, 25 MSH2, 82 MSH6, and 19 PMS2 carriers (median follow-up 5.6 years). Surveillance intervals were within advised time in >80%. Transvaginal ultrasound, endometrial sampling, and CA125 measurements were performed in 76.8%, 35.9%, and 40.6%, respectively. Four symptomatic ECs, one symptomatic OC, and one asymptomatic EC were diagnosed. Endometrial hyperplasia was found in eight carriers, of whom three were symptomatic. Risk-reducing surgery was performed in 73 (45.5%) carriers (median age 51 years), revealing two asymptomatic ECs. All ECs were diagnosed in FIGO I. Gynecological management in LS carriers varied largely, stressing the need for uniform, evidence-based guidelines. Most ECs presented early and symptomatically, questioning the surveillance benefit in its current form.
    Keywords:  DNA mismatch repair; Lynch syndrome; MLH1; MSH2; MSH6; PMS2; endometrial cancer; gynecological surveillance; ovarian cancer; risk-reducing surgery
    DOI:  https://doi.org/10.3390/cancers13030459
  7. Int J Mol Sci. 2021 Jan 28. pii: 1310. [Epub ahead of print]22(3):
    Herrera-Pariente C, Capó-García R, Díaz-Gay M, Carballal S, Muñoz J, Llach J, Sánchez A, Bonjoch L, Arnau-Collell C, Soares de Lima Y, Golubicki M, Jung G, Lozano JJ, Castells A, Balaguer F, Bujanda L, Castellví-Bel S, Moreira L.
      The genetic cause for several families with gastric cancer (GC) aggregation is unclear, with marked relevance in early-onset patients. We aimed to identify new candidate genes involved in GC germline predisposition. Whole-exome sequencing (WES) of germline samples was performed in 20 early-onset GC patients without previous germline mutation identified. WES was also performed in nine tumor samples to analyze the somatic profile using SigProfilerExtractor tool. Sequencing germline data were filtered to select those variants with plausible pathogenicity, rare frequency and previously involved in cancer. Then, a manual filtering was performed to prioritize genes according to current knowledge and function. These genetic variants were prevalidated with Integrative Genomics Viewer 2.8.2 (IGV). Subsequently, a further selection step was carried out according to function and information obtained from tumor samples. After IGV and selection step, 58 genetic variants in 52 different candidate genes were validated by Sanger sequencing. Among them, APC, FAT4, CTNND1 and TLR2 seem to be the most promising genes because of their role in hereditary cancer syndromes, tumor suppression, cell adhesion and Helicobacter pylori recognition, respectively. These encouraging results represent the open door to the identification of new genes involved in GC germline predisposition.
    Keywords:  early-onset; gastric cancer; germline predisposition; next-generation sequencing; somatic profiling; whole-exome sequencing
    DOI:  https://doi.org/10.3390/ijms22031310
  8. Int J Mol Sci. 2021 Jan 28. pii: 1266. [Epub ahead of print]22(3):
    Arakelyan A, Melkonyan A, Hakobyan S, Boyarskih U, Simonyan A, Nersisyan L, Nikoghosyan M, Filipenko M, Binder H.
      Mutations in the BRCA1 and BRCA2 genes are known risk factors and drivers of breast and ovarian cancers. So far, few studies have been focused on understanding the differences in transcriptome and functional landscapes associated with the disease (breast vs. ovarian cancers), gene (BRCA1 vs. BRCA2), and mutation type (germline vs. somatic). In this study, we were aimed at systemic evaluation of the association of BRCA1 and BRCA2 germline and somatic mutations with gene expression, disease clinical features, outcome, and treatment. We performed BRCA1/2 mutation centered RNA-seq data analysis of breast and ovarian cancers from the TCGA repository using transcriptome and phenotype "portrayal" with multi-layer self-organizing maps and functional annotation. The results revealed considerable differences in BRCA1- and BRCA2-dependent transcriptome landscapes in the studied cancers. Furthermore, our data indicated that somatic and germline mutations for both genes are characterized by deregulation of different biological functions and differential associations with phenotype characteristics and poly(ADP-ribose) polymerase (PARP)-inhibitor gene signatures. Overall, this study demonstrates considerable variation in transcriptomic landscapes of breast and ovarian cancers associated with the affected gene (BRCA1 vs. BRCA2), as well as the mutation type (somatic vs. germline). These results warrant further investigations with larger groups of mutation carriers aimed at refining the understanding of molecular mechanisms of breast and ovarian cancers.
    Keywords:  BRCA1; BRCA2; breast cancer; multi-layer self-organizing maps; ovarian cancer; somatic and germline mutations; transcriptome portrayal
    DOI:  https://doi.org/10.3390/ijms22031266
  9. Fam Cancer. 2021 Feb 03.
    Frühwald MC, Nemes K, Boztug H, Cornips MCA, Evans DG, Farah R, Glentis S, Jorgensen M, Katsibardi K, Hirsch S, Jahnukainen K, Kventsel I, Kerl K, Kratz CP, Pajtler KW, Kordes U, Ridola V, Stutz E, Bourdeaut F.
      The rhabdoid tumor (RT) predisposition syndromes 1 and 2 (RTPS1 and 2) are rare genetic conditions rendering young children vulnerable to an increased risk of RT, malignant neoplasms affecting the kidney, miscellaneous soft-part tissues, the liver and the central nervous system (Atypical Teratoid Rhabdoid Tumors, ATRT). Both, RTPS1&2 are due to pathogenic variants (PV) in genes encoding constituents of the BAF chromatin remodeling complex, i.e. SMARCB1 (RTPS1) and SMARCA4 (RTPS2). In contrast to other genetic disorders related to PVs in SMARCB1 and SMARCA4 such as Coffin-Siris Syndrome, RTPS1&2 are characterized by a predominance of truncating PVs, terminating transcription thus explaining a specific cancer risk. The penetrance of RTPS1 early in life is high and associated with a poor survival. However, few unaffected carriers may be encountered. Beyond RT, the tumor spectrum may be larger than initially suspected, and cancer surveillance offered to unaffected carriers (siblings or parents) and long-term survivors of RT is still a matter of discussion. RTPS2 exposes female carriers to an ill-defined risk of small cell carcinoma of the ovaries, hypercalcemic type (SCCOHT), which may appear in prepubertal females. RT surveillance protocols for these rare families have not been established. To address unresolved issues in the care of individuals with RTPS and to propose appropriate surveillance guidelines in childhood, the SIOPe Host Genome working group invited pediatric oncologists and geneticists to contribute to an expert meeting. The current manuscript summarizes conclusions of the panel discussion, including consented statements as well as non-evidence-based proposals for validation in the future.
    Keywords:  ATRT; Germline; Predisposition; Rhabdoid; SMARCB1; Surveillance
    DOI:  https://doi.org/10.1007/s10689-021-00229-1
  10. Genet Med. 2021 Feb 02.
    Camp SY, Kofman E, Reardon B, Moore ND, Al-Rubaish AM, Aljumaan M, Al-Ali AK, Van Allen EM, Taylor-Weiner A, AlDubayan SH.
      PURPOSE: Cohort-based germline variant characterization is the standard approach for pathogenic variant discovery in clinical and research samples. However, the impact of cohort size on the molecular diagnostic yield of joint genotyping is largely unknown.METHODS: Head-to-head comparison of the molecular diagnostic yield of joint genotyping in two cohorts of 239 cancer patients in the absence and then in the presence of 100 additional germline exomes.
    RESULTS: In 239 testicular cancer patients, 4 (7.4%, 95% confidence interval [CI]: 2.1-17.9) of 54 pathogenic variants in the cancer predisposition and American College of Medical Genetics and Genomics (ACMG) genes were missed by one or both computational runs of joint genotyping. Similarly, 8 (12.1%, 95% CI: 5.4-22.5) of 66 pathogenic variants in these genes were undetected by joint genotyping in another independent cohort of 239 breast cancer patients. An exome-wide analysis of putative loss-of-function (pLOF) variants in the testicular cancer cohort showed that 162 (8.2%, 95% CI: 7.1-9.6) pLOF variants were only detected in one analysis run but not the other, while 433 (22.0%, 95% CI: 20.2-23.9%) pLOF variants were filtered out by both analyses despite having sufficient sequencing coverage.
    CONCLUSION: Our analysis of the standard germline variant detection method highlighted a substantial impact of concurrently analyzing additional genomic data sets on the ability to detect clinically relevant germline pathogenic variants.
    DOI:  https://doi.org/10.1038/s41436-020-01074-w
  11. Fam Cancer. 2021 Feb 06.
    Cojocaru E, Gennatas S, Thway K, Fisher C, Smrke A, Strauss D, Hayes A, Smith M, Jones RL, Benson C, McVeigh TP.
      INTRODUCTION: Desmoid-type fibromatosis (DF) are locally infiltrative, non-metastasizing tumours associated with significant morbidity and mortality if located intra-abdominally, retroperitoneally or in head and neck localisation. They are mostly sporadic, due to somatic CTNNB1 mutations. Alternatively, they can be associated with germline pathogenic variants in APC causing Familial Adenomatous Polyposis (FAP). Germline APC variants and somatic CTNNB1 mutations are mutually exclusive.AIMS AND METHODS: We conducted a retrospective descriptive analysis of patients with DF seen at the Royal Marsden NHS Foundation Trust Sarcoma Unit in London. We aimed to describe the methods of screening for FAP in patients with DF from a specialist unit. Patients diagnosed between 1992 and 2020 were selected from the prospectively maintained Sarcoma Unit database.
    RESULTS: 226 patients were identified and 67% (n = 152) were female. Median age at diagnosis was 37.5 (range 2-81) years. Tumour localisation was limbs/pelvis in 30.9% (N = 70), intra-abdominal 16.8% (N = 38), abdominal wall 23.5% (N = 53), thorax 18.6% (N = 42), head and neck 3.1% (N = 7) and vertebral/paravertebral 7.1% (N = 16). Colonoscopy was requested in 65 patients (28.8% of all cases) and was completed in forty-six (20.4%). Molecular testing of CTNNB1 testing was requested in 35 cases (15.5%). APC germline test was requested in 12 cases. Four patients in our cohort had an FAP-associated DF.
    CONCLUSIONS: CTNNB1 ± APC testing and colonoscopy are useful tools for the screening of patients with DF. CTNNB1 molecular testing should be performed in all cases of newly diagnosed DF. Negative CTNNB1 results, alongside clinical assessment, should prompt APC testing and/or colonoscopy.
    Keywords:  Beta-catenin; CTNNB1; Desmoid fibromatosis; Familial Adenomatous Polyposis (FAP) 
    DOI:  https://doi.org/10.1007/s10689-021-00230-8
  12. Front Genet. 2020 ;11 611823
    Xu A, Huang MF, Zhu D, Gingold JA, Bazer DA, Chang B, Wang D, Lai CC, Lemischka IR, Zhao R, Lee DF.
      Osteosarcoma is one of the most frequent common primary malignant tumors in childhood and adolescence. Long non-coding RNAs (lncRNAs) have been reported to regulate the initiation and progression of tumors. However, the exact molecular mechanisms involving lncRNA in osteosarcomagenesis remain largely unknown. Li-Fraumeni syndrome (LFS) is a familial cancer syndrome caused by germline p53 mutation. We investigated the tumor suppressor function of lncRNA H19 in LFS-associated osteosarcoma. Analyzing H19-induced transcriptome alterations in LFS induced pluripotent stem cell (iPSC)-derived osteoblasts, we unexpectedly discovered a large group of snoRNAs whose expression was significantly affected by H19. We identified SNORA7A among the H19-suppressed snoRNAs. SNORA7A restoration impairs H19-mediated osteogenesis and tumor suppression, indicating an oncogenic role of SNORA7A. TCGA analysis indicated that SNORA7A expression is associated with activation of oncogenic signaling and poor survival in cancer patients. Using an optimized streptavidin-binding RNA aptamer designed from H19 lncRNA, we revealed that H19-tethered protein complexes include proteins critical for DNA damage response and repair, confirming H19's tumor suppressor role. In summary, our findings demonstrate a critical role of H19-modulated SNORA7A expression in LFS-associated osteosarcomas.
    Keywords:  H19 lncRNA; Li-Fraumeni syndrome; iPSCs; osteosarcoma; p53; snoRNA
    DOI:  https://doi.org/10.3389/fgene.2020.611823
  13. Clin Transl Gastroenterol. 2021 Feb 03. 12(2): e00301
    Gargallo-Puyuelo CJ, Lanas Á, Carrera-Lasfuentes P, Ferrández Á, Quintero E, Carrillo M, Alonso-Abreu I, García-González MA.
      INTRODUCTION: Epidemiological studies estimate that having a first-degree relative (FDR) with colorectal cancer (CRC) increases 2-fold to 3-fold the risk of developing the disease. Because FDRs of CRC patients are more likely to co-inherit CRC risk variants, we aimed to evaluate potential differences in genotype distribution of single nucleotide polymorphisms (SNPs) related to CRC risk between FDRs of patients with nonsyndromic CRC (cases) and individuals with no family history of CRC (controls).METHODS: We designed a case-control study comprising 750 cases and 750 Spanish Caucasian controls matched by sex, age, and histological findings after colonoscopy. Genomic DNA from all participants was genotyped for 88 SNPs associated with CRC risk using the MassArray (Sequenom) platform.
    RESULTS: Ten of the 88 SNPs analyzed revealed significant associations (P < 0.05) with a family history of CRC in our population. The most robust associations were found for the rs17094983G>A SNP in the long noncoding RNA LINC01500 (odds ratio = 0.72; 95% confidence interval: 0.58-0.88, log-additive model), and the rs11255841T>A SNP in the long noncoding RNA LINC00709 (odds ratio = 2.04; 95% confidence interval: 1.19-3.51, dominant model). Of interest, the observed associations were in the same direction than those reported for CRC risk.
    DISCUSSION: FDRs of CRC patients show significant differences in genotype distribution of SNPs related to CRC risk as compared to individuals with no family history of CRC. Genotyping of CRC risk variants in FDRs of CRC patients may help to identify subjects at risk that would benefit from stricter surveillance and CRC screening programs.
    DOI:  https://doi.org/10.14309/ctg.0000000000000301
  14. Transl Oncol. 2021 Jan 27. pii: S1936-5233(21)00004-8. [Epub ahead of print]14(3): 101012
    Janysek DC, Kim J, Duijf PHG, Dray E.
      Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.
    Keywords:  BRCA1; BRCA2; DNA damage responses; Drug response; Familial breast cancer; Inherited cancer; PARP-1; Synthetic lethality
    DOI:  https://doi.org/10.1016/j.tranon.2021.101012
  15. Continuum (Minneap Minn). 2021 02 01. 27(1): 185-204
    Fink JK.
      PURPOSE OF REVIEW: This article guides clinicians in the clinical recognition and differential diagnosis of hereditary myelopathies.RECENT FINDINGS: Rather than a disease, a disease process, or relating to specific cellular vulnerability, the term hereditary myelopathy refers to diverse inherited disorders in which major aspects of the clinical syndrome reflect disturbance of elements within the spinal cord (specifically, the dorsal columns and dorsal root ganglia, corticospinal tracts, and anterior horn cells). It is important to note that the clinical features of almost all hereditary myelopathies reflect not only disturbance of elements within the spinal cord but also disturbance of extraspinal structures (particularly, but not limited to, peripheral nerves and the cerebellum) and that these extraspinal clinical features can be very helpful in recognizing specific myelopathy syndromes. The value of classifying disorders as inherited myelopathies lies primarily in facilitating their clinical recognition and differential diagnosis. It is useful to recognize that many hereditary myelopathies conform to one of four clinical paradigms: (1) spinocerebellar ataxia, (2) motor neuron disorder, (3) leukodystrophy, or (4) distal motor-sensory axonopathy predominantly affecting the central nervous system. Although they are myelopathies, spinal dysraphisms such as spina bifida and myelomeningocele are not included in this context because they are not usually due to single-gene mutation and have low hereditability.
    SUMMARY: This article illustrates clinical paradigms of hereditary myelopathy with clinical examples emphasizing the spectrum, clinical recognition, and differential diagnosis of hereditary myelopathies.
    DOI:  https://doi.org/10.1212/CON.0000000000000934
  16. JMIR Form Res. 2021 Feb 05. 5(2): e25184
    Sato A, Haneda E, Suganuma N, Narimatsu H.
      BACKGROUND: Breast cancer is the most common form of cancer in Japan; genetic background and hereditary breast and ovarian cancer (HBOC) are implicated. The key to HBOC diagnosis involves screening to identify high-risk individuals. However, genetic medicine is still developing; thus, many patients who may potentially benefit from genetic medicine have not yet been identified.OBJECTIVE: This study's objective is to develop a chatbot system that uses augmented intelligence for HBOC screening to determine whether patients meet the National Comprehensive Cancer Network (NCCN) BRCA1/2 testing criteria.
    METHODS: The system was evaluated by a doctor specializing in genetic medicine and certified genetic counselors. We prepared 3 scenarios and created a conversation with the chatbot to reflect each one. Then we evaluated chatbot feasibility, the required time, the medical accuracy of conversations and family history, and the final result.
    RESULTS: The times required for the conversation were 7 minutes for scenario 1, 15 minutes for scenario 2, and 16 minutes for scenario 3. Scenarios 1 and 2 met the BRCA1/2 testing criteria, but scenario 3 did not, and this result was consistent with the findings of 3 experts who retrospectively reviewed conversations with the chatbot according to the 3 scenarios. A family history comparison ascertained by the chatbot with the actual scenarios revealed that each result was consistent with each scenario. From a genetic medicine perspective, no errors were noted by the 3 experts.
    CONCLUSIONS: This study demonstrated that chatbot systems could be applied to preliminary genetic medicine screening for HBOC.
    Keywords:  IBM Watson; artificial intelligence; augmented intelligence; cancer; chatbot; familial cancer; feasibility; genetics; hereditary cancer; preliminary screening; screening
    DOI:  https://doi.org/10.2196/25184