bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–11–13
eightteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Malignant Perivascular Epithelioid Cell Tumor (PEComa) of the Uterus as Part of the Hereditary Cancer Syndrome: A Case Diagnosed with Multiple Malignancies.
  2. Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer.
  3. Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center.
  4. Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.
  5. Rare MYC-N11S germline mutation indicative of inherited breast cancer in a multigeneration family.
  6. Comprehensive Clinical and Genetic Analysis of CHEK2 in Croatian Men with Prostate Cancer.
  7. Overview of familial syndromes with increased skin malignancies.
  8. Inherited heterozygous Fanconi anemia gene mutations in a therapy-related CMML patient with a rare NUP98-HOXC11 fusion: A case report.
  9. Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.
  10. Unraveling POLN germline mutations in familial nasopharyngeal carcinoma: Complementary evidence from gene association and molecular studies.
  11. NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects.
  12. Concurrent Pathogenic Variants of BRCA1, MUTYH and CHEK2 in a Hereditary Cancer Family.
  13. DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex.
  14. From the patient to the population: Use of genomics for population screening.
  15. Lack of Association Between oral Squamous cell Carcinoma and Li-Fraumeni Syndrome.
  16. Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.
  17. Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue.
  18. Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality.
  1. Turk Patoloji Derg. 2022 Dec 11.
    Malignant Perivascular Epithelioid Cell Tumor (PEComa) of the Uterus as Part of the Hereditary Cancer Syndrome: A Case Diagnosed with Multiple Malignancies.
    Sultan Caliskan, Omer Salih Akar, Seda Gun, Mehmet Kefeli.
      A perivascular epithelioid cell tumor (PEComa) is an uncommon mesenchymal tumor composed of perivascular epithelioid cells. These tumor cells show variable immunoreactivity for both melanocytic and myogenic markers. Occurrence of PEComa has been reported at various anatomical sites, including the gynecological tract, uterus being the most common. Although most patients have sporadic PEComas, a subset may be associated with the inactivation of TSC1 or TSC2 genes and the occurrence of TFE3 gene fusions. However, a relationship between PEComas and other tumors is rare. We report a 41-year-old female patient with malignant PEComa who was admitted to the hospital with a complaint of vaginal bleeding. Because she had previously been diagnosed with colorectal and breast carcinomas at an early age, we performed a comprehensive genetic analysis to identify molecular alterations present in her background that unveiled multiple malignancy predispositions. Next-generation sequencing (NGS) analysis revealed two heterozygous germline pathogenic variants in the ATM and TP53 genes and a heterozygous variant of unknown significance (VUS) in the BRCA2 gene. The patient was diagnosed with the Li-Fraumeni Syndrome owing to the medical and family history and also the presentation of a pathogenic mutation of the TP53 gene. There are very few case reports in the literature describing PEComa in the Li-Fraumeni syndrome, and this is the first report of a uterine PEComa in a patient with Li-Fraumeni syndrome.
    DOI:  https://doi.org/10.5146/tjpath.2022.01592
  2. JAMA Oncol. 2022 Nov 11.
    Inherited Cancer Susceptibility Gene Sequence Variations Among Patients With Appendix Cancer.
    Andreana N Holowatyj, Mary K Washington, Sean V Tavtigian, Cathy Eng, Carolyn Horton.
       Importance: Germline sequence variations in APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, and TP53 genes are associated with susceptibility to gastrointestinal cancers. As a rare cancer, the evaluation of appendiceal cancer (AC) predisposition has been limited.
    Objective: To assess the prevalence and spectrum of inherited cancer susceptibility gene sequence variations in patients with AC and the utility of germline genetic testing for this population.
    Design, Setting, and Participants: This cohort study included patients with AC who underwent germline genetic testing of 14 cancer susceptibility genes performed by a clinical testing laboratory between March 1, 2012, and December 31, 2016. Data were analyzed from March to August 2022. Clinical, individual, and family histories were obtained from clinician-completed test requisition forms. Multigene panel testing was performed by targeted custom capture and sequencing and chromosome rearrangement analysis.
    Main Outcomes and Measures: The main outcomes were germline sequence variation prevalence and spectrum in patients with AC.
    Results: Among the 131 patients with AC in the cohort (90 female [68.7%]), a total of 16 deleterious sequence variations were identified in 15 patients (11.5%). Similarly, when limited to the 74 patients with AC as the first and only primary tumor, a total of 8 patients (10.8%) had at least 1 deleterious sequence variation in a cancer susceptibility gene. Overall, 6 patients (4.6%) had a deleterious sequence variation observed in MUTYH (5 with monoallelic MUTYH and 1 with biallelic MUTYH). All 4 patients with Lynch syndrome (3.1%) had a sequence variation in the MLH1 gene, of whom 3 were aged 50 years or older at AC diagnosis. Five patients (3.8%) had deleterious sequence variations in other cancer predisposition genes (1 with APC [c.3920T>A, p.I1307K], 2 with CHEK2 [c.470T>C, p.I157T], 1 with SMAD4 [c.263 287dup, p.L98IFS*14], and 1 with TP53 [c.524G>A, p.R175H]).
    Conclusions and Relevance: In this cohort study, 1 in every 10 patients with AC who underwent testing for hereditary cancer predisposition carried an inherited gene sequence variation associated with cancer susceptibility. Given the high frequency and broad spectrum of germline gene sequence variations, these data suggest that genetic evaluation might be warranted for all patients diagnosed with this rare malignant tumor. A systemic sequencing effort for all patients with AC may also identify cancer vulnerabilities to exploit for therapeutic development in a cancer type for which clinical trials are limited.
    DOI:  https://doi.org/10.1001/jamaoncol.2022.5425
  3. ESMO Open. 2022 Nov 07. pii: S2059-7029(22)00237-X. [Epub ahead of print]7(6): 100607
    Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center.
    Alliance Against Cancer
       BACKGROUND: Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation.
    MATERIALS AND METHODS: We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history.
    RESULTS: Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P = 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH).
    CONCLUSION: Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.
    Keywords:  DNA microsatellite instability; colorectal cancer; colorectal cancer genes; gene testing; inherited cancers
    DOI:  https://doi.org/10.1016/j.esmoop.2022.100607
  4. Br J Haematol. 2022 Nov 09.
    Inherited cancer predisposing mutations in patients with therapy-related myeloid neoplasms.
    Andrew J Shih, Tomi Jun, Andrew D Skol, Riyue Bao, Lei Huang, Sapana Vora, Megan E McNerney, Eric A Hungate, Michelle M Le Beau, Richard A Larson, Aaron Elliott, Hsiao-Mei Lu, Robert Huether, Felicia Hernandez, Friedrich Stölzel, James M Allan, Kenan Onel.
      Some patients with therapy-related myeloid neoplasms (t-MN) may have unsuspected inherited cancer predisposition syndrome (CPS). We propose a set of clinical criteria to identify t-MN patients with high risk of CPS (HR-CPS). Among 225 t-MN patients with an antecedent non-myeloid malignancy, our clinical criteria identified 52 (23%) HR-CPS patients. Germline whole-exome sequencing identified pathogenic or likely pathogenic variants in 10 of 27 HR-CPS patients compared to 0 of 9 low-risk CPS patients (37% vs. 0%, p = 0.04). These simple clinical criteria identify t-MN patients most likely to benefit from genetic testing for inherited CPS.
    Keywords:  cancer predisposition; germline; leukaemia; therapy-related myeloid neoplasm; whole-exome sequencing
    DOI:  https://doi.org/10.1111/bjh.18543
  5. BMJ Case Rep. 2022 Nov 11. pii: e251336. [Epub ahead of print]15(11):
    Rare MYC-N11S germline mutation indicative of inherited breast cancer in a multigeneration family.
    Laura Budurlean, Maria Baker, James Broach.
      We present a case of unexplained familial breast cancer (BC) from six family members, including four affected and two unaffected women, for whom clinical genetic testing panels were inconclusive. Exome sequencing data revealed heterozygous and rare germline variants to be inherited in an autosomal dominant manner in the family, in addition to several unclassified mutations in DNA repair and cell cycle-regulating genes that were not included in the family's clinical genetic testing. A rare MYC-N11S germline mutation with conflicting interpretations of pathogenicity in the literature, and predicted to be deleterious, was present in all affected individuals. Whole exome sequencing provided a more comprehensive picture of inherited BC in this family that was missed by cancer gene panels alone.
    Keywords:  Breast cancer; Cancer intervention; Genetic screening / counselling; Genetics
    DOI:  https://doi.org/10.1136/bcr-2022-251336
  6. Genes (Basel). 2022 Oct 27. pii: 1955. [Epub ahead of print]13(11):
    Comprehensive Clinical and Genetic Analysis of CHEK2 in Croatian Men with Prostate Cancer.
    Kira Kirchner, Marija Gamulin, Tomislav Kulis, Bianca Sievers, Zeljko Kastelan, Davor Lessel.
      Germline pathogenic and likely pathogenic (P/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P/LP variant in CHEK2 (4/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.
    Keywords:  CHEK2; aggressive prostate cancer; prostate cancer
    DOI:  https://doi.org/10.3390/genes13111955
  7. Arch Dermatol Res. 2022 Nov 07.
    Overview of familial syndromes with increased skin malignancies.
    Hui Yu Juan, Albert E Zhou, Karl M Hoegler, Amor Khachemoune.
      The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li-Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients.
    Keywords:  Familial syndrome; Melanoma; Nonmelanoma skin cancer
    DOI:  https://doi.org/10.1007/s00403-022-02447-8
  8. Front Oncol. 2022 ;12 1036511
    Inherited heterozygous Fanconi anemia gene mutations in a therapy-related CMML patient with a rare NUP98-HOXC11 fusion: A case report.
    Kefeng Shen, Meilan Zhang, Jiachen Wang, Wei Mu, Jin Wang, Chunyan Wang, Shugang Xing, Zhenya Hong, Min Xiao.
      Fanconi anemia (FA) genes play critical roles in the repair of DNA lesions. Non-FA (or underlying FA) patients harboring heterozygous germline FA gene mutations may also face an increased risk of developing bone marrow failure, primary immunodeficiency disease, and hereditary cancer predisposition syndromes. We report a female patient who suffered from ovarian cancer at 50 years of age. During the initial treatment, six cycles of docetaxel and carboplatin (DC) combination chemotherapy were administered followed by two cycles of docetaxel maintenance therapy. Then, she received a routine follow-up every 3 months for the next 3 years, and all the results of the examination and laboratory tests were normal. Unfortunately, at 54 years of age, she developed a secondary cancer of therapy-related (t-) chronic myelomonocytic leukemia (t-CMML). After two courses of a highly intensive induction chemotherapy regimen with DAC (decitabine) and HAA (homoharringtonine, cytarabine), the patient suffered from severe and persistent bone marrow failure (BMF). Targeted next-generation sequencing (NGS) of a panel of 80 genes was performed on her initial bone marrow aspirate sample and identified PTPN11, NRAS, and DNMT3A somatic mutations. In addition, RNA sequencing (RNA-seq) revealed a rare NUP98-HOXC11 fusion. Whole-exome sequencing (WES) verified RAD51C, BRIP1, PALB2, and FANCG heterozygous germline mutations of the FA pathway, which were further confirmed in buccal swab samples by Sanger sequencing. For this patient, we hypothesized that an altered FA pathway resulted in genomic instability, hypersensitivity to DNA-crosslinking agents or cytotoxic chemotherapeutics, and unsuccessful DNA damage repair. Consequently, she developed ovarian cancer and secondary t-CMML and then suffered from BMF and delayed post-chemotherapy bone marrow recovery after several chemotherapy courses. This case highlights the importance of genetic counseling in patients with hematopoietic neoplasms with high clinical suspicion for carrying cancer susceptibility gene mutations, which require timely diagnosis and personalized management.
    Keywords:  Fanconi anemia gene; NUP98-HOXC11 fusion; hereditary cancer predisposition syndromes; ovarian cancer; therapy-related CMML (t-CMML)
    DOI:  https://doi.org/10.3389/fonc.2022.1036511
  9. Ann Surg Oncol. 2022 Nov 05.
    Genetic Testing Among Patients with High-Risk Breast, Ovarian, Pancreatic, and Prostate Cancers.
    Nina M Clark, Emma A Roberts, Catherine Fedorenko, Qin Sun, Marianne Dubard-Gault, Cynthia Handford, Rachel Yung, Heather H Cheng, Jonathan G Sham, Barbara M Norquist, Meghan R Flanagan.
       BACKGROUND: The National Comprehensive Cancer Network recommends genetic testing in patients with potentially hereditary breast, ovarian, pancreatic, and prostate cancers (HBOPP). Knowledge of genetic mutations impacts decisions about screening and treatment.
    METHODS: A retrospective cohort study of 28,586 HBOPP patients diagnosed from 2013 to 2019 was conducted using a linked administrative-cancer database in the Seattle-Puget Sound SEER area. Guideline-concordant testing (GCT) was assessed annually according to guideline updates. Frequency of testing according to patient/cancer characteristics was evaluated using chi-squared tests, and factors associated with receipt of genetic testing were identified using multivariable logistic regression.
    RESULTS: Testing occurred in 17% of HBOPP patients, increasing from 9% in 2013 to 21% in 2019 (p < 0.001). Ovarian cancer had the highest testing (40%) and prostate cancer the lowest (4%). Age < 50, female sex, non-Hispanic White race, commercial insurance, urban location, family history of HBOPP, and triple negative breast cancer (TNBC) were associated with increased testing (all p < 0.05). GCT increased from 38% in 2013 to 44% in 2019, and was highest for early age at breast cancer diagnosis, TNBC, male breast cancer, and breast cancer with family history of HBOPP (all > 70% in 2019), and lowest for metastatic prostate cancer (6%).
    CONCLUSIONS: The frequency of genetic testing for HBOPP cancer has increased over time. Though GCT is high for breast cancer, there are gaps in concordance among patients with other cancers. Increasing provider and patient education, genetic counseling, and insurance coverage for testing among HBOPP patients may improve guideline adherence.
    DOI:  https://doi.org/10.1245/s10434-022-12755-y
  10. EBioMedicine. 2022 Nov 03. pii: S2352-3964(22)00508-4. [Epub ahead of print]86 104326
    Unraveling POLN germline mutations in familial nasopharyngeal carcinoma: Complementary evidence from gene association and molecular studies.
    Pei Pei Chong.
      
    DOI:  https://doi.org/10.1016/j.ebiom.2022.104326
  11. Clin Cancer Res. 2022 Nov 08. pii: CCR-22-1703. [Epub ahead of print]
    NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defects.
    Sami Belhadj, Aliya Khurram, Chaitanya Bandlamudi, Guillermo Palou-Márquez, Vignesh Ravichandran, Zoe Steinsnyder, Temima Wildman, Amanda Catchings, Yelena Kemel, Semanti Mukherjee, Benjamin Fesko, Kanika Arora, Miika Mehine, Sita Dandiker, Aalin Izhar, John Petrini, Susan Domchek, Katherine L Nathanson, Jamie Brower, Fergus Couch, Zsofia Stadler, Mark Robson, Michael Walsh, Joseph Vijai, Michael Berger, Fran Supek, Rachid Karam, Sabine Topka, Kenneth Offit.
       PURPOSE: To explore the role of NBN as a pan-cancer susceptibility gene.
    METHODS: Matched germline and somatic DNA samples from 34,046 patients were sequenced using MSK-IMPACT and presumed pathogenic germline variants (PGVs) identified. Allele specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation.
    RESULTS: We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors (OR=2.7, CI:1.4-5.5 p=0.0024; pan-cancer), including lung and pancreatic tumors compared to breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR=2.22, CI:1.3-3.6 p=0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared to controls in the European population (OR=1.9, CI:1.3-2.7, p=0.0004), a finding confirmed in the replication cohort (OR=1.8: CI: 1.2-2.6, p=0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to g-irradiation and lower levels of radiation-induced KAP1 phosphorylation.
    CONCLUSION: Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1703
  12. Cancer Genet. 2022 Nov 01. pii: S2210-7762(22)00271-X. [Epub ahead of print]268-269 128-136
    Concurrent Pathogenic Variants of BRCA1, MUTYH and CHEK2 in a Hereditary Cancer Family.
    Nihat Bugra Agaoglu, Ozden Hatirnaz Ng, Busra Unal, Ozlem Akgun Dogan, Ufuk Amanvermez, Jale Yildiz, Levent Doganay, Arezou A Ghazani, Huma Q Rana.
      Concurrent pathogenic variants (PVs) in cancer predisposition genes have been reported in 0.1-2% of hereditary cancer (HC) patients. Determining concurrent PVs is crucial for the diagnosis, treatment, and risk assessment of unaffected family members. Next generation sequencing based diagnostic tests, which are widely used in HCs, enable the evaluation of multiple genes in parallel. We have screened the family members of a patient with bilateral breast cancer who was found to have concurrent PVs in BRCA1 (NM_007294.3;c.5102_5103del, p.Leu1701Glnfs*14) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu). Further analysis revealed concurrent PVs in CHEK2 (NM_007194.4;c.1427C>T, p.Thr476Met) and MUTYH (NM_001128425.1;c.884C>T, p.Pro295Leu) in the maternal uncle of the index case. Eight additional family members were found to have PVs in BRCA1 and MUTYH among 26 tested relatives. The sister and the brother of the index case who were diagnosed with breast and colon cancers, respectively, presented with the same genotype as the index case. Each family member was evaluated individually for clinical care and surveillance. This is the first report describing a family with BRCA1, MUTYH and CHEK2 concurrent PVs. Our findings provide valuable information for the assessment and management considerations for families with concurrent PVs.
    Keywords:  BRCA1; CHEK2; Concurrent variants; Hereditary cancer; MUTYH
    DOI:  https://doi.org/10.1016/j.cancergen.2022.10.144
  13. Cancers (Basel). 2022 Oct 27. pii: 5278. [Epub ahead of print]14(21):
    DNA Repair Mechanisms, Protein Interactions and Therapeutic Targeting of the MRN Complex.
    Claire McCarthy-Leo, Fatima Darwiche, Michael A Tainsky.
      Repair of a DNA double-strand break relies upon a pathway of proteins to identify damage, regulate cell cycle checkpoints, and repair the damage. This process is initiated by a sensor protein complex, the MRN complex, comprised of three proteins-MRE11, RAD50, and NBS1. After a double-stranded break, the MRN complex recruits and activates ATM, in-turn activating other proteins such as BRCA1/2, ATR, CHEK1/2, PALB2 and RAD51. These proteins have been the focus of many studies for their individual roles in hereditary cancer syndromes and are included on several genetic testing panels. These panels have enabled us to acquire large amounts of genetic data, much of which remains a challenge to interpret due to the presence of variants of uncertain significance (VUS). While the primary aim of clinical testing is to accurately and confidently classify variants in order to inform medical management, the presence of VUSs has led to ambiguity in genetic counseling. Pathogenic variants within MRN complex genes have been implicated in breast, ovarian, prostate, colon cancers and gliomas; however, the hundreds of VUSs within MRE11, RAD50, and NBS1 precludes the application of these data in genetic guidance of carriers. In this review, we discuss the MRN complex's role in DNA double-strand break repair, its interactions with other cancer predisposing genes, the variants that can be found within the three MRN complex genes, and the MRN complex's potential as an anti-cancer therapeutic target.
    Keywords:  DNA repair pathway; MRN complex; variants of uncertain significance
    DOI:  https://doi.org/10.3390/cancers14215278
  14. Front Genet. 2022 ;13 893832
    From the patient to the population: Use of genomics for population screening.
    Chloe Mighton, Salma Shickh, Vernie Aguda, Suvetha Krishnapillai, Ella Adi-Wauran, Yvonne Bombard.
      Genomic medicine is expanding from a focus on diagnosis at the patient level to prevention at the population level given the ongoing under-ascertainment of high-risk and actionable genetic conditions using current strategies, particularly hereditary breast and ovarian cancer (HBOC), Lynch Syndrome (LS) and familial hypercholesterolemia (FH). The availability of large-scale next-generation sequencing strategies and preventive options for these conditions makes it increasingly feasible to screen pre-symptomatic individuals through public health-based approaches, rather than restricting testing to high-risk groups. This raises anew, and with urgency, questions about the limits of screening as well as the moral authority and capacity to screen for genetic conditions at a population level. We aimed to answer some of these critical questions by using the WHO Wilson and Jungner criteria to guide a synthesis of current evidence on population genomic screening for HBOC, LS, and FH.
    Keywords:  familial hypercholestelemia; genetic testing; hereditary breast and ovarian cancer (HBOC); lynch syndrome; population screening; tier 1 conditions
    DOI:  https://doi.org/10.3389/fgene.2022.893832
  15. Head Neck Pathol. 2022 Nov 07.
    Lack of Association Between oral Squamous cell Carcinoma and Li-Fraumeni Syndrome.
    Erison Santana Dos Santos, Alan Roger Santos-Silva.
      
    DOI:  https://doi.org/10.1007/s12105-022-01495-w
  16. Int J Mol Sci. 2022 Nov 03. pii: 13426. [Epub ahead of print]23(21):
    Characteristics of BRCA2 Mutated Prostate Cancer at Presentation.
    Hyunho Han, Cheol Keun Park, Nam Hoon Cho, Jongsoo Lee, Won Sik Jang, Won Sik Ham, Young Deuk Choi, Kang Su Cho.
      Genetic alterations of DNA repair genes, particularly BRCA2 in patients with prostate cancer, are associated with aggressive behavior of the disease. It has reached consensus that somatic and germline tests are necessary when treating advanced prostate cancer patients. Yet, it is unclear whether the mutations are associated with any presenting clinical features. We assessed the incidences and characteristics of BRCA2 mutated cancers by targeted sequencing in 126 sets of advanced prostate cancer tissue sequencing data. At the time of diagnosis, cT3/4, N1 and M1 stages were 107 (85%), 54 (43%) and 35 (28%) samples, respectively. BRCA2 alterations of clinical significance by AMP/ASCO/CAP criteria were found in 19 of 126 samples (15.1%). The BRCA2 mutated cancer did not differ in the distributions of TNM stage, Gleason grade group or histological subtype compared to BRCA2 wild-type cancers. Yet, they had higher tumor mutation burden, and higher frequency of ATM and BRCA1 mutations (44% vs. 10%, p = 0.002 and 21% vs. 4%, p = 0.018, respectively). Of the metastatic subgroup (M1, n = 34), mean PSA was significantly lower in BRCA2 mutated cancers than wild-type (p = 0.018). In the non-metastatic subgroup (M0, n = 64), PSA was not significantly different (p = 0.425). A similar trend was noted in multiple metastatic prostate cancer public datasets. We conclude that BRCA2 mutated metastatic prostate cancers may present in an advanced stage with relatively low PSA.
    Keywords:  BRCA2; PSA; prostate cancer
    DOI:  https://doi.org/10.3390/ijms232113426
  17. Leukemia. 2022 Nov 08.
    Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue.
    Jeong-Ah Kim, Siqi Shen, Daniel R Matson, Lauren N Lovrien, Kelcy J Smith-Simmer, Sunduz Keles, Jane E Churpek, Emery H Bresnick.
      
    DOI:  https://doi.org/10.1038/s41375-022-01753-4
  18. Hum Mutat. 2022 Nov 09.
    Germline selection of PTPN11 (HGNC:9644) variants make a major contribution to both Noonan syndrome's high birth rate and the transmission of sporadic cancer variants resulting in fetal abnormality.
    Jordan Eboreime, Soo-Kyung Choi, Song-Ro Yoon, Anastasiia Sadybekov, Vsevolod Katritch, Peter Calabrese, Norman Arnheim.
      Some spontaneous germline gain-of-function mutations promote spermatogonial stem cell clonal expansion and disproportionate variant sperm production leading to unexpectedly high transmission rates for some human genetic conditions. To measure the frequency and spatial distribution of de novo mutations we divided three testes into 192 pieces each and used error-corrected deep-sequencing on each piece. We focused on PTPN11 (HGNC:9644) Exon 3 that contains 30 different PTPN11 Noonan syndrome mutation sites. We found 14 of these variants formed clusters among the testes; one testis had 11 different variant clusters. The mutation frequencies of these different clusters were not correlated with their case-recurrence rates nor were case recurrence rates of PTPN11 variants correlated with their tyrosine phosphatase levels thereby confusing PTPN11's role in germline clonal expansion. Six of the PTPN11 exon 3 de novo variants associated with somatic mutation-induced sporadic cancers (but not Noonan syndrome) also formed testis clusters. Further, three of these six variants were observed among fetuses that underwent prenatal ultrasound screening for Noonan syndrome-like features. Mathematical modeling showed that germline selection can explain both the mutation clusters and the high incidence of Noonan syndrome (1/1,000-1/2,500). This article is protected by copyright. All rights reserved.
    Keywords:  Noonan syndrome; RASopathies; SSC clonal expansion; fetal abnormality; germline selection; sporadic cancer
    DOI:  https://doi.org/10.1002/humu.24493
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