bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒02‒21
fifteen papers selected by
Joanna Zawacka-Pankau
University of Warsaw
  1. Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.
  2. Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.
  3. Bayesian predictive model to assess BRCA2 mutational status according to clinical history: Early onset, metastatic phenotype or family history of breast/ovary cancer.
  4. Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations.
  5. Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series.
  6. Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?
  7. Practice patterns and results of tumor and germline genetic evaluation of women with endometrial cancer in south Louisiana.
  8. Novel germline TRAF3IP3 mutation in a dyad with familial acute B lymphoblastic leukemia.
  9. Considerations for using population frequency data in germline variant interpretation: cancer syndrome genes as a model.
  10. Characterization of rare germline variants in familial multiple myeloma.
  11. Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.
  12. Clinicopathologic and Genomic Analysis of TP53-Mutated Endometrial Carcinomas.
  13. Germline Genetic Variation Modulates Tumor Immune Microenvironment.
  14. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
  15. Disparities in Genetic Testing and Care among Black women with Hereditary Breast Cancer.
  1. PLoS One. 2021 ;16(2): e0247363
    Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis.
    Sandoval RL, Leite ACR, Barbalho DM, Assad DX, Barroso R, Polidorio N, Dos Anjos CH, de Miranda AD, Ferreira ACSM, Fernandes GDS, Achatz MI.
      Brazil is the largest country in South America and the most genetically heterogeneous. The aim of the present study was to determine the prevalence of germline pathogenic variants (PVs) in Brazilian patients with breast cancer (BC) who underwent genetic counseling and genetic testing at a tertiary Oncology Center. We performed a retrospective analysis of the medical records of Brazilian patients with BC referred to genetic counseling and genetic testing between August 2017 and August 2019. A total of 224 unrelated patients were included in this study. Premenopausal women represented 68.7% of the cohort. The median age at BC diagnosis was 45 years. Multigene panel testing was performed in 219 patients, five patients performed single gene analysis or family variant testing. Forty-eight germline PVs distributed among 13 genes were detected in 20.5% of the patients (46/224). Eighty-five percent of the patients (91/224) fulfilled NCCN hereditary BC testing criteria. Among these patients, 23.5% harbored PVs (45/191). In the group of patients that did not meet NCCN criteria, PV detection rate was 3% (1/33). A total of 61% of the patients (28/46) harbored a PV in a high-penetrance BC gene: 19 (8.5%) BRCA1/2, 8 (3.5%) TP53, 1 (0.5%) PALB2. Moderate penetrance genes (ATM, CHEK2) represented 15.2% (7/46) of the positive results. PVs detection was statistically associated (p<0.05) with BC diagnosis before age 45, high-grade tumors, bilateral BC, history of multiple primary cancers, and family history of pancreatic cancer. According to the current hereditary cancer guidelines, 17.4% (39/224) of the patients had actionable variants. Nine percent of the patients (20/224) had actionable variants in non-BRCA genes, it represented 43.5% of the positive results and 51.2% of the actionable variants. Considering the observed prevalence of PVs in actionable genes beyond BRCA1/2 (9%, 20/224), multigene panel testing may offer an effective first-tier diagnostic approach in this population.
    DOI:  https://doi.org/10.1371/journal.pone.0247363
  2. NPJ Precis Oncol. 2020 Feb 24. 4(1): 4
    Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.
    Landrith T, Li B, Cass AA, Conner BR, LaDuca H, McKenna DB, Maxwell KN, Domchek S, Morman NA, Heinlen C, Wham D, Koptiuch C, Vagher J, Rivera R, Bunnell A, Patel G, Geurts JL, Depas MM, Gaonkar S, Pirzadeh-Miller S, Krukenberg R, Seidel M, Pilarski R, Farmer M, Pyrtel K, Milliron K, Lee J, Hoodfar E, Nathan D, Ganzak AC, Wu S, Vuong H, Xu D, Arulmoli A, Parra M, Hoang L, Molparia B, Fennessy M, Fox S, Charpentier S, Burdette J, Pesaran T, Profato J, Smith B, Haynes G, Dalton E, Crandall JR, Baxter R, Lu HM, Tippin-Davis B, Elliott A, Chao E, Karam R.
      Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.
    DOI:  https://doi.org/10.1038/s41698-020-0109-y
  3. Prostate. 2021 Feb 18.
    Bayesian predictive model to assess BRCA2 mutational status according to clinical history: Early onset, metastatic phenotype or family history of breast/ovary cancer.
    Leon P, Cancel-Tassin G, Bourdon V, Buecher B, Oudard S, Brureau L, Jouffe L, Blanchet P, Stoppa-Lyonnet D, Coulet F, Sobol H, Cussenot O.
      BACKGROUND: Mutations of the BRCA2 gene are the most frequent alterations found in germline DNA from men with prostate cancer (PrCa), but clinical parameters that could better orientate for BRCA2 mutation screening need to be established.METHODS: Germline DNA from 325 PrCa patients (median age at diagnosis: 57 years old) was screened for BRCA2 mutation. The mutation frequency was compared between three subgroups: patients with an age at diagnosis at 55 years old and under (Group I); a personal or family history of breast, uterine or ovarian cancer (Group II); or a metastatic disease (Group III). Frequency of BRCA2 mutations was established for each combination of phenotypes, and compared between patients meeting or not the criteria for each subgroup using Fisher's exact test. Mutual information, direct effect, elasticity and contribution to the mutational status of each phenotype, taking into account overlap between subgroups, were also estimated using Bayesian algorithms.
    RESULTS: The proportion of BRCA2 mutation was 5.9% in Group I, 10.9% in Group II and 6.9% in Group III. The frequency of BRCA2 mutation was significantly higher among patients of Group II (p = .006), and reached 15.6% among patients of this group who presented a metastatic disease. Mutual information, direct effect, elasticity and contribution to the mutational status were the highest for phenotype II. Fifteen (71.4%) of the 21 BRCA2 mutation carriers had an aggressive form of the disease. Four (19%) of them died from PrCa after a median follow-up duration of 64.5 months.
    CONCLUSIONS: Our results showed that a higher frequency of BRCA2 mutation carriers is observed, not only among PrCa patients with young onset or a metastatic disease, but also with a personal or a familial history of breast cancer.
    Keywords:  BRCA2; DNA damage and repair; mutation; prostate cancer; survival
    DOI:  https://doi.org/10.1002/pros.24109
  4. Front Oncol. 2020 ;10 582213
    Next-Generation Sequencing of DDX41 in Myeloid Neoplasms Leads to Increased Detection of Germline Alterations.
    Bannon SA, Routbort MJ, Montalban-Bravo G, Mehta RS, Jelloul FZ, Takahashi K, Daver N, Oran B, Pemmaraju N, Borthakur G, Naqvi K, Issa G, Sasaki K, Alvarado Y, Kadia TM, Konopleva M, Shamanna RK, Khoury JD, Ravandi F, Champlin R, Kantarjian HM, Bhalla K, Garcia-Manero G, Patel KP, DiNardo CD.
      Previously considered rare, inherited hematologic malignancies are increasingly identified. Germline mutations in the RNA helicase DDX41 predispose to increased lifetime risks of myeloid neoplasms with disease often occurring later in life which presents challenges for germline recognition. To improve identification of germline DDX41, individuals presenting with ≥1 DDX41 alteration on an institutional MDS/AML next-generation sequencing based panel with at least one at >40% variant allele frequency were flagged for review and genetic counseling referral. Of 5,801 individuals, 90 (1.5%) had ≥1 DDX41 mutation(s) identified. Thirty-eight (42%) patients with a median age of 66 years were referred for genetic counseling; thirty-one were male (81.5%). Thirty-five (92%) referred patients elected to pursue germline evaluation and in 33/35 (94%) a germline DDX41 variant was confirmed. Twenty-two patients (66%) with germline variants reported antecedent cytopenias, seven (21%) had a prior history of malignancy, and twenty-seven (82%) reported a family history of cancer. Predictive genetic testing for healthy family members under consideration as stem cell transplant donors was successfully performed in 11 family members, taking an average of 15 days. Near-heterozygous DDX41 mutations identified on next-generation sequencing, particularly nonsense/frameshift variants or those at recurrent germline "hot spots" are highly suggestive of a germline mutation. Next-generation sequencing screening is a feasible tool to screen unselected myeloid neoplasms for germline DDX41 mutations, enabling timely and appropriate care.
    Keywords:  AML; DDX41; MDS; germline; hereditary
    DOI:  https://doi.org/10.3389/fonc.2020.582213
  5. Breast Cancer Res Treat. 2021 Jan 28.
    Concurrent germline BRCA1, BRCA2, and CHEK2 pathogenic variants in hereditary breast cancer: a case series.
    Sukumar J, Kassem M, Agnese D, Pilarski R, Ramaswamy B, Sweet K, Sardesai S.
      BACKGROUND: Concurrent germline (g) pathogenic variants related to hereditary breast cancer represent a rare occurrence. While double heterozygosity in gBRCA1 and gBRCA2 has been reported in the past, herein we describe the first case of three known concurrent pathogenic variants identified in a family with a strong history of breast cancer. Case presentation The proband is a 55-year-old female diagnosed with synchronous bilateral breast cancers. She underwent a multi-gene panel testing indicating the presence of 3 concurrent heterozygous germline deleterious variants in BRCA1 (c.181T > G), BRCA2 (c.4398_4402delACATT), and CHEK2 (1100delC). The patient's two daughters (34 and 29 years-old) were found to be transheterozygous for inherited pathogenic variants in BRCA1 (c.181T > G) and CHEK2 (1100delC) genes.CONCLUSION: The cancer risk and phenotypic manifestations associated with transheterozygous or multiple concurrent deleterious germline variants in hereditary breast cancer requires further investigation. A personalized approach to counseling, screening, and risk reduction should be undertaken for these individuals.
    Keywords:  BRCA1; BRCA2; Breast cancer; CHEK2; DNAI1; Genetic; Germline; Variants
    DOI:  https://doi.org/10.1007/s10549-021-06095-w
  6. Front Genet. 2021 ;12 606537
    Prevalence of the Brazilian TP53 Founder c.1010G>A (p.Arg337His) in Lung Adenocarcinoma: Is Genotyping Warranted in All Brazilian Patients?
    Vieira IA, Andreis TF, Fernandes BV, Achatz MI, Macedo GS, Schramek D, Ashton-Prolla P.
      In Southern and Southeastern Brazil, there is a germline pathogenic variant with incomplete penetrance located in the oligomerization domain of TP53, c.1010G>A (p.Arg337His). Due to a founder effect, the variant is present in 0.3% of the general population of the region. Recently, this variant was identified in 4.4 and 8.9% of two apparently unselected, single center case series of Brazilian lung adenocarcinoma (LUAD) patients from the Southeastern and Central regions of the country, respectively. In the present study, our aim was to examine TP53 c.1010G>A allele and genotype frequencies in LUAD samples obtained from patients diagnosed in Southern Brazil. A total of 586 LUAD samples (tumor DNA) recruited from multiple centers in the region were tested, and the mutant allele was identified using TaqMan® assays in seven cases (7/586, 1.2%) which were submitted to next generation sequencing analyses for confirmation. Somatic EGFR mutations were more frequent in TP53 c.1010G>A carriers than in non-carriers (57.1 vs. 17.6%, respectively). Further studies are needed to confirm if TP53 c.1010G>A is a driver in LUAD carcinogenesis and to verify if there is a combined effect of EGFR and germline TP53 c.1010G>A. Although variant frequency was higher than observed in the general population, it is less than previously reported in LUAD patients from other Brazilian regions. Additional data, producing regional allele frequency information in larger series of patients and including cost-effectiveness analyses, are necessary to determine if TP53 c.1010G>A screening in all Brazilian LUAD patients is justified.
    Keywords:  Li-Fraumeni syndrome; R337H; TP53 (p.Arg337His); TP53 gene; founder variant; lung adenocarcinoma; non-small cell lung cancer; p53 protein
    DOI:  https://doi.org/10.3389/fgene.2021.606537
  7. Gynecol Oncol Rep. 2021 May;36 100717
    Practice patterns and results of tumor and germline genetic evaluation of women with endometrial cancer in south Louisiana.
    McDougal M, Nair-Fairless P, Weiss T, Dao E, Chapple AG, Jernigan A.
      The objectives were to describe rates of MMRd or MSI-H EC tumors, the prevalence of LS, the practice patterns of EC genetic evaluation and adherence to NCCN guidelines, and to identify disparities in the genetic evaluation of women with EC. A retrospective cohort study was performed on women with EC from 1/2013 to 12/2019, and information collected included demographics, personal and family history, EC diagnosis and treatment, and details of genetic evaluation. Statistical analysis included a multivariable logistic regression to adjust for all covariate effects simultaneously and Fisher exact tests of independence and Wilcoxon rank-sum tests to compare categorical and continuous covariates, respectively. Of the 286 women with EC, 80 EC tumors were tested, and 27.5% were MMRd or MSI-H. Of the 21 women who had germline testing, no cases of LS were identified. Before the NCCN recommended universal tumor testing, 17.6% of women had tumor testing performed compared to 60.0% after February of 2017 (OR = 2.51, 95% CI 1.89-3.32). Advanced cancer stage was nearly associated with an increased likelihood of tumor testing (OR = 1.40, 95% CI 1.00-1.97). No disparities were identified. We described patterns of genetic evaluation and tumor testing results for women with EC in south Louisiana and found similar rates of MMRd or MSI-H EC tumors as previously reported in other populations. Rates of tumor testing increased after the NCCN recommendation for universal tumor testing, but it is critical to identify weaknesses in this process and develop an algorithm to improve care for women with EC.
    Keywords:  DNA mismatch repair; Endometrial Neoplasms; Genetic counseling; Genetic testing; Hereditary nonpolyposis; Microsatellite instability
    DOI:  https://doi.org/10.1016/j.gore.2021.100717
  8. Cancer Rep (Hoboken). 2021 Jan 27. e1335
    Novel germline TRAF3IP3 mutation in a dyad with familial acute B lymphoblastic leukemia.
    Pommert L, Burns R, Furumo Q, Pulakanti K, Brandt J, Burke MJ, Rao S.
      BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children, representing 25% of all new cancer diagnoses. Advances in genomic sequencing have demonstrated that inherited genetic risk factors play a larger role in leukemia development than previously appreciated.AIM: We identified a father-daughter dyad with childhood B-cell ALL and aimed to investigate whether the pair shared a gene associated with leukemia predisposition.
    METHODS: We performed whole exome sequencing on their leukemia and germline samples and RNA-seq on their leukemia samples.
    RESULTS: We discovered a novel germline chromosomal structural variant in chromosome 1q32.2 within the TRAF3IP3 gene. TRAF3IP3 regulates B-cell lymphopoiesis, and this mutation likely resulted in a predisposition to leukemia by causing expansion of immature B-cell precursors which are highly vulnerable to secondary somatic mutations. Based on the lack of concordance in the somatic mutational profiles between this dyad's leukemia samples, we suspect that the acquired somatic mutations rather than this germline mutation are what dictated their leukemia phenotypes, which we confirmed through RNA-seq by comparing to sporadic cases of B-cell ALL.
    CONCLUSION: This research may have identified a novel gene involved in leukemogenesis which may also be involved in de novo cases of ALL. Additional studies are needed to further characterize this TRAF3IP3 structural variant, the co-occurring somatic mutations within these leukemia samples and their combined role in leukemogenesis.
    Keywords:  TRAF3IP3; dyad; familial ALL; familial leukemia; inherited leukemia; leukemia predisposition; pediatric acute lymphoblastic leukemia
    DOI:  https://doi.org/10.1002/cnr2.1335
  9. Hum Mutat. 2021 Feb 18.
    Considerations for using population frequency data in germline variant interpretation: cancer syndrome genes as a model.
    Davidson AL, Leonard C, Koufariotis LT, Parsons MT, Hollway GE, Pearson JV, Newell F, Waddell N, Spurdle AB.
      Aggregate population genomics data from large cohorts is vital for assessing germline variant pathogenicity. However, there are no specifications on how sequencing quality metrics should be considered, and whether exome-derived and genome-derived allele frequencies should be considered in isolation. Germline genome sequence data was simulated for nine read-depths to identify a minimum acceptable read-depth for detecting variants. gnomAD exome-derived and genome-derived datasets were assessed for read-depth, for six key cancer genes selected for variant curation by ClinGen expert panels. Non-Finnish European allele frequency or filter allele frequency of coding variants in these genes, assigned into frequency bins using modified ACMG-AMP criteria, were compared between exome-derived and genome-derived datasets. A 30X read-depth achieved acceptable precision and recall for detection of substitutions, but poor recall for small insertions/deletions. Exome-derived and genome-derived datasets exhibited low read-depth for different gene exons. Individual variants were mostly assigned to the same allele frequency bin (>95%) or filter allele frequency bin (>97%). Two major bin divergences were resolved by applying the minimal acceptable read-depth threshold. These findings show the importance of assessing read-depth separately for population datasets sourced from different short-read sequencing technologies before assigning a frequency-based ACMG-AMP classification code for variant interpretation. This article is protected by copyright. All rights reserved.
    Keywords:  ACMG-AMP criteria; Allele frequency; curation; gnomAD; sequence read-depth
    DOI:  https://doi.org/10.1002/humu.24183
  10. Blood Cancer J. 2021 Feb 13. 11(2): 33
    Characterization of rare germline variants in familial multiple myeloma.
    Catalano C, Paramasivam N, Blocka J, Giangiobbe S, Huhn S, Schlesner M, Weinhold N, Sijmons R, de Jong M, Langer C, Preuss KD, Nilsson B, Durie B, Goldschmidt H, Bandapalli OR, Hemminki K, Försti A.
      
    DOI:  https://doi.org/10.1038/s41408-021-00422-6
  11. Cold Spring Harb Mol Case Stud. 2021 Feb;pii: a005801. [Epub ahead of print]7(1):
    Treatment-emergent neuroendocrine prostate cancer with a germline BRCA2 mutation: identification of a candidate reversion mutation associated with platinum/PARP-inhibitor resistance.
    Pandya D, Shah M, Kaplan F, Martino C, Levy G, Kazanjian M, Batter S, Martignetti J, Frank RC.
      Neuroendocrine prostate cancer (NEPC) is a highly aggressive histologic subtype of prostate cancer associated with a poor prognosis. Its incidence is expected to increase as castration-resistant disease emerges from the widespread use of potent androgen receptor-targeting therapies, such as abiraterone and enzalutamide. Defects in homologous recombination repair genes, such as BRCA1/2, are also being increasingly detected in individuals with advanced prostate cancer. We present the case of a 65-yr-old man with a germline BRCA2 mutation who developed explosive treatment-emergent, small-cell neuroendocrine prostate cancer. He achieved a complete response to platinum-containing chemotherapy, but a limited remission duration with the use of olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, as maintenance therapy. Upon relapse, tumor genomic profiling revealed a novel 228-bp deletion in exon 11 of the BRCA2 gene. The addition of the anti-PD1 drug pembrolizumab to olaparib was ineffective. This case highlights the ongoing challenges in treating neuroendocrine prostate cancer, even in the setting of homologous recombination repair deficiency.
    Keywords:  prostate cancer
    DOI:  https://doi.org/10.1101/mcs.a005801
  12. Clin Cancer Res. 2021 Feb 18. pii: clincanres.4436.2020. [Epub ahead of print]
    Clinicopathologic and Genomic Analysis of TP53-Mutated Endometrial Carcinomas.
    Momeni-Boroujeni A, Dahoud W, Vanderbilt CM, Chiang S, Murali R, Rios-Doria E, Alektiar K, Aghajanian C, Abu-Rustum NR, Ladanyi M, Ellenson LH, Weigelt B, Soslow R.
      PURPOSE: Copy number-high endometrial carcinomas (ECs) were described by The Cancer Genome Atlas as high-grade endometrioid and serous cancers showing frequent copy number alterations (CNAs), low mutational burden (i.e. non-hypermutant), near universal TP53 mutation and unfavorable clinical outcomes. We sought to investigate and compare the clinicopathologic and molecular characteristics of non-hypermutant TP53-altered ECs of four histologic types.DESIGN: TP53-mutated ECs, defined as TP53-mutant tumors lacking microsatellite instability or pathogenic POLE mutations, were identified (n=238) in a cohort of 1,239 ECs subjected to clinical massively parallel sequencing of 410-468 cancer-related genes. Somatic mutations and CNAs (n=238), and clinicopathologic features were determined (n=185, initial treatment planning at our institution).
    RESULTS: TP53-mutated ECs encompassed uterine serous (n=102, 55.1%), histologically ambiguous high-grade EC-NOS (n=44, 23.8%), endometrioid of all tumor grades (n=28, 15.1%), and clear cell (n=11, 5.9%) carcinomas. PTEN mutations were significantly more frequent in endometrioid carcinomas, SPOP mutations in clear cell carcinomas, and CCNE1 amplification in serous carcinomas/EC-NOS; however, none of these genomic alterations were exclusive to any given histologic type. ERBB2 amplification was present at similar frequencies across histologic TP53-mutated types (7.7%-18.6%). Although overall survival was similar across histologic types, serous carcinomas presented more frequently at stage IV, had more persistent and/or recurrent disease, and reduced disease-free survival.
    CONCLUSIONS: TP53-mutated ECs display clinical and molecular similarities across histologic subtypes. Our data provide evidence to suggest performance of ERBB2 assessment in all TP53-mutated ECs. Given the distinct clinical features of serous carcinomas, histologic classification continues to be relevant.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-20-4436
  13. Cancer Discov. 2021 Feb 19.
    Germline Genetic Variation Modulates Tumor Immune Microenvironment.
      Patient genetic background contributed to antitumor immune responses at molecular and cellular levels.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2021-025
  14. Nat Commun. 2021 02 17. 12(1): 1078
    A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.
    Coignard J, Lush M, Beesley J, O'Mara TA, Dennis J, Tyrer JP, Barnes DR, McGuffog L, Leslie G, Bolla MK, Adank MA, Agata S, Ahearn T, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Arnold N, Aronson KJ, Arun BK, Augustinsson A, Azzollini J, Barrowdale D, Baynes C, Becher H, Bermisheva M, Bernstein L, Białkowska K, Blomqvist C, Bojesen SE, Bonanni B, Borg A, Brauch H, Brenner H, Burwinkel B, Buys SS, Caldés T, Caligo MA, Campa D, Carter BD, Castelao JE, Chang-Claude J, Chanock SJ, Chung WK, Claes KBM, Clarke CL, , , Collée JM, Conroy DM, Czene K, Daly MB, Devilee P, Diez O, Ding YC, Domchek SM, Dörk T, Dos-Santos-Silva I, Dunning AM, Dwek M, Eccles DM, Eliassen AH, Engel C, Eriksson M, Evans DG, Fasching PA, Flyger H, Fostira F, Friedman E, Fritschi L, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, Garcia-Barberan V, García-Closas M, García-Sáenz JA, Gaudet MM, Gayther SA, Gehrig A, Georgoulias V, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hall P, Hamann U, Harrington PA, Hart SN, He W, Hogervorst FBL, Hollestelle A, Hopper JL, Horcasitas DJ, Hulick PJ, Hunter DJ, Imyanitov EN, , , , Jager A, Jakubowska A, James PA, Jensen UB, John EM, Jones ME, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khusnutdinova E, Kiiski JI, Ko YD, Kosma VM, Kraft P, Kurian AW, Laitman Y, Lambrechts D, Le Marchand L, Lester J, Lesueur F, Lindstrom T, Lopez-Fernández A, Loud JT, Luccarini C, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Mebirouk N, Meindl A, Miller A, Milne RL, Montagna M, Nathanson KL, Neuhausen SL, Nevanlinna H, Nielsen FC, O'Brien KM, Olopade OI, Olson JE, Olsson H, Osorio A, Ottini L, Park-Simon TW, Parsons MT, Pedersen IS, Peshkin B, Peterlongo P, Peto J, Pharoah PDP, Phillips KA, Polley EC, Poppe B, Presneau N, Pujana MA, Punie K, Radice P, Rantala J, Rashid MU, Rennert G, Rennert HS, Robson M, Romero A, Rossing M, Saloustros E, Sandler DP, Santella R, Scheuner MT, Schmidt MK, Schmidt G, Scott C, Sharma P, Soucy P, Southey MC, Spinelli JJ, Steinsnyder Z, Stone J, Stoppa-Lyonnet D, Swerdlow A, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Teulé A, Thull DL, Tischkowitz M, Toland AE, Torres D, Trainer AH, Truong T, Tung N, Vachon CM, Vega A, Vijai J, Wang Q, Wappenschmidt B, Weinberg CR, Weitzel JN, Wendt C, Wolk A, Yadav S, Yang XR, Yannoukakos D, Zheng W, Ziogas A, Zorn KK, Park SK, Thomassen M, Offit K, Schmutzler RK, Couch FJ, Simard J, Chenevix-Trench G, Easton DF, Andrieu N, Antoniou AC.
      Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10-8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
    DOI:  https://doi.org/10.1038/s41467-020-20496-3
  15. Curr Breast Cancer Rep. 2020 Sep;12(3): 125-131
    Disparities in Genetic Testing and Care among Black women with Hereditary Breast Cancer.
    Reid S, Cadiz S, Pal T.
      Purpose of Review: Despite a steady improvement in breast cancer survival rates over the past several decades, mortality disparities remain among Black women, who have a 42% higher death rate compared to non-Hispanic white (NHW) women. Hereditary breast cancer (HBC) accounts for 5-10% of all breast cancer cases, the majority of which are due to the BRCA1 and BRCA2 (BRCA) genes. Despite the availability of BRCA testing for over 25 years, there remain disproportionately lower rates of genetic testing among Blacks compared to NHW due to a multitude of factors. The intent of this review is to discuss racial disparities focused on HBC across diverse populations and review the existing gaps to be addressed when delivering gene-based care.Recent findings: The factors contributing to the racial survival disparity are undoubtedly complex and likely an interplay between tumor biology, genomics, patterns of care and socioeconomic factors. Advances in genomic technologies that now allow for full characterization of germline DNA sequencing are integral in defining the complex and multifactorial cause of breast cancer and may help to explain the existing racial survival disparities.
    Summary: Identification of inherited cancer risk may lead to cancer prevention, early cancer detection, treatment guidance, and ultimately has great potential to improve outcomes. Consequently, advances in HBC diagnosis and treatment without widespread implementation have the potential to further widen the existing breast cancer mortality gap between Black and NHW women.
    Keywords:  BRCA; Breast cancer disparities; Genetic counseling; Genetic testing; Hereditary breast cancer; Racial disparities
    DOI:  https://doi.org/10.1007/s12609-020-00364-1
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