bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒04‒26
six papers selected by
Joanna Zawacka-Pankau
  1. High frequency of germline RUNX1 mutations in RUNX1 mutated AML patients.
  2. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG).
  3. Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.
  4. The supplemental value of mammographic screening over breast MRI alone in BRCA2 mutation carriers.
  5. Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis.
  6. Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort.
  1. Blood. 2020 Feb 13. pii: blood.2019003357. [Epub ahead of print]
    High frequency of germline RUNX1 mutations in RUNX1 mutated AML patients.
    Simon L, Spinella JF, Yao CY, Lavallée VP, Boivin I, Boucher G, Audemard E, Bordeleau ME, Lemieux S, Hebert J, Sauvageau G.
      RUNX1 is mutated in approximately 10% of adult AML. Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM) in which about 44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline versus acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these RUNX1 germline mutated AML. Moreover, two patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations with variable AML disease onset at 59 and 27 years, respectively. Together this data suggests a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlights the importance of testing for RUNX1 mutations in instances where allogeneic stem cell transplantation with related donor is envisioned.
    DOI:  https://doi.org/10.1182/blood.2019003357
  2. Genet Med. 2020 Apr 23.
    Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG).
    Li MM, Chao E, Esplin ED, Miller DT, Nathanson KL, Plon SE, Scheuner MT, Stewart DR, .
      
    Keywords:  next-generation sequencing (NGS); presumed germline pathogenic variants (PGPV); secondary findings; somatic variants; tumor testing
    DOI:  https://doi.org/10.1038/s41436-020-0783-8
  3. Breast Cancer Res Treat. 2020 Apr 21.
    Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women.
    Zeng C, Guo X, Wen W, Shi J, Long J, Cai Q, Shu XO, Xiang Y, Zheng W.
      PURPOSE: Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case-control study conducted in Shanghai, China.METHODS: We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study.
    RESULTS: Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants (P = 3.05 × 10-15). Among cases, 3.7% had a BRCA2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D. Patients with BRCA1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants.
    CONCLUSIONS: This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1. This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.
    Keywords:  Breast cancer risk; Chinese women; Clinical genetic testing; Hereditary breast cancer syndromes
    DOI:  https://doi.org/10.1007/s10549-020-05643-0
  4. Breast Cancer Res Treat. 2020 Apr 24.
    The supplemental value of mammographic screening over breast MRI alone in BRCA2 mutation carriers.
    Obdeijn IM, Mann RM, Loo CCE, Lobbes M, Voormolen EMC, van Deurzen CHM, de Bock G, , Hooning MJ.
      PURPOSE: BRCA2 mutation carriers are offered annual breast screening with MRI and mammography. The aim of this study was to investigate the supplemental value of mammographic screening over MRI screening alone.METHODS: In this multicenter study, proven BRCA2 mutation carriers, who developed breast cancer during screening using both digital mammography and state-of-art breast MRI, were identified. Clinical data were reviewed to classify cases in screen-detected and interval cancers. Imaging was reviewed to assess the diagnostic value of mammography and MRI, using the Breast Imaging and Data System (BI-RADS) classification allocated at the time of diagnosis.
    RESULTS: From January 2003 till March 2019, 62 invasive breast cancers and 23 ductal carcinomas in situ were diagnosed in 83 BRCA2 mutation carriers under surveillance. Overall screening sensitivity was 95.2% (81/85). Four interval cancers occurred (4.7% (4/85)). MRI detected 73 of 85 breast cancers (sensitivity 85.8%) and 42 mammography (sensitivity 49.9%) (p < 0.001). Eight mammography-only lesions occurred. In 1 of 17 women younger than 40 years, a 6-mm grade 3 DCIS, retrospectively visible on MRI, was detected with mammography only in a 38-year-old woman. The other 7 mammography-only breast cancers were diagnosed in women aged 50 years and older, increasing sensitivity in this subgroup from 79.5% (35/44) to 95.5% (42/44) (p ≤ 0.001).
    CONCLUSIONS: In BRCA2 mutation carriers younger than 40 years, the benefit of mammographic screening over MRI was very small. In carriers of 50 years and older, mammographic screening contributed significantly. Hence, we propose to postpone mammographic screening in BRCA2 mutation carriers to at least age 40.
    Keywords:  BRCA mutation carriers; MRI; Mammography; Screening
    DOI:  https://doi.org/10.1007/s10549-020-05642-1
  5. J Oncol. 2020 ;2020 8545643
    Effects of BRCA Germline Mutations on Triple-Negative Breast Cancer Prognosis.
    Pogoda K, Niwińska A, Sarnowska E, Nowakowska D, Jagiełło-Gruszfeld A, Siedlecki J, Nowecki Z.
      Germline BRCA1 and BRCA2 mutations confer an increased lifetime risk for breast cancer and ovarian cancer. Several studies have investigated prognosis among BRCA1/2 mutation carriers and noncarriers, but the prognostic impact on outcomes of breast cancer patients has not been determined. The aim of this study was to determine the prognosis of TNBC patients with and without BRCA1/2 germline mutation. Among 502 patients diagnosed with TNBC between 2005 and 2008, 124 patients with a strong family history of breast cancer or ovarian cancer as well as TNBC patients diagnosed under 45 years were referred to the Genetic Counseling Unit for genetic counselling and genetic tests. In 30 (24%) of them, the BRCA1/2 mutation was detected (the most common 5382insC in 18 (60%) patients). The median follow-up of the entire group was 60 months. BRCA1/2 mutation carriers were statistically significantly younger at TNBC diagnosis compared with nonmutation patients (41 vs 47 years, respectively). Patients with the BRCA1/2 mutation had smaller tumors (stage I: 47% vs 24.5% in noncarriers), but there was no significant difference in the regional nodal status (58.5-63% with cN0). Contralateral breast cancer developed in 26.5% of BRCA1/2 mutation carriers and in 14% of noncarriers. Other primary cancers were also slightly more common in BRCA1/2 mutation carriers (16.5% vs 9.5%). The performed analysis did not show any significant differences between the groups in recurrence-free survival (p=0.312). There was no significant difference between patients with or without BRCA1/2 mutation as regards overall survival (p=0.649) and the risk of TNBC death (p=0.333). The survival from detection of metastases was similar in two groups (p=0.865). Our study demonstrated that the BRCA1 mutation does not affect TNBC patients' outcomes.
    DOI:  https://doi.org/10.1155/2020/8545643
  6. BMC Cancer. 2020 Apr 22. 20(1): 345
    Broadening risk profile in familial colorectal cancer type X; increased risk for five cancer types in the national Danish cohort.
    Therkildsen C, Rasmussen M, Smith-Hansen L, Kallemose T, Lindberg LJ, Nilbert M.
      BACKGROUND: Familial colorectal cancer type X (FCCTX) is a phenotypically defined subset of hereditary colorectal cancer with unknown and potentially heterogeneous genetic aetiology. FCCTX has been characterized as a colorectal cancer-specific syndrome, which we herein challenge by estimating the risk for extra-colorectal cancer in the Danish FCCTX cohort.METHODS: Through the national hereditary non-polyposis colorectal cancer (HNPCC) register, 213 families fulfilling the Amsterdam I criteria and showing retained mismatch repair (MMR) function were identified. In here, sex and age-specific incidence rate ratios (IRR) were calculated for 30 extra-colorectal cancer types in comparison with the general Danish population.
    RESULTS: In total, 494 extra-colorectal cancers developed with significantly increased risks for cancers of the urinary tract, breast, stomach, pancreas, and eye tumours. The age groups at increased risks were 30-49 years for gastric cancer, 30-69 years for female breast cancer, 50-69 years for ocular melanoma and above age 70 for pancreatic cancer and urothelial cancer.
    CONCLUSIONS: Danish FCCTX families show an increased risk of several extra-colorectal cancer types. This observation may indicate unidentified disease-predisposing genetic variants in this phenotypically defined subset of hereditary colorectal cancer and calls for awareness during genetic counselling and follow-up.
    Keywords:  Amsterdam I criteria; Cancer syndrome; Hereditary cancer; Mismatch repair proficient; Tumour spectrum
    DOI:  https://doi.org/10.1186/s12885-020-06859-5
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