bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒02‒16
eight papers selected by
Joanna Zawacka-Pankau

  1. JAMA Oncol. 2020 Feb 13.
    Rainone M, Singh I, Salo-Mullen EE, Stadler ZK, O'Reilly EM.
      Importance: Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm with a rising incidence and is a leading public health challenge. Pancreatic ductal adenocarcinoma has been well characterized genomically, with findings of therapeutic actionability that have substantive implications for clinical practice based on recent high-level evidence.Observations: Pathogenic germline alterations (PGAs) are relatively common in individuals with PDAC, as evidenced in multiple recent data sets, with a frequency of approximately 10%. The most common PGAs are in BRCA1, BRCA2, and ATM and more rarely in PALB2, MLH1, MSH2, MSH6, PMS2, CDKN2A, and TP53, among others, with an aggregate frequency of 3.8% to 9.7%. These PGAs are of key interest owing to therapeutic actionability and the downstream identification of at-risk family members and possible hereditary cancer syndromes. Approximately 3% to 7% of individuals with PDAC harbor a BRCA1 or BRCA2 mutation, which are among the most frequently mutated genes in PDAC. Recent updates to the American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines recommend risk assessment for all individuals with PDAC irrespective of personal or family history or ethnicity. Treatment implications include the use of checkpoint inhibitor therapy for mismatch repair-deficient PDAC and the validation of poly-ADP (adenosine diphosphate)-ribose polymerase inhibitor (PARPi) therapy as a maintenance strategy in platinum-sensitive PDAC.
    Conclusions and Relevance: With increasing evidence and slow improvement of outcomes, PDAC has entered the era of precision medicine. Germline mutations have been identified in key genes with an aggregate frequency of 3.8% to 9.7%, several of which are therapeutically actionable with platinum, PARPi, and checkpoint inhibitor therapy. Potential therapeutic targets need to be actively sought and identified.
  2. BMC Med Genomics. 2020 Feb 10. 13(1): 21
    da Costa E Silva Carvalho S, Cury NM, Brotto DB, de Araujo LF, Rosa RCA, Texeira LA, Plaça JR, Marques AA, Peronni KC, Ruy PC, Molfetta GA, Moriguti JC, Carraro DM, Palmero EI, Ashton-Prolla P, de Faria Ferraz VE, Silva WA.
      BACKGROUND: The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) occurs in families with a history of breast/ovarian cancer, presenting an autosomal dominant inheritance pattern. BRCA1 and BRCA2 are high penetrance genes associated with an increased risk of up to 20-fold for breast and ovarian cancer. However, only 20-30% of HBOC cases present pathogenic variants in those genes, and other DNA repair genes have emerged as increasing the risk for HBOC. In Brazil, variants in ATM, ATR, CHEK2, MLH1, MSH2, MSH6, POLQ, PTEN, and TP53 genes have been reported in up to 7.35% of the studied cases. Here we screened and characterized variants in 21 DNA repair genes in HBOC patients.METHODS: We systematically analyzed 708 amplicons encompassing the coding and flanking regions of 21 genes related to DNA repair pathways (ABRAXAS1, ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD50, RAD51, TP53 and UIMC1). A total of 95 individuals with HBOC syndrome clinical suspicion in Southeast Brazil were sequenced, and 25 samples were evaluated for insertions/deletions in BRCA1/BRCA2 genes. Identified variants were assessed in terms of population allele frequency and their functional effects were predicted through in silico algorithms.
    RESULTS: We identified 80 variants in 19 genes. About 23.4% of the patients presented pathogenic variants in BRCA1, BRCA2 and TP53, a frequency higher than that identified among previous studies in Brazil. We identified a novel variant in ATR, which was predicted as pathogenic by in silico tools. The association analysis revealed 13 missense variants in ABRAXAS1, BARD1, BRCA2, CHEK2, CDH1, MLH1, PALB2, and PMS2 genes, as significantly associated with increased risk to HBOC, and the patients carrying those variants did not present large insertions or deletions in BRCA1/BRCA2 genes.
    CONCLUSIONS: This study embodies the third report of a multi-gene analysis in the Brazilian population, and addresses the first report of many germline variants associated with HBOC in Brazil. Although further functional analyses are necessary to better characterize the contribution of those variants to the phenotype, these findings would improve the risk estimation and clinical follow-up of patients with HBOC clinical suspicion.
    Keywords:  BRCA1; BRCA2; DNA repair genes; HBOC; Molecular diagnosis; Multi-gene panel screening; Next-generation sequencing
  3. Breast Cancer Res Treat. 2020 Feb 10.
    Sorscher S, Ansley K, Delaney SD, Ramkissoon S.
      BACKGROUND: BRCA germline pathogenic variants represent the most common inherited mechanism predisposing individuals to breast cancer, while germline pathogenic variants in one of the mismatch repair (MMR) genes represent the most common colon cancer-predisposing inherited syndrome, known as the Lynch syndrome (LS). Individuals who harbor pathogenic germline variants for both syndromes are extremely rare. Germline testing is now done routinely for patients with breast cancer and MMR testing is recommended for nearly all patients diagnosed with colon or rectal cancer (Benson et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) colon cancer (Version 4.2019-November 8, 2019)., Gradishar et al in NCCN clinical practice guidelines in oncology (NCCN guidelines) breast cancer (Version 3.2019-September 6, 2019) We report a patient with germline mutations in both BRCA2 and the MMR gene MLH1 who developed breast cancer. The breast cancer showed loss of heterozygosity (LOH) in BRCA2 (the molecular hallmark of cancers related to inheritance of a BRCA alteration) and was also deficient in mismatch repair gene protein expression (dMMR), the hallmark of LS-related cancers. We discuss the possible mechanisms of transformation that would explain the finding that the tumor showed both BRCA2 LOH and was dMMR, each of which would generally be considered a gatekeeper event for transformation of normal cells to malignancy.RESULTS: This report describes a patient with molecularly diagnosed breast and ovarian cancer syndrome (BRCA2) and LS. Next generation sequencing (NGS) and immunohistochemical (IHC) testing demonstrated her breast cancer to show BRCA2 LOH and to be dMMR.
    CONCLUSION: The patient presented represents the first reported case where both next generation sequencing (NGS) for BRCA LOH and MMR IHC testing of her breast cancer were performed and underscores the importance of using NGS including the reported mutational allelic frequency (MAF) and IHC use to predict the likely responsiveness to the recently approved PARP inhibitors and checkpoint inhibitor therapies (Robson et al in N Engl J Med 377:523-533, 2017, Lemery et al in 377(15):1409-1412,, 2017), key because the gatekeeper transforming event for tumors related to inherited cancer syndromes is loss of normal tumor suppressor gene (TSG) protein expression.
    Keywords:  BRCA; Lynch syndrome; Mutational allelic burden
  4. Genet Med. 2020 Feb 13.
    Clark DF, Michalski ST, Tondon R, Nehoray B, Ebrahimzadeh J, Hughes SK, Soper ER, Domchek SM, Rustgi AK, Pineda-Alvarez D, Anderson MJ, Katona BW.
      PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied.METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers.
    RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers.
    CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.
    Keywords:  CTNNA1; breast cancer; cancer risk assessment; diffuse gastric cancer; multigene panel testing
  5. Cancer Med. 2020 Feb 11.
    Cortesi L, Baldassarri B, Ferretti S, Razzaboni E, Bella M, Bucchi L, Canuti D, De Iaco P, De Santis G, Falcini F, Galli V, Godino L, Leoni M, Perrone AM, Pignatti M, Saguatti G, Santini D, Sassoli de'Bianchi P, Sebastiani F, Taffurelli M, Tazzioli G, Turchetti D, Zamagni C, Naldoni C.
      BACKGROUND: Up to 10% of individuals with breast cancer (BC) belong to families with hereditary syndromes. The aim of this study was to develop an instrument to identify individuals/families at high-hereditary risk for BC and offer dedicated surveillance programs according to different risks.METHODS: The instrument consisted of a primary questionnaire collecting history of BC and ovarian cancer (OC). This questionnaire was applied to women enrolled in the Emilia-Romagna Breast Cancer Screening Program. General practitioners (GPs) and specialists could propose the same questionnaire too. Women with a score of ≥ 2, were invited to complete an oncogenetic counseling. According to the Tyrer-Cuzick evaluation, women considered at high risk were invited to involve the most representative alive individual of the family affected with BC/OC for BRCA1/2 genetic testing.
    RESULTS: Since January 2012 and December 2016, 660 040 women were evaluated by the regional screening program, of which 22 289 (3.5%) were invited to the Spoke evaluation, but only 5615 accepted (25.2%). Totally, also considering women sent by GPs and specialists, 11 667 were assessed and 5554 were sent to the Hub evaluation. Finally, 2342 (42.8%) women fulfilled the criteria for genetic testing, and 544 (23.2%) resulted BRCA1/2 mutation carriers.
    CONCLUSIONS: To our knowledge, this is the first regional population-based multistep model that is aimed to identify individuals with BRCA1/2 mutations and to offer an intensive surveillance program for hereditary-high risk women. This tool is feasible and effective, even if more efforts must be performed to increase the acceptance of multiple assessments by the study population.
    Keywords:  Tyrer-Cuzick model; hereditary breast ovarian cancer; population-based screening
  6. Thyroid. 2020 Feb 11.
    Zhao Y, Yu T, Chen L, Xie D, Wang F, Fu L, Cheng C, Li Y, Zhu X, Miao G.
      Approximately 5% of all cases of PTC are inherited. However, the susceptibility gene(s) for nonsyndromic familial papillary thyroid carcinoma (FPTC) remain unclear. We performed whole genome sequencing (WGS) of peripheral-blood DNA samples from two affected family members with PTC. <i>CHEK2</i> transcript expression and the protein levels of CHK2 and p53 were evaluated in the thyroid tissues from two affected members of the kindred and sporadic PTC cases. The entire <i>CHEK2</i> coding sequence was examined by Sanger sequencing in blood DNA samples from 242 sporadic PTC patients. We identified a novel heterozygous germline mutation in <i>CHEK2</i> (c.417C→A) that was detected in all available affected members of a kindred with FPTC. This variant was found in only one out of 264,200 persons in the Genome Aggregation Database and the NHLBI Trans-Omics for Precision Medicine program. The <i>CHEK2</i> c.417C→A variant introduces a premature termination codon (Y139X). We found reduced CHK2 protein expression in tumor samples from the two patients who carried the variant as compared to sporadic cases without the variant. The Y139X loss-of-function variant led to reduced p53 phosphorylation and decreased p53 protein abundance. Additionally, two rare missense variants (R180C and H371Y) in <i>CHEK2</i> were identified in 5 (2%) of 242 patients with sporadic PTC. Our findings suggest that the <i>CHEK2</i> Y139X variant may be associated with FPTC.
  7. Eur J Obstet Gynecol Reprod Biol. 2020 Jan 30. pii: S0301-2115(20)30049-X. [Epub ahead of print]247 26-31
    Rudaitis V, Mikliusas V, Januska G, Jukna P, Mickys U, Janavicius R.
      BACKGROUND: Due to ineffective ovarian cancer (OC) screening programs, prophylactic bilateral salpingo-oophorectomy (PBSO) is suggested for BRCA1/2 genes mutation carriers. The reported incidence of clinically occult neoplasia and OC detected during PBSO varies widely (2-17 %), reflecting differences in studies design.OBJECTIVE: We aimed to prospectively evaluate the incidence of occult neoplasia in specimens collected during PBSO performed in a single tertiary center and to determine the effectiveness of this procedure in BRCA1/2 mutation carriers.
    STUDY DESIGN: Between January 2010 and October 2016 a total of 564 new germline BRCA1/2 mutation positive women were identified and 71 carriers underwent laparoscopic PBSO. Patients were prospectively followed-up after the surgery and data on operation, age, complications, histological reports and BRCA1/2 gene mutation types were collected and analyzed.
    RESULTS: Serous tubal intraepithelial carcinoma (STIC) was diagnosed in 7 (9.85 %) and OC in 4 (5.6 %) women (one advanced (FIGO IIIC) and 3 early (FIGO IA/C) stages); total incidence 15.5 %. Women's mean age at the time of surgery was 46.5 years. The mean age of women diagnosed with STIC and OC was 45.9 years (42-64). The mean follow up time for women being diagnosed with OC/STIC was 3.72 years; no recurrence was observed. The median time to perform laparoscopic PBSO was 43 min. (ranging from 25 to 65 min.), no surgical complications occurred during this operation. Interestingly, we found statistically significant (P = 0.0105) enrichment of STIC lesions in BRCA1 c.4035delA (an established Baltic founder mutation) carriers group.
    CONCLUSION: The incidence of pathological findings in BRCA1/2 mutation carries after PBSO is sufficiently high and our prospective study data supports PBSO as the most effective measure for reducing the risk of OC in BRCA1/2 mutation carriers. A novel finding of the enrichment of STIC lesions in BRCA1 c.4035delA carriers may show important biological differences in OC tumorigenesis between different BRCA1 mutations, which warrant further investigations.
    Keywords:  BRCA1; BRCA2; Ovarian cancer; Prophylactic salpingo-oophorectomy; Serous tubal intraepithelial carcinoma