bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2020‒11‒01
eight papers selected by
Joanna Zawacka-Pankau
University of Warsaw


  1. Breast Cancer Res Treat. 2020 Oct 30.
    Gomes R, Spinola PDS, Brant AC, Matta BP, Nascimento CM, de Aquino Paes SM, Bonvicino CR, Dos Santos ACE, Moreira MAM.
      PURPOSE: This study aimed to identify and classify genetic variants in consensus moderate-to-high-risk predisposition genes associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC), in BRCA1/2-negative patients from Brazil.METHODS: The study comprised 126 index patients who met NCCN clinical criteria and tested negative for all coding exons and intronic flanking regions of BRCA1/2 genes. Multiplex PCR-based assays were designed to cover the complete coding regions and flanking splicing sites of six genes implicated in HBOC. Sequencing was performed on HiSeq2500 Genome Analyzer.
    RESULTS: Overall, we identified 488 unique variants. We identified five patients (3.97%) that harbored pathogenic or likely pathogenic variants in four genes: ATM (1), CHEK2 (2), PALB2 (1), and TP53 (1). One hundred and thirty variants were classified as variants of uncertain significance (VUS), 10 of which were predicted to disrupt mRNA splicing (seven non-coding variants and three coding variants), while other six missense VUS were classified as probably damaging by prediction algorithms.
    CONCLUSION: A detailed mutational profile of non-BRCA genes is still being described in Brazil. In this study, we contributed to filling this gap, by providing important data on the diversity of genetic variants in a Brazilian high-risk patient cohort. ATM, CHEK2, PALB2 and TP53 are well established as HBOC predisposition genes, and the identification of deleterious variants in such actionable genes contributes to clinical management of probands and relatives.
    Keywords:  Breast cancer; HBOC; Hereditary cancer; Massive parallel sequencing; Ovarian cancer
    DOI:  https://doi.org/10.1007/s10549-020-05985-9
  2. JAMA Oncol. 2020 Oct 30.
    Samadder NJ, Riegert-Johnson D, Boardman L, Rhodes D, Wick M, Okuno S, Kunze KL, Golafshar M, Uson PLS, Mountjoy L, Ertz-Archambault N, Patel N, Rodriguez EA, Lizaola-Mayo B, Lehrer M, Thorpe CS, Yu NY, Esplin ED, Nussbaum RL, Sharp RR, Azevedo C, Klint M, Hager M, Macklin-Mantia S, Bryce AH, Bekaii-Saab TS, Sekulic A, Stewart KA.
      Importance: Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing.Objective: To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT).
    Design, Setting, and Participants: This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age.
    Exposures: Germline sequencing using a greater than 80-gene next-generation sequencing platform.
    Main Outcomes and Measures: Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families.
    Results: A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT.
    Conclusions and Relevance: This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.
    DOI:  https://doi.org/10.1001/jamaoncol.2020.6252
  3. Cancers (Basel). 2020 Oct 27. pii: E3140. [Epub ahead of print]12(11):
    Zanti M, Loizidou MA, Michailidou K, Pirpa P, Machattou C, Marcou Y, Kyriakou F, Kakouri E, Tanteles GA, Spanou E, Spyrou GM, Kyriacou K, Hadjisavvas A.
      In Cyprus, approximately 9% of triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer (TNBC) patients are positive for germline pathogenic variants (PVs) in BRCA1/2. However, the contribution of other genes has not yet been determined. To this end, we aimed to investigate the prevalence of germline PVs in BRCA1/2-negative TNBC patients in Cyprus, unselected for family history of cancer or age of diagnosis. A comprehensive 94-cancer-gene panel was implemented for 163 germline DNA samples, extracted from the peripheral blood of TNBC patients. Identified variants of uncertain clinical significance were evaluated, using extensive in silico investigation. Eight PVs (4.9%) were identified in two high-penetrance TNBC susceptibility genes. Of these, seven occurred in PALB2 (87.5%) and one occurred in TP53 (12.5%). Interestingly, 50% of the patients carrying PVs were diagnosed over the age of 60 years. The frequency of non-BRCA PVs (4.9%) and especially PALB2 PVs (4.3%) in TNBC patients in Cyprus appears to be higher compared to other populations. Based on these results, we believe that PALB2 and TP53 along with BRCA1/2 genetic testing could be beneficial for a large proportion of TNBC patients in Cyprus, irrespective of their age of diagnosis.
    Keywords:  NGS of gene panels; genetic predisposition to breast cancer; germline genetic testing; triple-negative breast cancer
    DOI:  https://doi.org/10.3390/cancers12113140
  4. Front Oncol. 2020 ;10 531790
    Hodgson A, Turashvili G.
      Hereditary breast and ovarian cancer (HBOC) syndrome is most commonly characterized by deleterious germline mutations in BRCA1 and BRCA2. HBOC patients are prone to the development of malignant neoplasms in multiple organs including the breast, ovary, and fallopian tube. From a pathological perspective, a number of morphological features have been described in BRCA-associated breast and tubo-ovarian cancers. For example, breast cancers diagnosed in BRCA1-mutation carriers are frequently of a high Nottingham grade and display medullary morphology and a triple-negative and/or a basal-like immunophenotype. In contrast, breast cancers in BRCA2-mutation carriers are similar to sporadic luminal-type tumors that are positive for hormone receptors and lack expression of human epidermal growth factor receptor 2. Cancers arising in the fallopian tube and ovary are almost exclusively of a high-grade serous histotype with frequent Solid, pseudo-Endometrioid, and Transitional cell carcinoma-like morphology ("SET features"), marked nuclear atypia, high mitotic index, abundant tumor infiltrating lymphocytes, and necrosis. In addition, pushing or infiltrative micropapillary patterns of invasion have been described in BRCA-associated metastases of tubo-ovarian high-grade serous carcinomas. Besides BRCA1 and BRCA2 mutations, alterations in a number of other homologous recombination genes with moderate penetrance, including PALB2, RAD51C, RAD51D, BRIP1, and others, have also been described in HBOC patients with varying frequency; however, distinct morphological characteristics of these tumors have not been well characterized to date. In this review, the above pathological features are discussed in detail and a focus is placed on how accurate pathologic interpretation plays an important role in allowing HBOC patients to receive the best possible management.
    Keywords:  BRCA; hereditary breast cancer; hereditary tubo-ovarian cancer; high-grade serous carcinoma; triple-negative breast cancer
    DOI:  https://doi.org/10.3389/fonc.2020.531790
  5. Breast Cancer Res Treat. 2020 Oct 28.
    Lattimore V, Parsons MT, Spurdle AB, Pearson J, Lehnert K, Sullivan J, Lintott C, Bawden S, Morrin H, Robinson B, Walker L.
      BACKGROUND: Diagnostic screening for pathogenic variants in breast cancer susceptibility genes, including BRCA1, BRCA2, PALB2, PTEN and TP53, may be offered to New Zealanders from suspected high-risk breast (and ovarian) cancer families. However, it is unknown how many high-risk pathogenic variant carriers in New Zealand are not offered genetic screening using existing triage tools and guidelines for breast (and ovarian) cancer patients.METHODS: Panel-gene sequencing of the coding and non-coding regions of the BRCA1 and BRCA2 genes, and the coding regions and splice sites of CDH1, PALB2, PTEN and TP53, was undertaken for an unselected cohort of 367 female breast cancer patients. A total of 1685 variants were evaluated using the ENIGMA and the ACMG/AMP variant classification guidelines.
    RESULTS: Our study identified that 13 (3.5%) breast cancer patients carried a pathogenic or likely pathogenic variant in BRCA1, BRCA2, PALB2, or PTEN. A significantly higher number of pathogenic variant carriers had grade 3 tumours (10/13) when compared to non-carriers; however, no other clinicopathological characteristics were found to be significantly different between (likely) pathogenic variant carriers and non-carriers, nor between variant of unknown significance carriers and non-carriers. Notably, 46% of the identified (likely) pathogenic variant carriers had not been referred for a genetic assessment and consideration of genetic testing.
    CONCLUSION: Our study shows a potential under-ascertainment of women carrying a (likely) pathogenic variant in a high-risk breast cancer susceptibility gene. These results suggest that further research into testing pathways for New Zealand breast cancer patients may be required to reduce the impact of hereditary cancer syndromes for these individuals and their families.
    Keywords:  Breast cancer; New Zealand; Panel gene; Variant classification
    DOI:  https://doi.org/10.1007/s10549-020-05986-8
  6. Genes Chromosomes Cancer. 2020 Oct 24.
    Garg K, Rabban J.
      Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome that results from germline mutation in the fumarate hydratase (FH) gene and is associated with an increased risk for smooth muscle tumors of the uterus and skin and renal cell carcinoma. HLRCC associated RCC develop in up to 25% of patients, often presenting in the 4th decade and are high stage, aggressive tumors with poor clinical outcome. Most women with HLRCC develop large and bulky uterine smooth muscle tumors (USMT) in the 2nd to 3rd decade, thus presenting the ideal opportunity for early detection of HLCC to enable timely implementation of surveillance for their RCC risk. However, the concept of screening women with USMT for HLRCC is challenging given that HLRCC is rare but USMT are common. In addition, FH deficiency in USMT can also result from sporadic FH gene aberrations, unrelated to HLRCC, further complicating any potential screening process. Recent studies show that tumor morphology can be used to identify FH deficiency in USMT and thereby direct patients to formal genetic counseling. The low magnification clues of staghorn shaped blood vessels and alveolar pattern should prompt for high magnification examination for eosinophilic cytoplasmic inclusions and oval nuclei containing prominent eosinophilic macronucleoli surrounded by a halo. Additional clues include Schwannoma-like growth and chain-like distribution of the tumor cells. Although immunostains exist for FH and 2SC, their role is limited in the presence of well-developed FH deficient morphology. The prevalence of germline pathogenic mutation in FH among women with USMT with FH deficient morphology is as high as 50% in some studies, with somatic FH mutation accounting for the remainder. Therefore, morphologic evaluation of USMT for features of FH deficiency can serve as a screening tool for HLRCC syndrome by triaging patients to formal hereditary risk assessment. This article is protected by copyright. All rights reserved.
    Keywords:  FH deficiency; HLRCC; Uterine smooth muscle tumors
    DOI:  https://doi.org/10.1002/gcc.22905
  7. Mol Genet Genomic Med. 2020 Oct 29. e1532
    Cannon-Albright LA, Teerlink CC, Stevens J, Snow AK, Thompson BA, Bell R, Nguyen KN, Sargent NR, Kohlmann WK, Neklason DW, Tavtigian SV.
      PURPOSE: While familial aggregation of colorectal cancer (CRC) is recognized, the majority of the germline predisposition factors remain unidentified, and many high-risk CRC pedigrees remain unexplained by known risk variants. Fanconi Anemia genes have been recognized to be associated with cancer risk. Notably, FANCM (OMIM 609644) variants have been reported to confer risk for CRC and breast cancer.METHODS: Exome sequencing of CRC-affected cousins in a set of 47 independent extended high-risk CRC pedigrees identified a candidate set of rare, shared variants. Variants were tested for association with risk in 744 Utah CRC cases and 1525 controls, and for segregation with CRC in affected relatives.
    RESULTS: A FANCM stopgain variant was observed in two CRC-affected cousin pairs, each from an independent Utah high-risk pedigree, and yielded a nonsignificant, but elevated OR = 2.05 in a set of Utah cases and controls. Segregation of the variant to other related CRC-affected cases was observed in the two extended pedigrees.
    CONCLUSION: A rare stopgain variant in FANCM (rs144567652) that is recognized as a breast cancer predisposition variant, and that has previously been proposed, but not confirmed, as a CRC predisposition variant, is validated here as a risk factor for familial CRC.
    Keywords:   FANCM ; UPDB; colorectal cancer; high-risk pedigree
    DOI:  https://doi.org/10.1002/mgg3.1532
  8. Breast Cancer Res. 2020 Oct 27. 22(1): 114
    O'Shaughnessy J, Brezden-Masley C, Cazzaniga M, Dalvi T, Walker G, Bennett J, Ohsumi S.
      BACKGROUND: The global observational BREAKOUT study investigated germline BRCA mutation (gBRCAm) prevalence in a population of patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC).METHODS: Eligible patients had initiated first-line cytotoxic chemotherapy for HER2-negative MBC within 90 days prior to enrollment. Hormone receptor (HR)-positive patients had experienced disease progression on or after prior endocrine therapy, or endocrine therapy was considered unsuitable. gBRCAm status was determined using baseline blood samples or prior germline test results. For patients with a negative gBRCAm test, archival tissue was tested for somatic BRCAm and homologous recombination repair mutations (HRRm). Details of first-line cytotoxic chemotherapy were also collected.
    RESULTS: Between March 2017 and April 2018, 384 patients from 14 countries were screened and consented to study enrollment; 341 patients were included in the full analysis set (median [range] age at enrollment: 56 [25-89] years; 256 (75.3%) postmenopausal). Overall, 33 patients (9.7%) had a gBRCAm (16 [4.7%] in gBRCA1 only, 12 [3.5%] in gBRCA2 only, and 5 [1.5%] in both gBRCA1 and gBRCA2). gBRCAm prevalence was similar in HR-positive and HR-negative patients. gBRCAm prevalence was 9.0% in European patients and 10.6% in Asian patients and was higher in patients aged ≤ 50 years at initial breast cancer (BC) diagnosis (12.9%) than patients aged > 50 years (5.4%). In patients with any risk factor for having a gBRCAm (family history of BC and/or ovarian cancer, aged ≤ 50 years at initial BC diagnosis, or triple-negative BC), prevalence was 10.4%, versus 5.8% in patients without these risk factors. HRRm prevalence was 14.1% (n = 9/64) in patients with germline BRCA wildtype.
    CONCLUSIONS: Patient demographic and disease characteristics supported the association of a gBRCAm with younger age at initial BC diagnosis and family history of BC and/or ovarian cancer. gBRCAm prevalence in this cohort, not selected on the basis of risk factors for gBRCAm, was slightly higher than previous results suggested. gBRCAm prevalence among patients without a traditional risk factor for harboring a gBRCAm (5.8%) supports current guideline recommendations of routine gBRCAm testing in HER2-negative MBC, as these patients may benefit from poly(ADP-ribose) polymerase (PARP) inhibitor therapy.
    TRIAL REGISTRATION: NCT03078036 .
    Keywords:  BRCA; Breast cancer susceptibility genes; Observational; Prevalence
    DOI:  https://doi.org/10.1186/s13058-020-01349-9