bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2021‒12‒19
six papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet
  1. Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity.
  2. Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients.
  3. Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions.
  4. Germline likely pathogenic variants in ataxia-telangiectasia-mutated gene in an Iranian family with hereditary diffuse gastric cancer without CDH1 mutation.
  5. Risk of cancer in heterozygous relatives of patients with Fanconi anemia.
  6. Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history.
  1. Genet Med. 2021 Nov 30. pii: S1098-3600(21)05370-3. [Epub ahead of print]
    Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity.
    Cristina Fortuno, Kelly McGoldrick, Tina Pesaran, Jill Dolinsky, Lily Hoang, Jeffrey N Weitzel, Victoria Beshay, Huei San Leong, Paul A James, Amanda B Spurdle.
      PURPOSE: Some variants identified by multigene panel testing of DNA from blood present with low variant allele fraction (VAF), often a manifestation of clonal hematopoiesis. Research has shown that the proportion of variants with low VAF is especially high in TP53, the Li-Fraumeni syndrome gene. Based on the hypothesis that variants with low VAF are positively selected as drivers of clonal hematopoiesis, we investigated the use of VAF as a predictor of TP53 germline variant pathogenicity.METHODS: We used data from 260,681 TP53 variants identified at 2 laboratories to compare the distribution of pathogenic and benign variants at different VAF intervals.
    RESULTS: Likelihood ratios toward pathogenicity associated with a VAF < 26% equated to the American College of Medical Genetics/Association of Molecular Pathology strong strength level and were applicable for 1 in 5 variants of unknown significance.
    CONCLUSION: In conclusion, detection of variants with low VAF in blood can be considered an in vivo functional assay to aid assessment of TP53 variant pathogenicity.
    Keywords:  ACMG; Clonal hematopoiesis; Li-Fraumeni syndrome; TP53; Variant allele fraction; Variant classification
    DOI:  https://doi.org/10.1016/j.gim.2021.10.018
  2. Hered Cancer Clin Pract. 2021 Dec 14. 19(1): 49
    Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients.
    Abdul Khalid Siraj, Tariq Masoodi, Rong Bu, Sandeep Kumar Parvathareddy, Kaleem Iqbal, Saud Azam, Maha Al-Rasheed, Dahish Ajarim, Asma Tulbah, Fouad Al-Dayel, Khawla Sami Al-Kuraya.
      BACKGROUND: The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited.METHODS: We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing.
    RESULTS: Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS.
    CONCLUSIONS: TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.
    Keywords:  Breast cancer; Li-Fraumeni syndrome; Lifetime risk; TP53 mutation
    DOI:  https://doi.org/10.1186/s13053-021-00206-w
  3. Front Genet. 2021 ;12 674094
    Characteristics of Germline Non-BRCA Mutation Status of High-Risk Breast Cancer Patients in China and Correlation with High-Risk Factors and Multigene Testing Suggestions.
    Yifan Su, Qianlan Yao, Yuyin Xu, Chengli Yu, Jing Zhang, Qian Wang, Jiwei Li, Di Shi, Baohua Yu, Yupeng Zeng, Xiaoli Zhu, Qianming Bai, Xiaoyan Zhou.
      Background: Expert consensus on BRCA1/2 genetic testing and clinical application in Chinese breast cancer patients recommends that BRCA1/2 testing should be performed in those with clinical risk factors, such as an early onset, triple-negative breast cancer (TNBC) or family history of cancer. With the increasing application of multigene panels, testing for genes beyond BRCA1/2 has become more prevalent. However, the non-BRCA mutation status of Chinese high-risk breast cancer patients has not been fully explored. Methods: A total of 230 high-risk breast cancer patients from Fudan University Shanghai Cancer Center who had undergone peripheral blood germline 72 genes next-generation sequencing (NGS) from June 2018 to June 2020 were enrolled for retrospective analysis. The 72 genes include common hereditary breast cancer genes, such as homologous recombination repair (HRR) genes and other DNA damage repair genes. High-risk factors included: 1) TNBC; 2) male breast cancer; 3) primary bilateral breast cancer; 4) diagnosed with breast cancer at age less than or equal to 40 years; or 5) at least one first- and/or second-degree relative with BRCA-related cancer (breast or ovarian or prostate or pancreatic cancer). Results: The germline pathogenic or likely pathogenic mutation rate was 29.6% (68/230) in high-risk breast cancer patients. Among them, 44 (19.1%, 44/230) were identified as harboring BRCA1/2 mutation, and 28 (12.2%, 28/230) patients carried non-BRCA germline variants. Variants were detected in 16 non-BRCA genes, including PALB2 (5, 2.2%), ATM (4, 1.7%), RAD51D (3, 1.3%), TP53 (3, 1.3%), CHEK2 (2, 0.9%), FANCA (2, 0.9%) and ATR, BARD1, BRIP1, ERCC3, HOXB13, MLH1, MRE11, PMS2, RAD51C, RAD54L (1, 0.4%). Besides, 22 (9.6%, 22/230) patients were non-BRCA HRR gene mutation (including ATM, ATR, BARD1, BRIP1, CHEK2, FANCA, MRE11, PALB2, RAD51C RAD51D and RAD54L) carriers. Among high-risk factors, family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036). In addition, TNBC showed a correlation with BRCA1 gene mutation status (p = 0.038). However, other high-risk factors have not shown significantly related to BRCA1/2, non-BRCA genes and non-BRCA HRR gene mutations (p > 0.05). In addition, 312 unique variants of uncertain significance (VUS) were identified among 175 (76.1%, 175/230) patients and 65 different genes. Conclusions: Non-BRCA gene mutations are frequently identified in breast cancer patients with high risk factors. Family history showed a correlation with both BRCA (p = 0.005) and non-BRCA HRR gene mutation status (p = 0.036), so we strongly suggest that breast cancer patients with a BRCA-related family history receive comprehensive gene mutation testing in China, especially HRR genes, which are not only related to high risk of breast cancer, but also potentially related to poly ADP ribose polymerase inhibitor (PARPi) targeted therapy. The exact relationship of rare gene mutations to breast cancer predisposition and the pathogenicity of VUS need to be further investigated.
    Keywords:  Chinese; breast cancer; germline mutation; high risk; non-BRCA genes
    DOI:  https://doi.org/10.3389/fgene.2021.674094
  4. J Cancer Res Ther. 2021 Oct-Dec;17(6):17(6): 1434-1437
    Germline likely pathogenic variants in ataxia-telangiectasia-mutated gene in an Iranian family with hereditary diffuse gastric cancer without CDH1 mutation.
    Majid Kheirollahi, Maryam Saneipour, Abbas Moridnia.
      Background: Gastric cancer (GC) is the fourth common cancer in the world and the second cause of cancer-related mortality. Germline mutations in the E-cadherin gene (CDH1) are the most common cause of hereditary diffuse GC (HDGC) and explain 25%-30% of cases. In HDGC families without the pathogenic CDH1 variant, there is poor management and therapeutic strategies, and detect other genetic defects in HDGC, except CDH1 gene will be useful for further clarification of the disease mechanisms and risk-reducing strategies. Here, we reported an Iranian pedigree with familial HDGC to assess the fundamental genetic causes by whole-exome sequencing (WES).Materials and Methods: WES performed in an Iranian with a history of familial GC in whom no pathogenic variants or indels has been found in CDH1 and CTNNA1 genes with Sanger sequencing and multiplex ligation-dependent probe amplification methods.
    Results: Prioritizing genes associate with HDGC recognized several variants include c.2572T>C, and c.3161C>G in ataxia-telangiectasia mutated (ATM), c.1114A>C in BRCA2, and finally c.1173A>G in PIK3CA. Protein function prediction software tools reveal that c.3161C>G in ATM is likely pathogen.
    Conclusion: The results of this study suggested a role for the known cancer predisposition gene ATM in families with HDGC with no pathogenic variant in CDH1. Our results suggested that mutations in ATM and other genes, particularly the mutations found in this study, should be considered even in one case of positive familial status of HDGC disease. The presence of these mutations in patients with familial history raises important issues regarding genetic counseling.
    Keywords:  Ataxia-telangiectasia-mutated gene; diffuse gastric cancer; whole-exome sequencing
    DOI:  https://doi.org/10.4103/jcrt.JCRT_344_19
  5. Genet Med. 2021 Nov 17. pii: S1098-3600(21)01127-8. [Epub ahead of print]
    Risk of cancer in heterozygous relatives of patients with Fanconi anemia.
    Lisa J McReynolds, Neelam Giri, Lisa Leathwood, Maureen O Risch, Ann G Carr, Blanche P Alter.
      PURPOSE: Fanconi anemia (FA) is a cancer-prone inherited bone marrow failure syndrome caused by biallelic pathogenic variants in one of >22 genes in the FA/BRCA DNA repair pathway. A major concern is whether the risk of cancer is increased in individuals with a single pathogenic FA gene variant.METHODS: We evaluated the risk of cancer in the relatives of patients with FA in the National Cancer Institute Inherited Bone Marrow Failure Syndrome cohort. We genotyped all available relatives and determined the rates, types of cancer and the age of patients at cancer diagnosis. We calculated the observed-to-expected (O/E) cancer ratios using data from the Surveillance, Epidemiology, and End Results Program adjusted for age, sex, and birth cohort.
    RESULTS: The risk of cancer was not increased among all FA relatives and FA heterozygotes (O/E ratios of 0.78 and 0.79, respectively). In particular, the risk of cancer was not increased among FANCA or FANCC heterozygotes (O/E ratios of 0.92 and 0.71, respectively). Relatives did not have typical FA cancers, and age at cancer diagnosis was not younger than expected.
    CONCLUSION: Understanding the risk of cancer in individuals with single pathogenic FA variants is critical for counseling and management. We did not find increased risk of cancer in these individuals. These findings do not extend to the known cancer predisposition autosomal dominant FA genes, namely BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.
    Keywords:  Cancer; Fanconi anemia; Heterozygotes
    DOI:  https://doi.org/10.1016/j.gim.2021.08.013
  6. Genet Med. 2021 Nov 18. pii: S1098-3600(21)05387-9. [Epub ahead of print]
    Breast and prostate cancer risk: The interplay of polygenic risk, rare pathogenic germline variants, and family history.
    Emadeldin Hassanin, Patrick May, Rana Aldisi, Isabel Spier, Andreas J Forstner, Markus M Nöthen, Stefan Aretz, Peter Krawitz, Dheeraj Reddy Bobbili, Carlo Maj.
      PURPOSE: We aimed to investigate to what extent polygenic risk scores (PRS), rare pathogenic germline variants (PVs), and family history jointly influence breast cancer and prostate cancer risk.METHODS: A total of 200,643 individuals from the UK Biobank were categorized as follows: (1) heterozygotes or nonheterozygotes for PVs in moderate to high-risk cancer genes, (2) PRS strata, and (3) with or without a family history of cancer. Multivariable logistic regression and Cox proportional hazards models were used to compute the odds ratio across groups and the cumulative incidence through life.
    RESULTS: Cumulative incidence by age 70 years among the nonheterozygotes across PRS strata ranged from 9% to 32% and from 9% to 35% for breast cancer and prostate cancer, respectively. Among the PV heterozygotes it ranged from 20% to 48% in moderate-risk genes and from 51% to 74% in high-risk genes for breast cancer, and it ranged from 30% to 59% in prostate cancer risk genes. Family history was always associated with an increased cancer odds ratio.
    CONCLUSION: PRS alone provides a meaningful risk gradient leading to a cancer risk stratification comparable to PVs in moderate risk genes, whereas acts as a risk modifier when considering high-risk genes. Including family history along with PV and PRS further improves cancer risk stratification.
    Keywords:  Breast cancer; Family history; Polygenic risk score; Prostate cancer; Rare pathogenic variants
    DOI:  https://doi.org/10.1016/j.gim.2021.11.009
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