Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma

Our plain-English summary of Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma, by M. Hylebos, K. Op de Beeck, J. van den Ende, et al (Familial Cancer, 2018).

The study

• Authors: M. Hylebos, K. Op de Beeck, J. van den Ende, P. Pauwels, M. Lammens, J.P. van Meerbeeck, G. Van Camp
• Journal: Familial Cancer
• Published: 2018;17(4):569-576
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other 'Cancer census genes' (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient's mother. The importance of this 'Cancer census gene' in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.

In plain English

This report described a Belgian family with several mesothelioma cases and analyzed the genes of one patient, diagnosed with malignant pleural mesothelioma in 2014 at age 60. His brother died of pleural mesothelioma and his uncle of peritoneal mesothelioma. Two relatives had worked 20–25 years at a company recycling jute bags in which asbestos had been stored. The patient, his brother and two cousins helped there during holidays. The fiber type was not stated. His tumor cell nuclei stained negative for BAP1, unlike normal surrounding cells. Earlier studies had linked the BAP1 gene to mesothelioma families. Yet no BAP1 gene change was found in his blood or tumor. His blood DNA carried variants in 11 other cancer-related genes, each predicted damaging by at least one of three computer programs. One, in RBM15, was rare and absent in his mother. A healthy brother carried it; two cousins did not. The authors concluded that the clustering appeared not to be due to an inherited BAP1 mutation, and that RBM15's role needs further research. No samples from other affected relatives were available.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic study of a single family (family case report). The index patient's tumor and blood were analyzed using BAP1 immunohistochemistry, whole exome sequencing, low-pass whole genome sequencing and multiplex amplicon quantification. Blood DNA from four relatives was also tested.
• Who was studied: One previously undescribed Belgian family. The index patient (III-1) was diagnosed with malignant pleural mesothelioma in 2014 at age 60; tumor and blood samples were taken from him. Peripheral blood was taken from four relatives who were healthy to date (II-1, III-4, III-8, III-9). The other family members with mesothelioma were deceased, so no samples were available from them.
• Exposure: Asbestos exposure at a company recycling jute bags in which asbestos had been stored. Family members II-2 and II-5 worked there for 20–25 years. The index patient, his brother (III-2) and two cousins (III-8, III-9) helped there during holidays. The mother and grandmother were sporadically exposed when repairing torn jute bags. Fiber type was not specified.
• Main results:
  • Two other relatives died of mesothelioma: the index patient's brother (III-2) of pleural mesothelioma at age 47, and his uncle (II-5) of peritoneal mesothelioma at age 52.
  • On immunohistochemistry, the nuclei of the index patient's malignant mesothelial cells were negative for BAP1. The nuclei of normal stromal cells were BAP1 positive. The tumor was classified as BAP1 negative based on nuclear staining.
  • Whole exome sequencing of the index patient's blood found no germline BAP1 variant of any type.
  • No somatic (tumor) BAP1 variants were identified in the index patient.
  • No germline copy number changes in the BAP1 region were seen in blood samples of the index patient and four family members.
  • The index patient's germline DNA carried heterozygous variants in 11 'Cancer census genes' that at least one of three prediction programs (Mutation Taster, PolyPhen-2, SIFT) predicted to be damaging.
  • Only the variants in RBM15, EGFR and RB1 had a highest population minor allele frequency below 0.01.
  • Of these three variants, only the RBM15 variant was absent from the index patient's mother's germline DNA.
  • The RBM15 variant was found in the index patient's brother (III-4) but not in his cousins (III-8 and III-9).
  • No additional somatic RBM15 alterations were seen in the index patient's tumor.
• The authors' conclusion: The authors concluded that the mesothelioma clustering in this family appears not to be attributable to inheritance of a germline BAP1 mutation. They considered the RBM15 variant the most interesting candidate.
• Limitations the authors state:
  • No samples were available from family members with mesothelioma or other cancers other than the index patient.
  • It is not clear how the RBM15 variant would be involved in the clustering, and further functional research is needed.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Malignant Mesothelioma, Germline Mutation, BAP1, Mesothelial Cells, EGFR.

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