Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s

Our plain-English summary of Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s, by M. Carbone, E.G. Flores, M. Emi, et al (PLoS Genetics, 2015).

The study

• Authors: M. Carbone, E.G. Flores, M. Emi, T.A. Johnson, T. Tsunoda, D. Behner, H. Hoffman, M. Hesdorffer, M. Nasu, A. Napolitano, A. Powers, M. Minaai, F. Baumann, P. Bryant-Greenwood, O. Lauk, M.B. Kirschner, W. Weder, I. Opitz, H.I. Pass, G. Gaudino, S. Pastorino, H. Yang
• Journal: PLoS Genetics
• Published: 2015;11(12):e1005633
• Cited by: 75 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

In plain English

This genetic and genealogical study tested mesothelioma patients for inherited mutations in the BAP1 gene. The patients were chosen because their personal or family histories suggested the 'BAP1 cancer syndrome'. Of 29 eligible patients, 22 gave blood, and none reported a history of asbestos exposure. Four of the 22 carried germline BAP1 mutations. Three of them, from Maryland, California and Texas, had an identical mutation (c.1717_1717delC). The authors had earlier found the same mutation in a Texas patient. These four apparently unrelated patients shared a rare genetic marker and long matching DNA stretches around BAP1, indicating a common ancestor. Genealogical records traced them nine generations back to a couple born in Germany in 1710 and 1712 who emigrated to North America. The family tree has about 80,000 predicted descendants and a core of 106 individuals, and it revealed new branches with BAP1-associated cancers. The authors suggested that mesothelioma in such families may not require asbestos exposure, though low-level exposure may be a co-factor that is hard to assess. They concluded that family histories, genetics and genealogy together can identify potential BAP1 mutation carriers.

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: Family genetic study: mutation screening of selected mesothelioma patients, followed by genome-wide SNP genotyping, shared-haplotype analysis, tumor tissue analysis and genealogical research to build a family tree (pedigree)
• Who was studied: Malignant mesothelioma patients recruited in the US because their family histories suggested the BAP1 cancer syndrome. Inclusion required pleural or peritoneal mesothelioma diagnosed before age 70, plus other mesotheliomas or BAP1-associated cancers in the patient or first-degree relatives. Of 29 eligible patients (all epithelioid mesothelioma), 22 took part. The four probands with the shared mutation and their families were from Maryland, California and Texas. Four unrelated healthy controls and public genome databases were used for comparison. Study dates are not given.
• Exposure: The exposure studied was inherited (germline) BAP1 gene mutations. None of the patients who met the inclusion criteria reported a history of asbestos exposure.
• Main results:
  • 4 of the 22 selected mesothelioma patients carried germline BAP1 mutations.
  • Three of the four mutation carriers (MARF11-III-1, MARF18-III-1, MARF40-III-1) had an identical mutation, c.1717_1717delC. The fourth carrier had a different mutation and had peritoneal mesothelioma.
  • The authors had previously found the same mutation in another apparently unrelated patient from Texas, MARF2-IV-2, making four probands with this mutation.
  • All four probands also carried a rare allele of a nearby SNP. The authors estimated the probability that any given person carries both this allele and the mutation at less than 8.0 x 10 to the power of minus 7.
  • Genome-wide analysis found relatedness only among the four probands. The most closely related pair (MARF11-III-1 and MARF40-III-1) had a kinship coefficient of 0.0186, about the level of second degree cousins.
  • Only the four probands shared significant DNA segments spanning the BAP1 gene. These shared segments ranged from 9.1 to 34.2 megabase pairs in length.
  • Mesothelioma tumor tissue showed BAP1 staining only in the cell body (cytoplasm), with none in the nucleus. Loss of the remaining normal gene copy (loss of heterozygosity) was confirmed in the two probands whose tumor tissue was available (MARF11-III-1 and MARF18-III-1).
  • Genealogical searches produced a pedigree named the 'K4' kindred, with about 80,000 predicted descendants. It linked the four probands to a couple born in Germany in 1710 (male) and 1712 (female) who immigrated to North America.
  • A condensed core pedigree of 106 individuals was constructed.
  • The pedigree identified new branches of the family, including individuals with cancers characteristic of the syndrome. For example, a niece of proband MARF11-III-1 had melanoma, renal carcinoma and peritoneal mesothelioma diagnosed almost simultaneously at age 55, and she tested positive for the germline BAP1 mutation.
  • The authors interpreted the absence of reported asbestos exposure in all four probands as suggesting that the high penetrance of mesothelioma in BAP1 mutant families may not require asbestos exposure.
  • The authors also suggested that in some families a low level of asbestos exposure may be a co-factor.
• The authors' conclusion: The authors concluded that a careful patient and family history, combined with molecular genetics and genealogical studies, can identify potential carriers of germline BAP1 mutations and build large family trees. Such trees can reveal additional family branches that may carry the mutation.
• Limitations the authors state:
  • Whether low-level asbestos exposure triggered mesothelioma in mutation carriers is difficult to verify in people without occupational exposure, because low exposure levels are hard to assess.
  • The family pedigree is incomplete and still being extended.
  • Mesothelioma tumor tissue was not available for two of the four probands.

Topics

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

Medical terms in this study, explained in our Lexicon: BAP1 Tumor Predisposition Syndrome, BAP1, Germline Mutation, Mesothelioma.

Related studies

• BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs — M. Carbone, L.K. Ferris, et al. (2012)
• Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist — L.M. Martorano, R.R. Winkelmann, et al. (2014)
• Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients — C.M. Cebulla, E.M. Binkley, et al. (2015)
• Germline BAP1 mutations predispose to malignant mesothelioma — J.R. Testa, M. Cheung, et al. (2011)
• Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma — K.G. Ewens, E. Lalonde, et al. (2018)
• Well-differentiated papillary mesothelioma: clustering in a Portuguese family with a germline BAP1 mutation — C. Ribeiro, S. Campelos, et al. (2013)

Browse return to medical research.