NEW YORK (GenomeWeb) – With a combination of genetic and genealogical studies, researchers from the University of Hawaii have traced an inherited cancer syndrome affecting seemingly unrelated patients back nine generations to a shared ancestor.
Haining Yang from the University of Hawaii Cancer Center and her colleagues recently uncovered an inherited cancer syndrome — marked by a high incidence of mesothelioma, uveal melanoma, and other cancers — that they linked to mutations in BRCA1-Associated Protein 1 (BAP1). As they reported today in PLOS Genetics, they have now identified four families living in different parts of the US with identical BAP1 mutations.
As genetic and genomic analyses indicated that these families had shared haplotypes, Yang and her colleagues used genealogical approaches to find that a German man and woman who had immigrated to the US in the 1700s are the common ancestors of all the patients. They further used this family tree to identify other branches harboring BAP1 mutations.
"Because BAP1 germline mutations are passed through multiple generations, building genealogical trees … will lead to the identification of many more families who carry these mutations and who will benefit from this information," Yang and her colleagues wrote in their paper.
Based on family history of cancer, the researchers recruited 22 mesothelioma patients to undergo DNA sequencing analysis to gauge whether they harbored germline BAP1 variants. Four of the 22 patients tested did: one had a heterozygous variant in exon 15, while the other three carried identical deletions affecting exon 13 — the same mutation the researchers had previously found in another family.
The mutation found in these patients, Yang and her colleagues reported, leads to a premature stop codon in BAP1 — a deubiquitylase whose tumor suppressor function has been ascribed to its ability to regulate gene transcription — and the resulting protein lacks its nuclear localization signal. An analysis of mesothelioma tissue from the patients shows BAP1 only hanging out in the cytoplasm, suggesting that the wild-type allele becomes altered in the tumor cells.
Though these families from Maryland, California, and Texas appeared to be unrelated, they also shared a rare allele of a synonymous SNP in exon 11, some 1,770 base pairs away from the BAP1 mutation. Other than these patients, the researchers reported that they hadn't observed this allele in any other mesothelioma patient tested in their lab. The allele was present in eight individuals from the 1000 Genomes Project, but those individuals all lacked the BAP1 deletion.
The presence of both the deletion and the rare SNP in all four patients suggests they all descend from a common ancestor.
Yang and her colleagues genotyped these four patients and four unrelated healthy controls to perform population genetic and shared haplotype analysis that also drew on more than 2,100 publicly available genotypes from the 1000 Genomes Project. Through a principal components analysis, the researchers found that these four patients clustered with 1000 Genomes Project populations with ancestry from Central Europe or Great Britain.
An identity-by-descent analysis based on these samples and 1000 Genomes Project samples further indicated that these patients were related — two had a kinship coefficient that suggested they were related as much as second degree cousins typically are. Haplotype structure analysis of the eight also showed that only the patients shared significant genetic swathes.
Based on a genealogical search of census data, birth and death certificates, hospital records, and the Ancestry.com database, Yang and her colleagues constructed a large pedigree of some 80,000 descendants that connected all four patients to a couple born in Germany in the 1700s.
The man was born in 1710, and his ancestors could be further traced back to 1588 in Switzerland, moving to Germany in the 17th century. The woman was born in 1712. They immigrated to North America and had at least 10 children, the researchers found.
One of their sons, who was born in 1748 in Virginia and migrated to Kentucky, was the forebear of three of the patients in the study, while another son, who was born in Virginia in 1750 and moved to Ohio, was the forebear of the fourth patient.
This large pedigree has enabled them to identify new branches and additional people affected by cancers linked to this syndrome, the researchers said.
"[This] is the largest pedigree of its kind for the BAP1 cancer syndrome and can be used in genetic counseling for predictive testing," Yang and her colleagues added. "This family pedigree is still in progress as new information is added to the pedigree as it is acquired. As more branches of the family [are] identified, they will be offered testing for BAP1."
Yang and her colleagues noted that they are enrolling BAP1 family members into a prospective study to see whether early diagnosis, based on yearly dermatological and ophthalmic evaluations, improves prognosis.