B Speight, E Colvin, E D Epurescu, J Drummond, S Verhoef, M Pereira, D G Evans, M Tischkowitz
{"title":"Low-level constitutional mosaicism of BRCA1 in two women with young onset ovarian cancer.","authors":"B Speight, E Colvin, E D Epurescu, J Drummond, S Verhoef, M Pereira, D G Evans, M Tischkowitz","doi":"10.1186/s13053-022-00237-x","DOIUrl":null,"url":null,"abstract":"<p><p>Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in ~ 52% of reads in DNA extracted from tumour, ~ 10% of reads in DNA extracted from peripheral blood leukocytes and ~ 10% of reads in DNA extracted from buccal mucosa. The second BRCA1 c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in ~ 59% of reads in DNA extracted from tumour, ~ 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in ~ 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.</p>","PeriodicalId":55058,"journal":{"name":"Hereditary Cancer in Clinical Practice","volume":null,"pages":null},"PeriodicalIF":2.0000,"publicationDate":"2022-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9446595/pdf/","citationCount":"4","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Hereditary Cancer in Clinical Practice","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13053-022-00237-x","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 4
Abstract
Germline pathogenic variants in BRCA1 and BRCA2 cause hereditary breast and ovarian cancer. The vast majority of these variants are inherited from a parent. De novo constitutional pathogenic variants are rare. Even fewer cases of constitutional mosaicism have been reported and these have mostly been described in women with breast cancer. Here we report low-level constitutional mosaicism identified by Next Generation Sequencing in two women with ovarian cancer. A BRCA1 c.5074G > A p.(Asp1692Asn) variant detected in the first female at 42 years, classed as likely pathogenic, was found in ~ 52% of reads in DNA extracted from tumour, ~ 10% of reads in DNA extracted from peripheral blood leukocytes and ~ 10% of reads in DNA extracted from buccal mucosa. The second BRCA1 c.2755_2758dupCCTG p.(Val920AlafsTer6) variant was detected in a female aged 53 years, classed as pathogenic, and was found in ~ 59% of reads in DNA extracted from tumour, ~ 14% of reads in DNA extracted from peripheral blood leukocytes and similarly in ~ 14% of reads in both DNA extracted from buccal mucosa and urine sample. Sanger sequencing confirmed the presence of these variants at a corresponding low level consistent with mosaicism that may not have been detected by this method alone. This report demonstrates the clinical benefit for two women of BRCA1/BRCA2 germline NGS testing at a depth that can detect low-level mosaicism. As well as informing appropriate treatments, tumour sequencing results may facilitate the detection and interpretation of low-level mosaic variants in the germline. Both results have implications for other cancer risks and for relatives when providing a family cancer risk assessment and reproductive risk. The implications for laboratory practice, clinical genetics management and genetic counselling for constitutional mosaicism of BRCA1/BRCA2 are discussed.
期刊介绍:
Hereditary Cancer in Clinical Practice is an open access journal that publishes articles of interest for the cancer genetics community and serves as a discussion forum for the development appropriate healthcare strategies.
Cancer genetics encompasses a wide variety of disciplines and knowledge in the field is rapidly growing, especially as the amount of information linking genetic differences to inherited cancer predispositions continues expanding. With the increased knowledge of genetic variability and how this relates to cancer risk there is a growing demand not only to disseminate this information into clinical practice but also to enable competent debate concerning how such information is managed and what it implies for patient care.
Topics covered by the journal include but are not limited to:
Original research articles on any aspect of inherited predispositions to cancer.
Reviews of inherited cancer predispositions.
Application of molecular and cytogenetic analysis to clinical decision making.
Clinical aspects of the management of hereditary cancers.
Genetic counselling issues associated with cancer genetics.
The role of registries in improving health care of patients with an inherited predisposition to cancer.