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Cancer genetics
Long-term tumour dormancy in a BRCA1 heterozygote
  1. Setor Amuzu1,2,
  2. Lili Fu3,
  3. Nadine Demko3,
  4. Barbara Rivera4,5,
  5. Celine Domecq6,
  6. Leanne de Kock2,7,
  7. Nancy Hamel6,
  8. Lucy Gilbert4,6,8,
  9. Paz Polak4,9,
  10. Jiannis Ragoussis1,2,
  11. William D Foulkes2,4,6,10
  1. 1 Genome Sciences, McGill Genome Centre, Montreal, Quebec, Canada
  2. 2 Department of Human Genetics, McGill University, Montreal, Quebec, Canada
  3. 3 Department of Pathology, McGill University, Montreal, Quebec, Canada
  4. 4 Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada
  5. 5 Program in Molecular Mechanisms and Experimental Therapy in Oncology (ONCOBELL), and Hereditary Cancer Program at ICO-IDIBELL, Bellvitge Biomedical Research Institut (IDIBELL), Barcelona, Spain
  6. 6 Cancer Research Program, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
  7. 7 Department of Pediatrics, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
  8. 8 Departments of Obstetrics & Gynaecology, McGill University, Montreal, Quebec, Canada
  9. 9 Department of Oncological Sciences, and The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  10. 10 Department of Medicine, McGill University, Montreal, Quebec, Canada
  1. Correspondence to Dr William D Foulkes; william.foulkes{at}mcgill.ca

https://doi.org/10.1136/jmedgenet-2021-108269

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    Ovarian high-grade serous carcinoma (HGSC) is thought to mainly arise from the Fallopian tubes from a precursor lesion known as serous tubal intraepithelial carcinoma (STIC).1 2 Germline pathogenic variants (GPVs) in BRCA1/2 are the most important causes of HGSC and risk-reducing salpingo-oophorectomy (RRSO) is offered to BRCA1/2 heterozygotes. We report a BRCA1 heterozygote who developed a pelvic HGSC 15 years post-RRSO, following an occult Fallopian tube HGSC that was missed on initial pathological examination. Exome sequencing of DNA derived from normal and tumour tissues showed that the pelvic tumour is a recurrence from the original Fallopian tube tumour.

    BRCA1 and BRCA2 GPVs are the strongest known risk factors for HGSC, and for this reason, RRSO is offered to women who are heterozygous for BRCA1/2 GPVs as standard of care, usually between the ages of 35 and 50 years. For women who have undergone RRSO, there persists a small but significant risk for peritoneal cancer.3 A systematic review found that 1.2% of BRCA1/2 patients undergoing RRSO had occult tubal carcinoma at the time of surgery. Moreover, 0.54% of these patients went on to develop peritoneal cancer post-RRSO, of which only 17% (4/24) had STICs at initial diagnosis.4 Incomplete removal of adnexa, lack of standard pathological sectioning protocol and early precursors unidentifiable by routine histological examination potentially explain the lack of detection of early carcinomas at the time of RRSO. Nonetheless, the failure to find a precursor for all recurrences, as well as the often-significantly delayed presentation of the peritoneal cancer after RRSO, highlights some unresolved aspects to the predominant model that most, if not all, pelvic HGSC arise from the Fallopian tube.3 4 Several studies have elucidated identical TP53 mutations in a primary HGSC and a second HGSC arising in the same woman, suggesting a common origin …

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    Footnotes

    • Twitter @Setfelix

    • Contributors SA performed data analysis and visualisation, and contributed to the manuscript draft; LF reviewed pathology and contributed to the draft; ND wrote the first draft; BR oversaw some of the experiments; CD carried out some of the Sanger sequencing; LdK prepared the samples and did some of the Sanger sequencing; NH oversaw some of the experiments; LG provided clinical data; PP oversaw data analysis; JR oversaw the whole-exome sequencing; WDF devised the project, oversaw the work and finalised the manuscript draft. All authors approved the submitted manuscript.

    • Funding The work in WDF’s lab was funded by a Canadian Institutes of Health Research Foundation Grant (FDN-148390).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.