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Distinct Pathways: Exploring Rare Clinical and Genetic Presentations in Breast Cancer Associated Hereditary Cancer Syndromes 

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction:
Hereditary cancer syndromes in patients present at an earlier age and require tailored treatment and management that is usually different from non-hereditary cancers. While there are some well-established genes that predispose to certain cancers and have common presentations supported by clinical guidelines for surveillance and risk management, unique presentations are also observed regularly in clinical practice. This is a result of increasing accessibility to cost effective Next Generation Sequencing (NGS) technologies; thus, these observations necessitate reporting and sharing with the clinical and scientific communities.

 

Methods:
A retrospective, observational study was conducted, rare case presentations were selected from cancer patients at the Hereditary Cancer Clinic at the Aga Khan University Hospital in Karachi, Pakistan who completed multi-gene NGS panel testing from May 2017 to June 2024. Results of genetic testing and patient history and presentation were recorded for 13 patients presenting with rare clinical presentations and unique genetic test results.

 

Results:
A total of 13 patients’ data (10 families were recruited/or their family members were included in the study) were included in the study. The mean age at diagnosis was 46 years (y). The most common breast cancer histological subtype was invasive ductal carcinoma, grade 2 and 3, triple negative disease, all presenting with positive family history of cancers. All the cases fell into two broad categories: some patients had P/LP variants in multiple genes and other patients had rare presentations while harbouring certain P/LP variants in genes, not associated with cancers they presented with. P/LP variants in BRCA1 (50%) were most prevalently found in these patients. Four patients had P/LP variants in multiple genes including BRCA1, MSH6, PMS 2, FANCM, PALB 2 and CHEK2. The highest number of P/LP noted in a single patient was three. Among these cases, one patient had P/LP variants in BRCA1 and CHEK2, presenting with breast cancer (31y) and later presented with secondary biliary cholangiocarcinoma. Out of three familial cases: in one, a niece had presented with ovarian cancer (58y) and her maternal uncle had squamous cell carcinoma of the esophagus (73y), both harboured a BRCA1 P/LP variant.  In another case, a P/LP ATM variant was observed in a daughter with breast cancer (31y) and her mother (62y) who later presented with renal clear cell carcinoma. Another consanguineous family showed monoallelic P/LP variant in MUTYH in mother with breast cancer (48y), whose two children had the similar but biallelic variant with metastatic colon carcinoma in early thirties.

 

Conclusion:
Germline P/LP variants play a central role in the development of breast cancer, particularly among patients who present at relatively younger ages and have an extensive family history of cancer. Our cases highlight the importance of multi gene panel testing, the need for tailored surveillance strategies for patients and family members as well as further exploration of unique cancer predisposition gene-gene interaction leading to unique disease  presentation which are not currently well elucidated. It will allow for tailored patient care approaches that allow for early detection and improved outcomes, as well as more personalized treatment plans once diagnosed.

 

Agenda

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