Multi-Gene Panel Testing Within the Context of Limited Family Structure in Single Cases of Breast Cancer
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction:
Knowledge of an individual’s family history is integral in predicting their cancer risks and assessing their likelihood of carrying a pathogenic or likely pathogenic (P/LP) variant in a hereditary cancer gene. Individuals with early-onset breast cancer who have limited to no information about their family history or have a small family may have an underestimated risk of carrying a P/LP variant in a hereditary cancer gene. The purpose of the study is to determine the frequency of P/LP variants detected on multi-gene panel testing in single cases of early-onset breast cancer with limited known family structure.
Methods:
A total of 169 female patients, diagnosed with breast cancer before the age of 50 years and who did not report a family history of breast cancer in any first- or second-degree relatives, were seen at a private community cancer institute for hereditary cancer risk assessment between January 2014 and October 2024. These individuals had limited family structure, which was defined as having fewer than two female first- or second-degree relatives on either the paternal or maternal side who lived to be over age 45 years. These patients underwent multi-gene panel testing that ranged in size from comprehensive cancer and pancreatitis panel testing to testing of only high- and moderate-penetrance breast cancer genes.
Results:
Sixteen (9.4%) of the 169 individuals evaluated in our cohort were found to harbor a P/LP variant in a hereditary cancer or pancreatitis gene, of which eight (4.7%) were found to carry a P/LP variant in a breast cancer susceptibility gene (ATM, BRCA1, CHEK2). The most frequently impacted gene was CHEK2, as six (3.5%) of the 169 patients were found to carry a P/LP variant in this gene. Four out of the six harbored one of the European founder variants in this gene (c.1100delC and p.I157T). Nine (5.3%) were found to carry a P/LP variant in an autosomal dominant cancer/tumor susceptibility gene (ATM, BRCA1, CHEK2, SDHA). Four (2.3%) others were found to carry a P/LP variant in an autosomal recessive cancer susceptibility gene (BLM, MSH3, NBN, NTHL1). Three (1.8%) were found to carry a P/LP variant in a pancreatitis gene (CFTR, SPINK1). As not all patients underwent genetic testing that included analysis of hereditary pancreatitis genes and non-breast cancer genes, there may be an underrepresentation of the true rate of individuals who carry aberrant variants in pancreatitis and non-breast cancer genes.
Conclusion:
Almost 10% of patients with early-onset breast cancer and limited family history structure who underwent multi-gene panel genetic testing were found to harbor a hereditary P/LP germline variant in a hereditary cancer or pancreatitis gene. The results of genetic counseling and testing services aid in decision-making for cancer treatment, future cancer surveillance and family planning. The frequency of P/LP variants unrelated to breast cancer risk identified in this study also suggests that healthcare providers should provide adequate education on the possibility of detecting incidental variants on multi-gene panel testing.
Knowledge of an individual’s family history is integral in predicting their cancer risks and assessing their likelihood of carrying a pathogenic or likely pathogenic (P/LP) variant in a hereditary cancer gene. Individuals with early-onset breast cancer who have limited to no information about their family history or have a small family may have an underestimated risk of carrying a P/LP variant in a hereditary cancer gene. The purpose of the study is to determine the frequency of P/LP variants detected on multi-gene panel testing in single cases of early-onset breast cancer with limited known family structure.
Methods:
A total of 169 female patients, diagnosed with breast cancer before the age of 50 years and who did not report a family history of breast cancer in any first- or second-degree relatives, were seen at a private community cancer institute for hereditary cancer risk assessment between January 2014 and October 2024. These individuals had limited family structure, which was defined as having fewer than two female first- or second-degree relatives on either the paternal or maternal side who lived to be over age 45 years. These patients underwent multi-gene panel testing that ranged in size from comprehensive cancer and pancreatitis panel testing to testing of only high- and moderate-penetrance breast cancer genes.
Results:
Sixteen (9.4%) of the 169 individuals evaluated in our cohort were found to harbor a P/LP variant in a hereditary cancer or pancreatitis gene, of which eight (4.7%) were found to carry a P/LP variant in a breast cancer susceptibility gene (ATM, BRCA1, CHEK2). The most frequently impacted gene was CHEK2, as six (3.5%) of the 169 patients were found to carry a P/LP variant in this gene. Four out of the six harbored one of the European founder variants in this gene (c.1100delC and p.I157T). Nine (5.3%) were found to carry a P/LP variant in an autosomal dominant cancer/tumor susceptibility gene (ATM, BRCA1, CHEK2, SDHA). Four (2.3%) others were found to carry a P/LP variant in an autosomal recessive cancer susceptibility gene (BLM, MSH3, NBN, NTHL1). Three (1.8%) were found to carry a P/LP variant in a pancreatitis gene (CFTR, SPINK1). As not all patients underwent genetic testing that included analysis of hereditary pancreatitis genes and non-breast cancer genes, there may be an underrepresentation of the true rate of individuals who carry aberrant variants in pancreatitis and non-breast cancer genes.
Conclusion:
Almost 10% of patients with early-onset breast cancer and limited family history structure who underwent multi-gene panel genetic testing were found to harbor a hereditary P/LP germline variant in a hereditary cancer or pancreatitis gene. The results of genetic counseling and testing services aid in decision-making for cancer treatment, future cancer surveillance and family planning. The frequency of P/LP variants unrelated to breast cancer risk identified in this study also suggests that healthcare providers should provide adequate education on the possibility of detecting incidental variants on multi-gene panel testing.