Multilocus inherited neoplasia alleles syndrome: a retrospective review from a Canadian single institution

www.nature.com/ejhg ARTICLE OPEN Multilocus inherited neoplasia alleles syndrome: a retrospective review from a Canadian single institution Kathleen Orrell1, Malek Horani1, Maria Carolina Sanabria-Salas ✉ Raymond H. Kim 1,2,3,4,5 1 , Khadijah Alshankati1, Rebecca Mantha1, Larissa Peck 2 and 1234567890();,: © The Author(s) 2026 Genetic testing in hereditary cancer is evolving from single-gene-focused approaches in affected individuals to multi-gene panel testing for affected individuals and unaffected relatives. The widespread use of multi-gene panel testing has led to the identification of individuals with two or more pathogenic or likely pathogenic variants in hereditary cancer susceptibility genes (CSGs), termed Multilocus Inherited Neoplasia Allele Syndrome (MINAS) carriers. It remains unclear whether MINAS carriers are at increased risk of multiple, atypical, or more severe cancer phenotypes, and currently, there is no consensus on how best to identify and manage cancer risk. In this retrospective study, we identified 54 MINAS carriers at Princess Margaret Cancer Center in Toronto, Canada. Demographic, clinical, and genetic data were extracted from medical records. Group comparisons were performed using Fisher’s exact or chi-square tests for categorical variables and independent t tests for age at cancer diagnosis. Statistical significance was set at p ≤ 0.05. The majority of affected MINAS carriers had a cancer consistent with the expression of at least one pathogenic variant. Approximately 28% of MINAS carriers were diagnosed with one atypical cancer. The most frequent gene pair combinations included hereditary breast cancer genes, with some carriers exhibiting earlier age of breast cancer onset than single CSG variants reported in the literature. Our study indicates that the cancer spectrum associated with CSGs is expanding and suggests that more intensive cancer surveillance for subgroups of MINAS carriers with hereditary breast cancer CSGs may be warranted. European Journal of Human Genetics; https://doi.org/10.1038/s41431-026-02142-6 INTRODUCTION Hereditary cancer syndromes account for approximately 5–10% of all cancers and describe a spectrum of cancers that are caused by inherited pathogenic or likely pathogenic variants in cancer susceptibility genes (CSGs) [1]. Hereditary cancer syndromes include BRCA1 and BRCA2 associated breast, ovarian, and prostate cancers, and lesserknown cancer syndromes, including CDH1-associated hereditary diffuse gastric cancer. Traditionally, hereditary cancers have been identified by recognizing clusters of related individuals with a high burden of cancer, followed by targeted testing of individual genes. With the advent of next generation sequencing, there has been a paradigm shift toward multi-gene panel testing, which allows for simultaneous detection of multiple CSGs. This in turn has enabled detection of pathogenic variants not predicted by phenotype or family history. Further, multi-gene panel testing has led to the detection of carriers of two or more pathogenic or likely pathogenic variants in CSGs, termed Multilocus Inherited Neoplasia Allele Syndrome, or MINAS [2]. The estimated prevalence of MINAS carriers is 0.2–2.4% [3–5]. Although early MINAS studies included both autosomal dominant (AD) and recessive (AR) gene pair combinations [3], more recent studies have analyzed AD-AD and AD-AR gene pair combinations separately, citing higher penetrance and higher frequency of malignancies in AD-AD gene pair combinations [4, 5]. Hereditary cancer syndromes have been associated with an elevated lifetime risk for specific cancers and more severe cancer phenotypes [6]. Carriers of single pathogenic variants in CSGs undergo lifelong specialized cancer surveillance. These genetic test results provide information on cancer risks and implications for other family members, such as the potential need for cascade testing [7]. The results of surveillance are actionable, guiding decision making around preventive or risk-reducing measures and the use of certain therapeutic agents in cancer treatments. Compared to single CSG variants, it has long been hypothesized that MINAS carriers are at elevated risk of multiple, atypical, and more severe cancers because of synergistic interactions CSGs may have in related tumourigenic pathways or in chromosomal proximity [2]. Synergistic interactions in MINAS cases refer to CSGs interacting in a way that may produce a more severe phenotype than would be expected from each CSG acting alone. In order to evaluate for synergistic effects of CSGs, studies have compared the clinical spectrum and characteristics of cancers in MINAS cases to single gene hereditary cancers. Most MINAS studies have focused on hereditary breast cancer genes, including BRCA1 and BRCA2. Some studies have found a younger age of onset and multiple malignancies in hereditary breast cancer MINAS cases compared to single gene hereditary breast cancers 1 Department of Medicine, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada. 2Bhalwani Familial Cancer Clinic, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. 3Ontario Institute for Cancer Research, Toronto, ON, Canada. 4Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Sinai Health System, Toronto, ON, Canada. 5Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada. ✉email: Received: 18 November 2025 Revised: 4 May 2026 Accepted: 13 May 2026 K. Orrell et al. 2 [3, 4, 8–13]. The largest study to date by Rebbeck et al. comparing BRCA1 and BRCA2 MINAS carriers found that the mean age of breast cancer onset was not significantly different from single BRCA variants [14]. Hereditary breast cancers differ in hormone receptor status based on the specific germline mutation, which significantly impacts both prognosis and treatment, as hormone receptor status is an independent predictor of survival [15]. BRCA1associated cancers are predominantly triple-negative, while BRCA2, ATM, and CHEK2-associated cancers are predominantly ER-positive. Li-Fraumeni-associated cancers show increased HER2positivity but variable hormone receptor status [16]. In this single-center retrospective cohort study, we identified carriers with AD-AD (i.e., MINAS) and AD-AR gene pair combinations who were diagnosed at Princess Margaret Cancer Center from January 1, 2017, to September 30, 2024. We extracted demographic, clinical, and genetic data from medical records and made comparisons using Fisher’s exact test, chi-square tests, or independent t tests, with statistical significance set at p ≤ 0.05. The objectives of this study were to characterize the clinical spectrum of cancers in an adult cohort of MINAS carriers and compare our findings to the hereditary cancer and MINAS literature. The o (...truncated)