Abstract 868: Heritable cancer mutations in multiple myeloma
Authors: Thibaud Santiago , Etra Aaron , Subaran Ryan , Soens Zachry , Newman Scott , Chen Rong , Chari Ajai , Cho Hearn J. , Jagannath Sundar , Madduri Deepu , Melnekoff David T. , Richard Shambavi , Richter Joshua , Sanchez Larysa , Lagana Alessandro , Parekh Samir , Onel Kenan 
Published: July 2021

Abstract
Background: Epidemiologic studies have shown familial aggregations of multiple myeloma (MM) and other hematologic malignancies, but little is known about heritable genetic susceptibilities in these patients. The purpose of this study is to investigate the prevalence of known germline cancer-predisposing mutations (CPM) in patients with multiple myeloma (MM).
Methods: We analyzed a set of 895 newly diagnosed MM patients from the Multiple Myeloma Research Foundation (MMRF) CoMMpass registry for whom whole-exome sequencing of germline DNA data was available. We used the clinical annotation pipeline from Sema4, a CLIA- and CAP-certified genetic testing laboratory, in a research context, to identify patients with pathogenic or likely pathogenic CPM according to ACMG variant classification guidelines, and compared their characteristics against those without CPM. Statistical significance was assessed using the Chi-Square and Fisher's Exact tests and defined as a two-sided p value &lt;0.05.
Results: We identified 83 germline CPM in 31 distinct genes in 79 (8.8%) of 895 patients. Homologous recombination (HR) pathway gene mutations were the most common (n = 38, 46%), with CHEK2 being the most frequently mutated gene (n = 10, 12%). Notably, the number of mismatch repair (MMR) gene defects was considerably higher (n = 6, 1:149) than the estimated prevalence in the general population. CPM carriers were significantly more likely to be diagnosed with MM before age 40 (6.3% vs 1.8%, p = 0.025) and to have a family history (FH) of MM or leukemia (16.4% vs 6.3%, p = 0.01) than those without a CPM. Likelihood of having a FH of any malignancy was also significantly higher in the CPM group (70.9% vs 54.5%, p = 0.028). Interestingly, common CHEK2 founder mutations were observed at a much higher rate in patients with a FH of MM or leukemia (8.7% vs 0.68%, p = 0.0013).
Conclusions: Our results suggest that a significant proportion of patients with MM carry germline cancer-predisposing mutations, especially those diagnosed at a very young age (&lt;40 years old), and those with a family history of MM or leukemia. The observation that 6 out of 895 patients with MM had pathogenic MMR variants suggests that MM may be a previously unsuspected component of Lynch syndrome. Common CHEK2 founder mutations were strikingly frequent in patients with a FH of MM, suggesting that FH modifies the penetrance of these variants in MM predisposition, as has been observed for other cancers.
Citation Format: Santiago Thibaud, Aaron Etra, Ryan Subaran, Zachry Soens, Scott Newman, Rong Chen, Ajai Chari, Hearn J. Cho, Sundar Jagannath, Deepu Madduri, David T. Melnekoff, Shambavi Richard, Joshua Richter, Larysa Sanchez, Alessandro Lagana, Samir Parekh, Kenan Onel. Heritable cancer mutations in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 868.