Is Low FMR1 CGG Repeat Length in Males Correlated with Family History of BRCA-Associated Cancers? An Exploratory Analysis of Medical Records

The FMR1 gene has been studied extensively with regard to expansions and premutations, but much less research has focused on potential effects of low CGG repeat length. Previous studies have demonstrated that BRCA1/2 positive women are more likely to have an FMR1 genotype with one low CGG allele, and that women with both FMR1 alleles in the low CGG repeat range are more likely to have had breast cancer compared to women with normal numbers of CGG repeats. However, there has been no research as to whether low CGG repeat length impacts cancer risks in men. Therefore, this study aimed to examine cancer incidence and related risk factors in men with low CGG repeat length in the FMR1 gene. We utilized subject data from the Marshfield Personalized Medicine Research Project to compare cancer-related diagnoses between 878 males with low CGG repeat length (< 24 repeats) and 368 male controls with CGG repeats in the normal range (24 to 40 repeats). We utilized ICD-9 codes to examine various cancer diagnoses, family histories of cancer, other non-malignant neoplasms, cancer surveillance, and genetic susceptibility. Men with low CGG repeats were identified to have significantly higher rates of family history of any cancer type (p = 0.011), family history of any BRCA-associated cancer (p = 0.002), and specifically, family history of prostate cancer (p = 0.007). The mean number of BRCA-associated cancer diagnoses (breast, prostate, pancreatic, and melanoma) per individual in the low CGG group was slightly higher than that of the control group, with this difference trending toward significance (p = 0.091). Additionally, men with low CGG repeats had significantly higher rates of connective/soft tissue neoplasms (p = 0.026). Additional research is needed to replicate the observations reported in this preliminary exploratory study, particularly including verification of ICD-9 codes and family history by a genetic counselor.