Germline heterozygous exons 8-11 pathogenic BARD1 gene deletion reported for the first time in a family with suspicion of a hereditary colorectal cancer syndrome: more than an incidental finding?

Abstract

Background: Colorectal cancer (CRC) is a highly prevalent disease in developed countries. Inherited Mendelian causes account for approximately 5% of CRC cases, with Lynch syndrome and familial adenomatous polyposis being the most prevalent forms. Scientific efforts are focused on the discovery of new candidate genes associated with CRC and new associations of phenotypes with well-established cancer-related genes. BRCA1-associated ring domain (BARD1) gene deleterious germline variants are associated with a moderate increase in the relative risk of breast cancer, but their association with other neoplasms, such as CRC, remains unclear.

Case presentation: We present the case of a 49-year-old male diagnosed with rectal adenocarcinoma whose maternal family fulfilled Amsterdam clinical criteria for Lynch syndrome. Genetic test confirmed the presence in heterozygosis of a germline pathogenic deletion of exons 8-11 in BARD1 gene. The predictive genetic study of the family revealed the presence of this pathogenic variant in his deceased cancer affected relatives, confirming co-segregation of the deletion with the disease.

Conclusions: To the best of our knowledge, this is the first published work in which this BARD1 deletion is detected in a family with familial colorectal cancer type X (FCCTX) syndrome, in which the clinical criteria for Lynch syndrome without alteration of the DNA mismatch repair (MMR) system are fulfilled. Whether this incidental germline finding is the cause of familial colorectal aggregation remains to be elucidated in scientific forums. Patients should be carefully assessed in specific cancer genetic counseling units to account for hypothetical casual findings in other genes, in principle unrelated to the initial clinical suspicion, but with potential impact on their health.

Keywords: Amsterdam clinical criteria; BARD1; Cancer genetic counseling; Colorectal cancer; Deletion; Familial colorectal cancer type X syndrome; Hereditary; Pathogenic variant.

Fig. 1

Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis: One hundred nanograms of genomic DNA of the proband and his relatives were analyzed for CNV confirmation/detection in BARD1 gene with SALSA MLPA P489 probemix (MRC Holland, Amsterdam, The Netherlands) according to manufacturer’s instructions on an ABI3500 Genetic Analyzer (Thermo Fisher Scientific). Data were analyzed with Coffalyser.NET software (MRC Holland)

Fig. 2

Family pedigree. The arrow denotes the proband. Blue color: colorectal cancer (CRC) affected. Green color: endometrial cancer affected. Orange color: cancer of unknown primary affected. Pink color: breast cancer affected. Plus ( +) and minus (-) sign represent carrier status of tested family members: BARD1 pathogenic deletion carrier is represented by plus ( +) sign, and no pathogenic deletion carrier is represented by minus (-). Obligate carrier status is represented by an asterisk (*)