Whole exome sequencing and single nucleotide polymorphism array analyses to identify germline alterations in genes associated with testosterone metabolism in a patient with androgen insensitivity syndrome and early-onset colorectal cancer

Abstract

BackgroundAndrogen insensitivity syndrome (AIS), a disorder of sexual development in 46, XY individuals, is caused by loss-of-function mutations in the androgen receptor (AR) gene. A variety of tumors have been reported in association with AIS, but no cases with colorectal cancer (CRC) have been described.Case presentationHere, we present a male patient with AIS who developed multiple early-onset CRCs and his pedigree. His first cousin was diagnosed with AIS and harbored the same AR gene mutation, but with no signs of CRC. The difference in clinical management for the two patients was that testosterone treatment was given to the proband for a much longer time compared with the cousin. The CRC family history was negative, and no germline mutations in well-known CRC-related genes were identified. A single nucleotide polymorphism array revealed a microduplication on chromosome 22q11.22 that encompassed a microRNA potentially related to CRC pathogenesis. In the proband, whole exome sequencing identified a polymorphism in an oncogene and 13 rare loss-of-function variants, of which two were in CRC-related genes and four were in genes associated with other human cancers.ConclusionsBy pathway analysis, all inherited germline genetic events were connected in a unique network whose alteration in the proband, together with continuous testosterone stimulation, may have played a role in CRC pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40880-016-0115-1) contains supplementary material, which is available to authorized users.

Germline copy number variations in BRCA1/2 negative families: Role in the molecular etiology of hereditary breast cancer in Tunisia

“…In the present study none of our two patients expressed the phenotype characterizing this disorder. However, mutations in KANSL1 gene were also detected in multiple cancers [ 45 ] including bladder cancer [ 44 ] and germline copy number variation in this gene was also described in early colorectal cancer [ 57 ]. Moreover, among genes affected by this CNV, PLEKHM1 (which is not deleted in Koolen–de Vries syndrome) is also considered as an ovarian cancer predisposing gene [ 58 ].…”

Association between polymorphisms in sex hormones synthesis and metabolism and prostate cancer aggressiveness

“…In relation to rs9332969, despite we not report any allelic variation (100% of patients and controls are carriers), this SNP seems to be an attractive candidate biomarker for PCa aggressiveness because is a missense variant with an amino acid change (R841H) [ 29 ]. R841H variation causes androgen insensitivity syndrome [ 42 ]. This is due because AR protein with R841H variation alters the interaction with androgens which result in a partial AR functional disruption [ 42 ] and its frequency and effect had not been previously studied in the European population [ 43 ].…”

“…R841H variation causes androgen insensitivity syndrome [ 42 ]. This is due because AR protein with R841H variation alters the interaction with androgens which result in a partial AR functional disruption [ 42 ] and its frequency and effect had not been previously studied in the European population [ 43 ].…”

The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel

“…NGS approaches can prevent such errors by covering unexplored mutations in non-coding regions. Establishing a reliable NGS analytical system that considers variations specific to ethnic and population subgroups, where comparisons are drawn to healthy populations of the same ethnicity, is critical for accurate analysis [ 26 , 27 , 28 , 29 ].…”