Abstract
Bloom syndrome is an autosomal recessive disorder characterized by chromosomal instability and increased cancer risk, caused by biallelic mutations in the RECQL-helicase gene BLM. Previous studies have led to conflicting conclusions as to whether carriers of heterozygous BLM mutations have an increased risk to develop colorectal cancer (CRC). We recently identified two carriers of a pathogenic BLM mutation in a cohort of 55 early-onset CRC patients (≤45 years of age), suggesting an overrepresentation compared to the normal population. Here, we performed targeted sequencing using molecular inversion probes to screen an additional cohort of 185 CRC patients (≤50 years of age) and 532 population-matched controls for deleterious BLM mutations. In total, we identified three additional CRC patients (1.6%) and one control individual (0.2%) that carried a known pathogenic BLM mutation, suggesting that these mutations are enriched in early-onset CRC patients (P = 0.05516). A comparison with local and publically available databases from individuals without suspicion for hereditary cancer confirmed this enrichment (P = 0.003534). Analysis of family members of the five BLM mutation carriers with CRC suggests an incomplete penetrance for CRC development. Therefore, these data indicate that carriers of deleterious BLM mutations are at increased risk to develop CRC, albeit with a moderate-to-low penetrance.
Highlights
In autosomal recessive cancer predisposing syndromes such as Bloom syndrome (MIM2109000), Nijmegen breakage syndrome (MIM251260), and Fanconi anemia (MIM227650), the risk for cancer is age-dependent and varies between cancer types
We previously identified deleterious BLM mutations, a splice site mutation (c.3558 + 1G > T ) and a nonsense mutation (c.2695C > T; p.Arg899*), in two individuals that were diagnosed with colorectal cancer at the age of 29 and 37 years, respectively (Fig. 1a and Table 1; deVoer et al unpublished data)
Since there are no precise numbers on the frequency of pathogenic BLM mutations in the general population, we queried the data browser from the Exome Aggregation Consortium (ExAC; n = 61,486)[10], a publically available dataset containing exomes from individuals of European, African or Asian ancestry
Summary
In autosomal recessive cancer predisposing syndromes such as Bloom syndrome (MIM2109000), Nijmegen breakage syndrome (MIM251260), and Fanconi anemia (MIM227650), the risk for cancer is age-dependent and varies between cancer types. We performed whole-exome sequencing on a cohort of individuals diagnosed with CRC (n = 5 5) before the age of 45 years, and we identified two individuals with heterozygous BLM mutations that are known to play a role in Bloom syndrome (De Voer et al unpublished data). To reveal whether these mutations contribute to the risk for CRC development, we have performed a case-control sequencing study using targeted enrichment by molecular inversion probe technology[8] followed by Ion semiconductor sequencing to compare the prevalence of Bloom syndrome-causing mutations in patients with CRC and healthy controls
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