Comprehensive molecular characterisation of hereditary non-polyposis colorectal tumours with mismatch repair proficiency

Background: Hereditary non-polyposis colorectal cancer (CRC) without mismatch repair (MMR) defects occurs in almost half of high-risk CRC families, but its genetic cause(s) is(are) still unknown. We aimed to identify unique molecular features that differentiate hereditary from sporadic MMR-proficient colorectal tumours.

Methods: Genomic alterations in 16 tumours from 14 Amsterdam I-II families were studied using the genome-wide copy number OncoScan™ FFPE microarray. Somatic mutation hotspots in BRAF, KRAS, PIK3CA and TP53 were analysed in 37 colorectal tumours from 26 families and in 99 sporadic MMR-proficient CRCs, using direct automated sequencing and KASPar genotyping assays. CpG methylation index was studied in 25 tumours from 19 families by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA).

Results: Our findings indicate that hereditary MMR-proficient tumours have overlapping genomic profiles to those obtained in sporadic cases, both suggestive of high chromosomal instability, and no high CpG methylation index. Nevertheless, we identified a significant increase in the frequency of chromosome 2p and 2q gains, and of 10 q loss in Amsterdam I families, as well as low frequency of >2 Mb copy-neutral or -gained loss of heterozygosity (LOH). No statistically significant differences in the frequency of BRAF, KRAS, PIK3CA and TP53 mutations or in the gene mutation patterns were observed. However, TP53 mutations appeared almost twice more frequently in sporadic tumours.

Conclusions: Overall, hereditary MMR-proficient CRCs display similar molecular characteristics than their sporadic counterparts. However, the differences identified, such as the chromosome 2 gain, 10 q loss, or the under-representation of TP53 mutations, if validated in larger series, might be of relevance in the clinical setting and/or in the identification of germline defects underlying some of these familial cases.