Exome sequencing in 51 early onset non‐familial CRC cases

Abstract

Background Colorectal cancer ( CRC ) cases with an age of onset <40 years suggests a germline genetic cause. In total, 51 simplex cases were included to test the hypothesis of CRC as a mendelian trait caused by either heterozygous autosomal dominant or bi‐allelic autosomal recessive pathogenic variants. Methods The cohort was whole exome sequenced ( WES ) at 100× coverage. Both a dominant‐ and recessive model were used for searching predisposing genetic factors. In addition, we assayed recessive variants of potential moderate risk that were enriched in our young‐onset CRC cohort. Variants were filtered using a candidate cancer gene list or by selecting variants more likely to be pathogenic based on variant type (e.g., loss‐of‐function) or allele frequency. Results We identified one pathogenic variant in PTEN in a patient subsequently confirmed to have a hereditary hamartoma tumor syndrome (Cowden syndrome) and one patient with a pathogenic heterozygous variant in PMS 2 that was originally not identified by WES due to low quality reads resulting from pseudogenes. In addition, we identified three heterozygous candidate missense variants in known cancer susceptibility genes ( BMPR 1A , BRIP 1 , and SRC ) , three truncating variants in possibly novel cancer genes ( CLSPN , SEC 24B , SSH 2 ) and four candidate missense variants in ACACA , NR 2C2 , INPP 4A, and DIDO 1 . We also identify five possible autosomal recessive candidate genes: ATP 10B , PKHD 1 , UGGT 2 , MYH 13 , TFF 3 . Conclusion Two clear pathogenic variants were identified in patients that had not been identified clinically. Thus, the chance of detecting a hereditary cancer syndrome in patients with CRC at young age but without family history is 2/51 (4%) and therefore the clinical benefit of genetic testing in this patient group is low. Of note, using stringent filtering, we have identified a total of ten candidate heterozygous variants and five possibly biallelic autosomal recessive candidate genes that warrant further study.

Hormone receptor expression of colorectal cancer diagnosed during the peri-partum period

“…It is notable that all the women in our series lacked any known predisposition to CRC, including IBD, alcohol consumption, hereditary CRC syndromes and a family history of CRC (26, 27, 28, 29, 30, 31, 32). No germline mutations were detected, which is consistent with a study that found low probability of having a known germline mutation in patients with CRC <40 years old (33). However, numerous VUS were identified in all of the women, which may merit further exploration.…”

High-throughput gene screen reveals modulators of nuclear shape

“…DIDO1 was recently shown to recognize the histone 3 lysine residue 4 trimethylation mark in a pH-dependent manner through a PHD domain ( Tencer et al. , 2017 ) and was identified as a possible germline variant in familial colorectal cancer ( Thutkawkorapin et al. , 2019 ).…”

Candidate Gene Discovery in Hereditary Colorectal Cancer and Polyposis Syndromes–Considerations for Future Studies

“…The phenotypes that were studied included either polyposis, familial colon and/or rectal cancer, or a mixture of the aforementioned phenotypes. Age-based inclusion criteria were applied in twelve out of the 32 unique discovery cohorts [ 13 , 43 , 47 , 49 , 53 , 54 , 56 , 59 , 64 , 65 , 67 , 69 , 70 , 71 , 72 , 75 , 76 ]. However, this age-based inclusion criterion was heterogeneous ranging from an age at diagnosis ≤35 years [ 47 ] to diagnosis <60 years [ 43 ], to at least one relative diagnosed <60 years [ 53 , 64 , 69 , 72 , 75 , 76 ].…”

“…In general, we observed prioritization based on either complete screening of WES or WGS data or, more targeted, by focusing on specific genes or regions that are more likely to be involved in hereditary cancer. The main applied variant prioritization strategies included linkage ( n = 8 studies [ 41 , 43 , 52 , 55 , 61 , 66 , 73 , 75 ]), variants shared among affected relatives or absence of the variant in unaffected relatives ( n = 19 studies [ 41 , 43 , 48 , 51 , 52 , 53 , 55 , 57 , 60 , 61 , 63 , 64 , 66 , 67 , 68 , 69 , 70 , 74 , 76 ]) and gene function ( n = 14 studies [ 13 , 47 , 53 , 57 , 58 , 59 , 63 , 64 , 65 , 71 , 72 , 74 , 75 , 76 ]). Other approaches include the prioritization of recurrent variants ( n = 7 studies [ 13 , 39 , 40 , 44 , 50 , 56 , 65 ]) and prioritization based on expected recessive or dominant mode-of-inheritance ( ...…”

“…Within the 37 candidate gene discovery studies, the applied MAF cut-off ranged from 0.00–0.20 ( Table S1 : Applied MAF). Four studies explicitly adapted their MAF cut-off to presumed dominant or recessively inherited genetic predispositions in their study populations [ 40 , 44 , 62 , 71 ]. These four studies applied more stringent MAF cut-offs in dominant scenarios (MAF < 0.01–0.001) and looser MAF cut-offs for recessive inheritance patterns (MAF < 0.03–0.01) [ 40 , 44 , 62 , 71 ].…”