We studied 278 probands selected solely on the basis of having developed MSS CRC at a young age of onset. Exclusion of cases with tumor microsatellite instability was aimed at excluding cases that had a high likelihood of having HNPCC-Lynch Syndrome, the most common cause of hereditary CRC. We determined that the relative risk for CRC in this cohort was greatest in siblings (RR 2.67; 95% C.I=1.50–4.41), which was nearly double the relative risk of CRC in parents (RR 1.5; 95% C.I.=1.14–1.94). However, because the confidence intervals overlap, we can only say that the data are suggestive of a trend for siblings of young onset CRC patients to have an increased RR for CRC over that of the parents. It is possible that environmental factors could contribute to the greater CRC risk observed in siblings rather than parents. In particular, increased CRC rates in the second half of the twentieth century may be attributable to the substantial decrease in physical activity coupled with excess energy intake and may now be manifesting in sibilings who shared these exposures during childhood and younger adulthood.10
However, while we cannot rule out some shared environmental exposures as the explanation for CRC in siblings, these results may suggest an autosomal recessive mechanism for CRC predisposition. Biallelic mutations in MYH
, a base excision repair gene, have recently been discovered to predispose to CRC, often, but not always, in association with an attenuated polyposis phenotype. To determine if MYH mutations accounted for this increased risk in siblings, we tested for MYH
mutations in our 11 cases with affected siblings and did not find any mutations, either biallelic nor monoallelic, to explain our observations. This suggests the possibility of additional genes to be discovered as predisposing causes of CRC.
A paper recently published by the Swedish Family-Cancer Database found similar results11
by studying 6,774 offspring diagnosed with CRC between 0–68 years. In this population-based study, 306 had only a parent affected, 100 had only a sibling affected, and 10 had both a parent and sibling affected. Standardized incidence ratios (SIRs) were presented for CRC in first degree relatives. The SIR for offspring of a parent with CRC was 2.13 and the SIR was 2.75 when a sib was affected. When looking only at right sided tumors, there was a 1.8 fold increased risks in siblings compared to offspring of an affected parent. They concluded that the most likely explanation for the high risk of right sided CRC among siblings was recessive inheritance predisposition, which they suggested could account for 0.75% of all CRC. DNA MMR status of the incident CRC cases was not known in the Swedish Family- Cancer Database, however, to minimize that the known hereditary condition of HNPCC might confound results, kindreds with three or more CRC affected relatives were excluded from their analysis. MYH
gene testing was not able to be conducted in this epidemiologic study, but as the authors highlight, the 0.75% recessive inheritance rate detected in their population exceeds the rate attributable to MYH-related recessive inheritance reported in the literature. Our results corroborate this autosomal recessive inheritance predisposition and indicate that this autosomal recessive inheritance pattern is present in a population known to have CRC not related to DNA MMR or MYH
In an editorial in the Journal of the National Cancer Institute discussing similar results in a Swedish study,12
Zelen suggested that length-based bias and surveillance bias are important considerations in such studies.13
Length-based bias is the consequence of the fact that large families are more likely to be found because there are simply more people available to become probands in large families. Thus, the distribution of family size is not representative of the population at large. Surveillance bias reflects the assumption that people who are relatives of the proband may, because of heightened awareness and/or concern, be more likely to detect disease. Length-based bias is not an issue for this work as the statistical test was done to see if the proband-relatives population has cancer rates that differ from the population as a whole (SEER-based rates). Thus, while the probands are more likely to come from large families, the rates within the probands were not analyzed, the incidences were not collapsed to family-based single measure. The proband-relatives are therefore suitable for relative risk analyses. Surveillance bias would only be relevant if the severity of the disease upon detection was being addressed; however, the presence of CRC was the only endpoint measured in this study. Even so, we compared rates in the first year following detection in the proband with rates in subsequent years and found no significant difference.
Though the methodology between our study and the Hemminki and Chen paper differed, our conclusions are strikingly similar. First degree relatives of MSS CRC patients do have an increased risk for the development of GI tract cancer in general and of CRC in particular. Siblings have a higher GI tract cancer risk than parents, indicating that MSS young onset CRC may confer an increased familial risk for CRC that follows an autosomal recessive pattern of inheritance.