Hereditary Ovarian Cancer: Molecular Genetics, Pathology, Management, and Heterogeneity

Future Prospects: DNA Variants Modify HBOC and LS (Lynch Syndome) Cancer Risk:
What does the future hold with respect to molecular genetics and cancer control in hereditary cancer, inclusive of HBOC and Lynch syndrome?

This projection relates to the truism that cancer-causing mutations do not act in a vacuum, since they are likely to be impacted by additional low-penetrant modifier genes in concert with myriad environmental events.
For example, in the HBOC syndrome, the work of Smith et al. (2007) estimated that in high-risk families the breast cancer risk might be caused not only by the BRCA/2 mutation, but also may be increased by modifier genes. This is important, since in genetic counseling we have ensured mutation-negative family members from BRCA kindreds that they are at general population risk rather than at extremely high cancer risk. The implication is that they do not require intensive screening recommendation. However, if these findings are confirmed, then patients testing negative for a BRCA mutation in the setting of HBOC families with BRCA relatives, should be considered for continued surveillance, perhaps less than we would consider should they be positive for the BRCA mutation but, nevertheless, more than we would recommend for those individuals who are judged to be more truly sporadic and thereby at general population risk. However, these findings merit confirmation in a well-designed prospective study (Gronwald et al., 2007).

In the case of Lynch syndrome, Wijnen et al. (2009) have shown that genome-wide association studies have identified common low-risk variants impacting CRC. These investigators genotyped these variants in 675 individuals from the Dutch Lynch Syndrome Registry who were known carriers of Lynch syndrome-associated mutations. They genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1. Results disclosed a significant association between CRC risk in these Lynch syndrome mutation carriers and the single nucleotide polymorphisms (SNPs) rs16892766 on chromosome 8q23.3 and rs3802842 on chromosome 11q23.1. They concluded that the two loci which they identified may be helpful in identifying Lynch syndrome family members who require more intensive surveillance specifically for CRC. The possibility exists that the presence of one of these identified low-risk variants may slightly increase risk of CRC for members of Lynch syndrome families who are negative for an MMR mutation.