Germline Genomic Homozygosity and Cancer Risk

To the Editor: Dr Assié and colleagues¹ reported a significant association between germline homozygosity in the human genome and increased cancer risk. They also reported an increased loss of heterozygosity (LOH) in cancer cells at the same sites as those of increased genome homozygosis. These findings are important for consanguineous populations, and the authors cited studies that showed an increased risk of cancer in inbreeding populations. However, they have considered only studies from Pakistan and Croatia, which are supportive of their findings.

Human inbreeding is widespread in developing countries of the tropical and subtropical regions of the Eastern hemisphere and involves ethnically different populations.² These populations overall have a lower incidence of cancers than Western populations, with the exception of Pakistan, which has a higher incidence of breast and other cancers.³ In their article, Assié et al¹ cite a study from Pakistan showing that inbreeding increases the risk of breast cancer. Among citizens of the United Arab Emirates, however, inbreeding seems to decrease the risk of several cancers, including breast cancer.⁴ Because this opposite result is from a distinct ethnic group, the risk differences may arise from different frequencies in different populations of the low-penetrance, tumor-susceptibility alleles that Assié et al propose as the main mechanism of increased cancer risk.

If LOH at a particular locus is carcinogenic (eg, involving a tumor suppressor allele), human inbreeding will decrease the odds of cancer because it decreases heterozygosity. In the offspring, inbreeding increases the probability of homozygosity of the wild-type allele. Homozygosity of a mutated cancer allele (and a cancerous phenotype) is unlikely because most homozygotes will die prematurely, as suggested by animal experiments for Brca1⁵ and by the lack of reports of cancerous human BRCA1 and BRCA2 homozygotes in spite of statistical odds to the contrary. Thus, at least 2 mechanisms that rely on increased homozygosis may be called into play in consanguineous populations to protect against cancer.