The discovery of the BRCA genes (BRCA1 and BRCA2) 20 years ago heralded a new era in cancer prevention. For the first time, it was possible to potentially glimpse the future to avoid cancer. However, only about half of the strong hereditary breast and ovarian cancer family histories were attributable to mutations in these two genes. Researchers, clinicians, and patients alike started searching for another explanation.
And so the hunt for “BRCA3” began. Five years of research culminated in the identification of a gene that was previously associated with the cell cycle—specifically CHEK2. It was discovered in families with many different and young cancers, suggestive of Li-Fraumeni syndrome (LFS), but where no molecular cause could be identified. These families were negative for p53 mutations (p53 is the gene that controls when cells divide), and some of these families were found to have CHEK2 mutations.
Because LFS families have cancer types that overlap with those from BRCA-positive families, expectations were high that CHEK2 would be the answer to the elusive hereditary breast cancers not explained by BRCA. However, after its discovered association with inherited cancer, CHEK2 appeared to raise more questions than it answered: It explained only a small portion of LFS family histories1,2 and accounted for almost no hereditary breast and ovarian cancer family histories,3 and, more concerning, a particular mutation (1100delC) appeared to be relatively common in certain ancestries and even in unaffected women.4 In the age of expensive, sequential genetic testing, CHEK2 fell out of favor, with experts recommending against using it clinically.5
However, some clinicians and researchers persevered and, over the last decade, population-based, case-control, and family studies firmly established CHEK2 as an inherited cancer predisposition gene. The link between CHEK2 and hereditary breast cancer was confirmed by studies that show absence of the protein product in breast tumors from patients with germline CHEK2 mutations.6,7,8,9 A previously suggested association between prostate cancer and CHEK2 was also confirmed,10,11,12 but CHEK2’s role in hereditary ovarian cancer was disproven, which effectively eliminated its candidacy as “BRCA3.”13,14 A suspected link to colon cancer remains controversial.15,16,17,18,19
Additionally, there are indications that bladder, lung, pancreas, melanoma, and some hematologic malignancies (non-Hodgkin’s lymphoma and acute myeloid leukemia) and other hematologic abnormalities such as myelodysplastic syndromes may be associated with CHEK2 mutations.20,21
Today’s plummeting cost of genetic testing has enabled broader testing than ever before (in the form of multi-gene cancer-predisposition panels). This increased testing has cemented CHEK2’s role in hereditary cancer by consistently identifying mutations in this gene in patients with certain types of cancer.22,23,24
Many CHEK2 mutations are found in family histories where suspicion for the mutation is low, which has been surprising to some and expected to others. By virtue of its very role (a kinase that is activated in response to DNA damage25), CHEK2 should be responsible for a variety of hereditary cancers. This indeed appears to be the case, as breast, bilateral breast, prostate, and colon cancers are all associated with CHEK2 mutations in various studies.
The CHEK2 journey, which began as a hopeful finding, was followed by a tenuous road back to legitimacy, and finally culminated a decade later in a clear role for CHEK2 in the inherited-cancer gene arsenal. This story illustrates how genetic testing with larger panels continues to improve our understanding of the genetics behind many common diseases.
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