In this study, we used a population-based series of cases and applied extensive direct sequencing to estimate the contribution of germline TP53 mutations to two subgroups of early-onset breast cancer likely enriched for genetic causes, and found that 5 of 94 tested cases were carriers (5%; 95% CI, 2–12%). That is, germline mutations in TP53 might play a larger role in breast cancer than previously thought. Our study also showed that, in the context of early-onset beast cancer, TP53 mutation carriers can be evident outside the traditional clinically defined Li-Fraumeni family syndrome.
Few studies have tested for germline TP53
mutations in women with breast cancer outside the context of pedigrees meeting Li-Fraumeni criteria (6
), and only one using population-based sampling (27
). For example, although Walsh and colleagues (28
) selected a clinic-based series of 300 women with breast cancer and four or more relatives with breast or ovarian cancer, they tested for germline mutations in TP53
only for 31 families, with 10 meeting C-LF or LF-L criteria and 21 with at least two cases of breast cancer diagnosed before the age of 35 years. They found three carrier families, two with CL-F syndrome and one with LF-L syndrome. Similarly, Gonzalez and colleagues (29
) tested for TP53
germline mutations in 525 women submitted for diagnostic testing without specifying the ascertainment criteria. They found that 95% of mutation carriers who had family history recorded met either the CL-F syndrome or the LF-C criteria. Due to their study design, however, neither of these studies can address the prevalence of mutations in women from families not meeting clinical CL-F, LF-L, or LF-C criteria.
On the other hand, and similar to our study, Lalloo and colleagues (27
) tested 100 women from the United Kingdom with very early onset breast cancer diagnosed at age 30 years or younger, unselected for family history, and found a TP53
mutation prevalence of 4% (95% CI, 1.1–10%). Two case carriers met the study’s definition for “familial breast cancer” and both fulfilled the CL-F or LF-L criteria. The other two case carriers had no family history of breast or ovarian cancer and did not meet either the CL-F or the LF-L criteria.
The finding of TP53
mutation carriers outside of the definition of CL-F, LF-L, and LF-C syndrome might in part be due to more extensive TP53
mutation screening. Lalloo and colleagues (27
) performed direct sequencing of 10 coding exons, splice site junctions, and the promoter region of TP53
). We conducted extensive sequencing of the TP53
region (≈4,500 bp) with determination of whether the PCR products represented both copies of the gene.
Our findings are reliable because subjects were drawn from a population-based source with a thorough method for collecting family history. The ABCFS collection of family cancer history included asking relatives about their personal and family history. This enabled us to categorize pedigrees according to the C-LF, LF-L, and LF-C criteria using any affected individual as the “index” case, thereby increasing the likelihood of identifying pedigrees meeting the criteria. For each of the cases in our study with a germline TP53 mutation, four generations of pedigree information were available for review. Thus, we are confident that we did not under-categorize pedigrees into meeting Li-Fraumeni criteria.
Whereas our previous work had identified that 20% of these cases carried a disease-predisposing mutation in a known breast cancer susceptibility gene, we have now found that an additional 5% carried a pathogenic mutation in TP53. Therefore, almost as many cases in these targeted subgroups are caused by TP53 mutations as they are by mutations in BRCA2. Yet, even within the EO-FH group, less than 30% could be attributed to known mutations in BRCA1, BRCA2, CHEK2, ATM, or TP53. Thus, whereas TP53 might contribute to early-onset breast cancer more so than previously thought, a large proportion of early-onset breast cancer—even within multiple-case families—is due to genetic mutations in yet to be identified genes or mutations in known genes that current methods do not detect.
Our work and that of others suggest that TP53
mutation testing for subgroups of families with early-onset breast cancer might be warranted (27
). Future work could refine the use of clinical TP53
germline testing for pedigrees not fitting the current Li-Fraumeni criteria and incorporate factors such as age of onset of breast cancer and tumor histology.