The risk of prostate cancer in men with LFS is 25 times that of the general population!

Recently, a study found that men with Li-Fraumeni syndrome (LFS) have a risk of prostate cancer 25 times that of the general population.
For the first time, the study found that gTP53 mutations are significantly associated with the risk of prostate cancer
.

The results were published in European Urology magazine
.

Prostate cancer is associated with germline mutations in susceptibility genes.
Prostate cancer is a highly hereditary disease
.

Recent studies have shown that about 5% to 20% of prostate cancer patients are associated with germline mutations in recognized cancer susceptibility genes, such as BRCA2 and ATM
.

Germline TP53 pathogenic mutation (gTP53) is associated with an autosomal dominant genetic disease LFS
.

Typical LFS patients are characterized by early-onset, multiple primary cancers, and almost universally develop at least one cancer in their lifetime
.

There is no literature to prove the correlation between prostate cancer and gTP53 mutation
.

An International Agency for Research on Cancer (IARC) database report on TP53 shows that only 1.
7% of patients with gTP53 mutations have prostate cancer, which is much lower than the lifetime risk of prostate cancer (14%) for ordinary American men
.

However, this analysis is misleading because the database is heavily biased towards young men rather than men who are associated with typical prostate cancer risk
.

LFS patients require extensive cancer screening.
Guidelines usually recommend extensive cancer screenings for LFS patients from childhood, such as annual whole-body magnetic resonance imaging (MRI), brain imaging, targeted ultrasound, gastrointestinal and skin tumor assessments And women breast screening
.

Therefore, LFS should be considered in the tumor treatment plan
.

The current cancer screening for patients with LFS does not include prostate cancer
.

Moreover, the current treatment plan for prostate cancer does not consider the impact of gTP53 mutation status
.

Research Method This is a multi-center retrospective study that explored the correlation between the risk of prostate cancer in men with LFS and the incidence of gTP53 mutations
.

The LFS cohort (n=163 men from 132 families) came from the four LFS family databases of Dana Farber Cancer Institute, Huntsman Cancer Institute, Memorial Sloan Kettering Cancer Center, and University of Pennsylvania
.

A dataset of four families diagnosed with LFS
.

LFS family entry criteria: 1) male, 2) the last follow-up age is 18 years old, 3) genetic testing confirmed gTP53 heterozygosity or obligate carrier (obligate carrier)
.

The prostate cancer cohort (n=6850) was composed of four databases of prostate cancer patients who had undergone tumor tissue or germline sequencing
.

Main findings The study on the incidence of prostate cancer in the LFS population finally included 163 men ≥18 years of age, gTP53 pathogenic mutations, or gTP53 positive carriers (Figure 1)
.

Figure 1 Summary of results The study found that the incidence of prostate cancer was 19% (31/163), including 48% (26/54) of patients ≥50 years of age (Table 1)
.

In a restricted analysis of 117 patients who did not develop prostate cancer at the time of genetic testing, 6 patients were diagnosed with prostate cancer after a period of time (median follow-up of 3 months).
This subgroup of LFS patients was diagnosed with prostate cancer.
The risk is 25 times that of the general population (P<0.
0001), and the incidence of prostate cancer increases in all age groups (Figure 1, Table 2)
.

Table 1 The age distribution of prostate cancer in the LFS cohort Table 2 The incidence of prostate cancer in the LFS cohort and the SEER database The incidence of gTP53 mutations in prostate cancer The analysis of 6850 prostate cancer patients from four large data showed that the incidence of gTP53 mutations was 0.
55% ( 0.
27%~ 0.
84%)
.

Compared with the gnomAD non-cancer population database, the relative risk of gTP53 was significantly higher by 9.
1 (P<0.
0001) (Figure 1)
.

Clinicopathological characteristics of gTP53 carriers in prostate cancer patients Table 3 Characteristics of 67 cases of gTP53 mutant prostate cancer The median age of gTP53 mutant prostate cancer patients is 56 years (Table 3)
.

In the total cohort, 55% of patients had a family history of LFS, and only 26% of patients did not meet any of the diagnostic criteria for LFS
.

Almost all patients have a family history of cancer, 30% have a family history of prostate cancer, and 61% have a family history of breast cancer
.

Among men with LFS, prostate cancer is the only and most commonly found cancer (58%, 18/31)
.

Among prostate cancer patients, 29% have locally advanced (N1) or new metastatic disease
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44% of patients with gTP53 mutations have higher grades (Gleason score ≥8, Figure 1)
.

When prostate cancer was diagnosed, the prostate cancer specific antigen (PSA) ranged from 1.
1 to 171ng/dl, 68% of patients were screened to find prostate cancer, and 3 patients (50, 51, 63) had advanced symptoms ( Gleason score 9~10) Prostate cancer is found
.

Conclusion The study found that the risk of prostate cancer in men with LFS is 25 times that of the general population.
For the first time, the study found that gTP53 mutations are significantly associated with the risk of prostate cancer
.

Studies suggest that gTP53 pathogenic mutations may indicate aggressive prostate cancer.
Prostate cancer should be considered for LFS screening, and TP53 should be considered for prostate cancer susceptible germline genetic testing
.

Reference: KN Maxwell, HH Cheng, J.
Powers et al.
, Inherited TP53 Variants and Risk of Prostate Cancer, Eur Urol (2021), https://doi.
org/ 10.
1016/j.
eururo.
2021.
10.
036 ：Tougao@medlive.
cn