TP53 Variants and Prostate Cancer Risk Journal Club - Zachary Klaassen
March 23, 2023
In this UroToday Journal Club, Zachary Klaassen discusses "Inherited TP53 Variants and Risk of Prostate Cancer" comparing two cohorts: a Li-Fraumeni syndrome cohort of 163 men from 132 families and a prostate cancer cohort of 7,000 patients. This study aims to determine if gTP53 predisposes to prostate cancer, as there is no known association. Results showed that the incidence rate of prostate cancer in the Li-Fraumeni syndrome cohort was higher than that of the general population. The incidence rate of prostate cancer was 40 per 1000 in men aged 50 to 59 and 90 per 1000 in men aged 60 to 74, compared to 2 and 7.1, respectively, in the general population. A higher rate of germline pathogenic variants in the prostate cancer cohort compared to the general population was also found.
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Read the Full Video Transcript
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're discussing a recent publication entitled, Inherited TP53 Variants and Risk of Prostate Cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto, and joining me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication led by Dr. Maxwell and published in European Urology.
As most will know, prostate cancer is highly heritable, with 5-20% of cases associated with known and identified germline pathogenic variants. P53 pathogenic variants are known to cause Li-Fraumeni syndrome, which is characterized by early-onset, multiple primary cancers, with nearly all affected individuals having at least one cancer in their lifetime. However, there is substantial variability in the penetrance, and to date, there have been no documented associations between p53 and prostate cancer.
Patients with Li-Fraumeni are recommended to undergo extensive cancer screening as a result of the multitude of effects of p53 variants on underlying biology. And so starting in childhood, yearly full-body MRI, as well as brain imaging, targeted ultrasound, investigations for gastrointestinal and skin cancers, as well as breast cancer screening in women, is recommended. Further, we know that in these patients, there is an increased risk of secondary cancers associated with radiotherapy, and so typically surgical interventions are prioritized ahead of radiotherapy. In this context, it may be clear, therefore, that it would be important to understand the potential association between p53 variants or Li-Fraumeni syndrome in the risk of prostate cancer.
To assess this, the authors compared two cohorts, the first being a Li-Fraumeni cohort comprised of 163 men from 132 families across four databases of families with Li-Fraumeni from Dana-Farber, Huntsman, MSK, and the University of Pennsylvania. Patients were eligible if they were male, their age at last follow-up was at least 18 years, and had confirmatory genetic testing confirming Li-Fraumeni syndrome. In addition, the authors compiled a cohort of patients with prostate cancer, numbering just under 7,000, among four large cohorts of patients who had received tumor or tumor and germline sequencing. And in both cohorts, pedigrees were collected and the authors ensured that patients were not represented in both.
In terms of TP53 variant review, all variants were referenced using the ClinVar database and classified according to American College of Medical Genetics guidelines. The authors further subclassified patients as having full penetrance or attenuated variants, and the authors performed testing of ancillary tissues to exclude clonal hematopoiesis of indeterminate potential among patients in the TPS cohort. And then in the prostate cancer cohort, that did not have Li-Fraumeni syndrome, somatic interference was excluded through a variety of approaches, including restricting of variants with at least 35% variant fraction, a confirmation using both tumor and normal tissues, as well as the comparison of variant allele fractions with other observed variants.
In a subset of patients with the variants of TP53, next-generation sequencing was performed using either the UW-OncoPlex platform or MSK-IMPACT, and tumor data were analyzed by expert molecular pathologists to identify both somatic TP53 second allele inactivation, including loss of heterozygosity. The Li-Fraumeni syndrome cohort was restricted to those without a prostate cancer diagnosis at the time of genetic testing to allow for a calculation of the prostate cancer risk and incidence rates. The authors then assessed the standardized incidence rates of prostate cancer compared to the general population and used the SEER cohort to derive this general population risk. They calculated both overall and age-specific incidence rates. Summarization of the follow-up was performed using the reverse Kaplan-Meier estimation, and among the patients in the prostate cancer cohort, the relative risk of TP53 variants was compared using the Fisher's exact test.
At this point in time, I'm going to hand it over to Zach to walk us through the results.
Zachary Klaassen: Thanks, Chris. This table looks at the age distribution of men with prostate cancer in the Li-Fraumeni syndrome cohort. You can see here that this is not that much different than a regular prostate cancer cohort, and that the most common ages were 50 to 59 and 60 to 69 years of age, as well as a few men in their thirties and forties.
This table looks at the annual prostate cancer incidence rates per 1000 in the Li-Fraumeni syndrome cohort, as well as the SEER Registry, which serves as a reflection of the general population. This is where we see some interesting findings. You can see the rate per 1000 for men 0 to 49 years of age at 3.9, compared to 0.05 in SEER. With regards to men that were 50 to 59, 40 per 1000, compared to only 2 per 1000 in SEER, and again, in 60 to 74, 90 per 1000, compared to a 7.10. So, certainly, a higher incidence rate compared to the general population.
This is, again, more of a figure reflecting the prostate cancer incidence in these males compared to the SEER population. We can see here, again, this increase with the Li-Fraumeni syndrome patients in gray compared to SEER, with a remarkably higher incidence rate per 1000 person-years.
This table looks at the germline and pathogenic variants in the prostate cancer cohort, compared with the general population. You can see here, this is broken down by the four prostate cancer cohorts, with relative rates compared to the general population of 11, 14, 4.5, 6.6, and combined relative risk of 9.1 in the prostate cancer population for p53 germline mutation, compared to the general population.
This table looks at the characteristics of 67 prostate cancer patients with confirmed germline p53. On the right is the prostate cancer cohort, and on the left is the Li-Fraumeni syndrome cohort. And we can see here that there were 31 patients in the LFS cohort and 36 in the prostate cancer cohort. The median age for both of these cohorts was 56 years of age. When we look at the personal history of cancer, 35% of patients did not have a history of cancer in the LFS cohort and 42% in the prostate cancer cohort. Most commonly, as you can see here, was sarcoma, 26% personal history in the LFS cohort, and 8.3% in the prostate cancer cohort.
When looking at a family history of cancer, most commonly it was breast cancer, 68% in the LFS cohort and 46% in the prostate cancer cohort. the family history of prostate cancer, interestingly, was 29% in the LFS cohort and 31% in the prostate cancer cohort. With regards to Gleason score, quite comparable between the two cohorts, about 50/50 for Gleason 6 to 7, and Gleason 8 to 10. The median PSA, not much different than the usual population of PSA of 6 from both cohorts, and the majority of these were found on screening for prostate cancer. With regards to the stage of diagnosis, 81% localized in the LFS cohort and 54 in the prostate cancer cohort, compared to N1 or de novo M1 at 19% in the LFS cohort and 46% in the prostate cancer cohort.
This lollipop figure looks at the distribution of TP53 pathogenic and likely pathogenic variants. You can see the most common was R181C/H. And the take-home message from this figure is that these five codons were associated with attenuated variants, accounting for 28 of 67 cases of prostate cancer, working out to 42% of the cases.
This is a nice summary slide that the authors put together looking at the results. You can see in the top left here, prostate cancer incidence, 25-fold higher incidence of prostate cancer compared to SEER in those patients with germline p53 mutations. With regard to variant prevalence, 0.6% with prostate cancer in the study have germline p53, with a 9x elevated risk. With regard to tumor features in the bottom left, high grade and stage, 44% Gleason equal to or greater than 8, and 29% with advanced or metastatic disease with two-thirds of the tumors having a second allele inactivation. Within terms of the variant spectrum, as we just discussed, there were several hotspots at sites of non-classical LFS, as we mentioned, the p.R181H/C. So, in conclusion, from this slide, p53 is in fact a prostate cancer risk gene.
Several discussion points from this study are of note. Li-Fraumeni syndrome men had a 25-fold increased risk of prostate cancer compared to the general population, with a further 0.55% of men with prostate cancer in a large sequencing cohort having a germline p53 mutation. Over half of these germline p53 mutation variants were considered attenuated or hypomorphic variants, not typically associated with classical Li-Fraumeni syndrome. In the prostate cancer sequencing cohort, the relative risk of carrying a germline p53 variant was comparable to that of BRCA2, a gene for which prostate cancer screening recommendations are recommended and are modified based on their genetic risk factors. So taken together, this argues for consideration of prostate cancer screening in the Li-Fraumeni syndrome guidelines.
So in conclusion, this study contributes to a greater understanding of p53-associated cancer risk, demonstrating that adult cancer, such as prostate cancer, in Li-Fraumeni syndrome are understudied and merit further attention. The attenuator or hypomorphic germline p53 alleles provide a plausible hypothesis as to why some germline p53 patients develop late adulthood cancers that would not have been appreciated previously in those with more severe germline p53 variants that predispose a high cancer burden and earlier mortality. Taken together, screening guidelines for adults with attenuated LFS phenotypes are needed urgently. This study also suggests that the current LFS screening guidelines should be updated to consider annual prostate cancer screening in men with at least 10 years of life expectancy. While germline p53 mutation rates are low in prostate cancer cohorts, the clinical importance of the finding for the patient and family is significant. And finally, the authors suggest that evaluation of p53 in germline genetic testing in prostate cancer patients should be performed ideally by paired tumor-normal testing to rule out somatic interference.
Thank you very much for your attention, and we hope you enjoyed this UroToday Journal Club Discussion.
Christopher Wallis: Hello, and thank you for joining us for this UroToday Journal Club discussion. Today, we're discussing a recent publication entitled, Inherited TP53 Variants and Risk of Prostate Cancer. I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto, and joining me today is Zach Klaassen, an Assistant Professor in the Division of Urology at the Medical College of Georgia. This is the citation for this recent publication led by Dr. Maxwell and published in European Urology.
As most will know, prostate cancer is highly heritable, with 5-20% of cases associated with known and identified germline pathogenic variants. P53 pathogenic variants are known to cause Li-Fraumeni syndrome, which is characterized by early-onset, multiple primary cancers, with nearly all affected individuals having at least one cancer in their lifetime. However, there is substantial variability in the penetrance, and to date, there have been no documented associations between p53 and prostate cancer.
Patients with Li-Fraumeni are recommended to undergo extensive cancer screening as a result of the multitude of effects of p53 variants on underlying biology. And so starting in childhood, yearly full-body MRI, as well as brain imaging, targeted ultrasound, investigations for gastrointestinal and skin cancers, as well as breast cancer screening in women, is recommended. Further, we know that in these patients, there is an increased risk of secondary cancers associated with radiotherapy, and so typically surgical interventions are prioritized ahead of radiotherapy. In this context, it may be clear, therefore, that it would be important to understand the potential association between p53 variants or Li-Fraumeni syndrome in the risk of prostate cancer.
To assess this, the authors compared two cohorts, the first being a Li-Fraumeni cohort comprised of 163 men from 132 families across four databases of families with Li-Fraumeni from Dana-Farber, Huntsman, MSK, and the University of Pennsylvania. Patients were eligible if they were male, their age at last follow-up was at least 18 years, and had confirmatory genetic testing confirming Li-Fraumeni syndrome. In addition, the authors compiled a cohort of patients with prostate cancer, numbering just under 7,000, among four large cohorts of patients who had received tumor or tumor and germline sequencing. And in both cohorts, pedigrees were collected and the authors ensured that patients were not represented in both.
In terms of TP53 variant review, all variants were referenced using the ClinVar database and classified according to American College of Medical Genetics guidelines. The authors further subclassified patients as having full penetrance or attenuated variants, and the authors performed testing of ancillary tissues to exclude clonal hematopoiesis of indeterminate potential among patients in the TPS cohort. And then in the prostate cancer cohort, that did not have Li-Fraumeni syndrome, somatic interference was excluded through a variety of approaches, including restricting of variants with at least 35% variant fraction, a confirmation using both tumor and normal tissues, as well as the comparison of variant allele fractions with other observed variants.
In a subset of patients with the variants of TP53, next-generation sequencing was performed using either the UW-OncoPlex platform or MSK-IMPACT, and tumor data were analyzed by expert molecular pathologists to identify both somatic TP53 second allele inactivation, including loss of heterozygosity. The Li-Fraumeni syndrome cohort was restricted to those without a prostate cancer diagnosis at the time of genetic testing to allow for a calculation of the prostate cancer risk and incidence rates. The authors then assessed the standardized incidence rates of prostate cancer compared to the general population and used the SEER cohort to derive this general population risk. They calculated both overall and age-specific incidence rates. Summarization of the follow-up was performed using the reverse Kaplan-Meier estimation, and among the patients in the prostate cancer cohort, the relative risk of TP53 variants was compared using the Fisher's exact test.
At this point in time, I'm going to hand it over to Zach to walk us through the results.
Zachary Klaassen: Thanks, Chris. This table looks at the age distribution of men with prostate cancer in the Li-Fraumeni syndrome cohort. You can see here that this is not that much different than a regular prostate cancer cohort, and that the most common ages were 50 to 59 and 60 to 69 years of age, as well as a few men in their thirties and forties.
This table looks at the annual prostate cancer incidence rates per 1000 in the Li-Fraumeni syndrome cohort, as well as the SEER Registry, which serves as a reflection of the general population. This is where we see some interesting findings. You can see the rate per 1000 for men 0 to 49 years of age at 3.9, compared to 0.05 in SEER. With regards to men that were 50 to 59, 40 per 1000, compared to only 2 per 1000 in SEER, and again, in 60 to 74, 90 per 1000, compared to a 7.10. So, certainly, a higher incidence rate compared to the general population.
This is, again, more of a figure reflecting the prostate cancer incidence in these males compared to the SEER population. We can see here, again, this increase with the Li-Fraumeni syndrome patients in gray compared to SEER, with a remarkably higher incidence rate per 1000 person-years.
This table looks at the germline and pathogenic variants in the prostate cancer cohort, compared with the general population. You can see here, this is broken down by the four prostate cancer cohorts, with relative rates compared to the general population of 11, 14, 4.5, 6.6, and combined relative risk of 9.1 in the prostate cancer population for p53 germline mutation, compared to the general population.
This table looks at the characteristics of 67 prostate cancer patients with confirmed germline p53. On the right is the prostate cancer cohort, and on the left is the Li-Fraumeni syndrome cohort. And we can see here that there were 31 patients in the LFS cohort and 36 in the prostate cancer cohort. The median age for both of these cohorts was 56 years of age. When we look at the personal history of cancer, 35% of patients did not have a history of cancer in the LFS cohort and 42% in the prostate cancer cohort. Most commonly, as you can see here, was sarcoma, 26% personal history in the LFS cohort, and 8.3% in the prostate cancer cohort.
When looking at a family history of cancer, most commonly it was breast cancer, 68% in the LFS cohort and 46% in the prostate cancer cohort. the family history of prostate cancer, interestingly, was 29% in the LFS cohort and 31% in the prostate cancer cohort. With regards to Gleason score, quite comparable between the two cohorts, about 50/50 for Gleason 6 to 7, and Gleason 8 to 10. The median PSA, not much different than the usual population of PSA of 6 from both cohorts, and the majority of these were found on screening for prostate cancer. With regards to the stage of diagnosis, 81% localized in the LFS cohort and 54 in the prostate cancer cohort, compared to N1 or de novo M1 at 19% in the LFS cohort and 46% in the prostate cancer cohort.
This lollipop figure looks at the distribution of TP53 pathogenic and likely pathogenic variants. You can see the most common was R181C/H. And the take-home message from this figure is that these five codons were associated with attenuated variants, accounting for 28 of 67 cases of prostate cancer, working out to 42% of the cases.
This is a nice summary slide that the authors put together looking at the results. You can see in the top left here, prostate cancer incidence, 25-fold higher incidence of prostate cancer compared to SEER in those patients with germline p53 mutations. With regard to variant prevalence, 0.6% with prostate cancer in the study have germline p53, with a 9x elevated risk. With regard to tumor features in the bottom left, high grade and stage, 44% Gleason equal to or greater than 8, and 29% with advanced or metastatic disease with two-thirds of the tumors having a second allele inactivation. Within terms of the variant spectrum, as we just discussed, there were several hotspots at sites of non-classical LFS, as we mentioned, the p.R181H/C. So, in conclusion, from this slide, p53 is in fact a prostate cancer risk gene.
Several discussion points from this study are of note. Li-Fraumeni syndrome men had a 25-fold increased risk of prostate cancer compared to the general population, with a further 0.55% of men with prostate cancer in a large sequencing cohort having a germline p53 mutation. Over half of these germline p53 mutation variants were considered attenuated or hypomorphic variants, not typically associated with classical Li-Fraumeni syndrome. In the prostate cancer sequencing cohort, the relative risk of carrying a germline p53 variant was comparable to that of BRCA2, a gene for which prostate cancer screening recommendations are recommended and are modified based on their genetic risk factors. So taken together, this argues for consideration of prostate cancer screening in the Li-Fraumeni syndrome guidelines.
So in conclusion, this study contributes to a greater understanding of p53-associated cancer risk, demonstrating that adult cancer, such as prostate cancer, in Li-Fraumeni syndrome are understudied and merit further attention. The attenuator or hypomorphic germline p53 alleles provide a plausible hypothesis as to why some germline p53 patients develop late adulthood cancers that would not have been appreciated previously in those with more severe germline p53 variants that predispose a high cancer burden and earlier mortality. Taken together, screening guidelines for adults with attenuated LFS phenotypes are needed urgently. This study also suggests that the current LFS screening guidelines should be updated to consider annual prostate cancer screening in men with at least 10 years of life expectancy. While germline p53 mutation rates are low in prostate cancer cohorts, the clinical importance of the finding for the patient and family is significant. And finally, the authors suggest that evaluation of p53 in germline genetic testing in prostate cancer patients should be performed ideally by paired tumor-normal testing to rule out somatic interference.
Thank you very much for your attention, and we hope you enjoyed this UroToday Journal Club Discussion.