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Prostate cancer is a highly hereditary cancer, and it is estimated that about 40% to 50% of prostate cancers are related to genetic factors
.
Germline mutations in multiple DNA damage repair genes have been demonstrated to be associated with genetic susceptibility to prostate cancer
.
DNA damage repair genes represented by BRCA1 and BRCA2 are the most well-recognized prostate cancer susceptibility genes so far, other DNA damage repair genes such as ATM, PALB2, CHEK2 and mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) It is also thought to be associated with an increased risk of prostate cancer
.
Other genes that may be associated with hereditary prostate cancer include genes such as HOXB13
.
Germline mutations in the above susceptibility genes not only lead to an increased risk of prostate cancer, but also make prostate cancer have unique clinicopathological phenotypes, such as early age of onset, familial aggregation, strong invasiveness, and poor prognosis
.
At the same time, germline mutations in the above susceptibility genes are also drug targets, so the clinical management strategy of familial prostate cancer is quite different from that of sporadic prostate cancer
.
DNA damage repair gene germline mutation in prostate cancer Although the frequency of DNA damage repair gene germline mutation in limited-stage prostate cancer is low (4.
6%), in metastatic prostate cancer, it is as high as 11.
8% (82/692) of patients Carry germline mutations in DNA damage repair genes, including BRCA2 (mutation rate 5.
3%), ATM (mutation rate 1.
6%), CHEK2 (mutation rate 1.
9%), BRCA1 (mutation rate 0.
9%), RAD51D (mutation rate 0.
4%) and PALB2 (mutation rate 0.
4%)
.
Pathogenic germline mutations in these genes are not only strongly associated with increased risk of prostate cancer in men, but also with rapid tumor progression and poor prognosis
.
Prostate cancer with germline mutations in other genes Some studies have found that healthy men with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) have a 2-5 times higher risk of prostate cancer than non-carriers
.
However, the frequency of germline mutations in mismatch repair genes is low in prostate cancer
.
Domestic research data showed that the pathogenic germline mutation rates of MSH6 and MSH2 genes in 316 cases of prostate cancer were both 0.
63% (1/316), and no patients with germline pathogenic mutations of MLH1 and PMS2 genes were found
.
Previous studies on the Caucasian population have found HOXB13 gene mutations (mainly G84E) in familial prostate cancer patients, but based on research data from the China Prostate Cancer Genetics Consortium, after testing 671 Chinese patients, it was found that only There were 3 cases with HOXB13 mutation, and the mutation hotspot was G135E, which was inconsistent with the Caucasian population
.
This mutation is only valuable for tumor risk assessment in immediate family members
.
Opinions of the Risk Assessment and Genetic Testing Expert Group: It is recommended that the genetically high-risk population of prostate cancer who meets any of the following conditions consider germline mutation testing of DNA damage repair genes, including BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, etc.
Genes: 1) Known family members carry pathogenic mutations in the above genes
.
2) There is a clear family history of tumors, and there are multiple cases in the same family including bile duct cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, kidney cancer, melanoma, small bowel cancer and Patients with urothelial cancer, especially if they were diagnosed ≤50 years old; and had a brother, father, or other family member diagnosed with or died of prostate cancer before the age of 60
.
3) Suspicious or unknown family history, recommended after full genetic counseling and evaluation
.
4) The pathogenic mutations of the above genes were found in the tumor tissue test, but the germline verification was not carried out
.
5) Intraductal carcinoma and ductal adenocarcinoma
.
6) High risk and above, locally advanced and metastatic prostate cancer
.
In addition, prostate cancer patients with a clear family history of tumors are recommended to consider the HOXB13 gene germline mutation detection; it is recommended to use the next-generation sequencing method to simultaneously perform germline mutation detection on multiple prostate cancer susceptibility genes
.
Treatment strategies The treatment methods of prostate cancer mainly include surgery (radical prostatectomy), radiotherapy, endocrine therapy, chemotherapy, targeted therapy and immunotherapy
.
Hereditary prostate cancer is not much different from sporadic prostate cancer in terms of surgery, radiotherapy and endocrine therapy, while hereditary prostate cancer has a highly unstable genome due to germline mutations in DNA damage repair genes.
It is sensitive to inhibitors and immunotherapy, so this consensus will focus on specific treatment strategies for hereditary prostate cancer
.
1.
Platinum-based chemotherapy Expert group opinion: The efficacy of platinum-based drugs on hereditary prostate cancer is not yet sufficient, and further research is needed
.
2.
Opinions of the expert group on poly(ADP-ribose) polymerase inhibitor (PARPi) targeted therapy: It is recommended that mCRPC patients undergo homologous recombination repair gene germline mutation testing, and patients with positive mutations are preferentially treated with PARP inhibitors
.
3.
Opinion of the immunotherapy expert group: It is recommended that mCRPC patients undergo dMMR or MSI-H testing.
If MSI-H or dMMR type is diagnosed, pembrolizumab treatment can be considered, and further genetic counseling and MMR gene germline can be considered Mutation detection
.
Opinion of the family management expert group: It is recommended that healthy males with BRCA1/2 mutations start PSA screening and digital anorectal examination from the age of 40, and mpMRI is recommended for carriers >55 years old with elevated PSA
.
References: [1].
Expert consensus on clinical diagnosis and treatment of familial hereditary tumors in China (2021 edition) (7)—familial hereditary prostate cancer [J].
China Clinical Oncology, 2022, 49(02): 59-63.
Review School: XY Typesetting: LR Execution: LR
.
Germline mutations in multiple DNA damage repair genes have been demonstrated to be associated with genetic susceptibility to prostate cancer
.
DNA damage repair genes represented by BRCA1 and BRCA2 are the most well-recognized prostate cancer susceptibility genes so far, other DNA damage repair genes such as ATM, PALB2, CHEK2 and mismatch repair genes (MLH1, MSH2, MSH6 and PMS2) It is also thought to be associated with an increased risk of prostate cancer
.
Other genes that may be associated with hereditary prostate cancer include genes such as HOXB13
.
Germline mutations in the above susceptibility genes not only lead to an increased risk of prostate cancer, but also make prostate cancer have unique clinicopathological phenotypes, such as early age of onset, familial aggregation, strong invasiveness, and poor prognosis
.
At the same time, germline mutations in the above susceptibility genes are also drug targets, so the clinical management strategy of familial prostate cancer is quite different from that of sporadic prostate cancer
.
DNA damage repair gene germline mutation in prostate cancer Although the frequency of DNA damage repair gene germline mutation in limited-stage prostate cancer is low (4.
6%), in metastatic prostate cancer, it is as high as 11.
8% (82/692) of patients Carry germline mutations in DNA damage repair genes, including BRCA2 (mutation rate 5.
3%), ATM (mutation rate 1.
6%), CHEK2 (mutation rate 1.
9%), BRCA1 (mutation rate 0.
9%), RAD51D (mutation rate 0.
4%) and PALB2 (mutation rate 0.
4%)
.
Pathogenic germline mutations in these genes are not only strongly associated with increased risk of prostate cancer in men, but also with rapid tumor progression and poor prognosis
.
Prostate cancer with germline mutations in other genes Some studies have found that healthy men with germline mutations in mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) have a 2-5 times higher risk of prostate cancer than non-carriers
.
However, the frequency of germline mutations in mismatch repair genes is low in prostate cancer
.
Domestic research data showed that the pathogenic germline mutation rates of MSH6 and MSH2 genes in 316 cases of prostate cancer were both 0.
63% (1/316), and no patients with germline pathogenic mutations of MLH1 and PMS2 genes were found
.
Previous studies on the Caucasian population have found HOXB13 gene mutations (mainly G84E) in familial prostate cancer patients, but based on research data from the China Prostate Cancer Genetics Consortium, after testing 671 Chinese patients, it was found that only There were 3 cases with HOXB13 mutation, and the mutation hotspot was G135E, which was inconsistent with the Caucasian population
.
This mutation is only valuable for tumor risk assessment in immediate family members
.
Opinions of the Risk Assessment and Genetic Testing Expert Group: It is recommended that the genetically high-risk population of prostate cancer who meets any of the following conditions consider germline mutation testing of DNA damage repair genes, including BRCA2, BRCA1, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, PMS2, etc.
Genes: 1) Known family members carry pathogenic mutations in the above genes
.
2) There is a clear family history of tumors, and there are multiple cases in the same family including bile duct cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, endometrial cancer, gastric cancer, kidney cancer, melanoma, small bowel cancer and Patients with urothelial cancer, especially if they were diagnosed ≤50 years old; and had a brother, father, or other family member diagnosed with or died of prostate cancer before the age of 60
.
3) Suspicious or unknown family history, recommended after full genetic counseling and evaluation
.
4) The pathogenic mutations of the above genes were found in the tumor tissue test, but the germline verification was not carried out
.
5) Intraductal carcinoma and ductal adenocarcinoma
.
6) High risk and above, locally advanced and metastatic prostate cancer
.
In addition, prostate cancer patients with a clear family history of tumors are recommended to consider the HOXB13 gene germline mutation detection; it is recommended to use the next-generation sequencing method to simultaneously perform germline mutation detection on multiple prostate cancer susceptibility genes
.
Treatment strategies The treatment methods of prostate cancer mainly include surgery (radical prostatectomy), radiotherapy, endocrine therapy, chemotherapy, targeted therapy and immunotherapy
.
Hereditary prostate cancer is not much different from sporadic prostate cancer in terms of surgery, radiotherapy and endocrine therapy, while hereditary prostate cancer has a highly unstable genome due to germline mutations in DNA damage repair genes.
It is sensitive to inhibitors and immunotherapy, so this consensus will focus on specific treatment strategies for hereditary prostate cancer
.
1.
Platinum-based chemotherapy Expert group opinion: The efficacy of platinum-based drugs on hereditary prostate cancer is not yet sufficient, and further research is needed
.
2.
Opinions of the expert group on poly(ADP-ribose) polymerase inhibitor (PARPi) targeted therapy: It is recommended that mCRPC patients undergo homologous recombination repair gene germline mutation testing, and patients with positive mutations are preferentially treated with PARP inhibitors
.
3.
Opinion of the immunotherapy expert group: It is recommended that mCRPC patients undergo dMMR or MSI-H testing.
If MSI-H or dMMR type is diagnosed, pembrolizumab treatment can be considered, and further genetic counseling and MMR gene germline can be considered Mutation detection
.
Opinion of the family management expert group: It is recommended that healthy males with BRCA1/2 mutations start PSA screening and digital anorectal examination from the age of 40, and mpMRI is recommended for carriers >55 years old with elevated PSA
.
References: [1].
Expert consensus on clinical diagnosis and treatment of familial hereditary tumors in China (2021 edition) (7)—familial hereditary prostate cancer [J].
China Clinical Oncology, 2022, 49(02): 59-63.
Review School: XY Typesetting: LR Execution: LR
