DNA damage repair gene germline profiling for metastatic prostate cancer patients of different ancestries

Abdi, Bilal; Basset, Noémie; Perrot, É; Benderra, Marc-Antoine; Khalil, Ahmed; Oudard, Stéphane; Blanchet, Pascal; Brureau, Laurent; Coulet, Florence; Cussenot, Olivier; Cancel‐Tassin, Géraldine

doi:10.1002/pros.24374

Cited by 4 publications

(5 citation statements)

References 31 publications

(86 reference statements)

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“…In a study of patients with metastatic PCa from Sweden, CHEK2 was also the most frequently germline mutated DNA repair gene (3.8%) highlighting the importance of CHEK2 mutations for aggressive PCa in the Nordic population. According to various reports including ours on the PROGENE study, germline CHEK2 mutations are found with a frequency between 0.5% and 2% in metastatic PCas [5].…”

Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

“…BRCA1 cannot be considered as a strong driver of PCa. Germline and somatic BRCA1 mutations are found in <1% of metastatic PCas [5].…”

Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

“…Estimation of the distribution of germline and tumour alterations for the most frequently mutated genes in patients with metastatic PCa, based on data reported in Abdi et al., 2022 [5], Mahal et al., 2020 [6] and Deek et al., 2021 [42] [41]. x ‐axis: gene; y ‐axis: average mutation frequency of the reported gene in patients with metastatic PCa.…”

Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

“…Due to the use of PSA testing and an ageing population, a large proportion of PCa is diagnosed at an early stage, which could lead to over-as well as under-treatment. The cause of this variability in disease progression is linked to the different genetic background related to family history and ancestry [4][5][6], but also to the genetic drift of the tumours themselves with various molecular profiles [7], combined or exclusive to each other [8]. The molecular typologies discovered in recent years, both in terms of germline and tumour genomics, define a taxonomy of PCas [9] that could be linked to different evolutionary profiles or therapeutic responses, introducing PCa to precision cancer medicine.…”

Section: Introductionmentioning

confidence: 99%

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Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

et al. 2023

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ObjectiveTo review the current status of germline and somatic (tumour) genetic testing for prostate cancer (PCa), and its relevance for clinical practice.MethodsA narrative synthesis of various molecular profiles related to their clinical context was carried out. Current guidelines for genetic testing and its feasibility in clinical practice were analysed. We report the main identified genetic sequencing results or functional genomic scores for PCa published in the literature or obtained from the French PROGENE study.ResultsThe molecular alterations observed in PCa are mostly linked to disruption of the androgen receptor (AR) pathway or DNA repair deficiency. The main known germline mutations affect the BReast CAncer gene 2 (BRCA2) and homeobox B13 (HOXB13) genes, whereas AR and tumour protein p53 (TP53) are the genes with most frequent somatic alterations in tumours from men with metastatic PCa. Molecular tests are now available for detecting some of these germline or somatic alterations and sometimes recommended by guidelines, but their utilisation must combine rationality and feasibility. They can guide specific therapies, notably for the management of metastatic disease. Indeed, following androgen deprivation, targeted therapies for PCa currently include poly‐(ADP‐ribose)‐polymerase (PARP) inhibitors, immune checkpoint inhibitors, and prostate‐specific membrane antigen (PSMA)‐guided radiotherapy. The genetic tests currently approved for targeted therapies remain limited to the detection of BRCA1 and BRCA2 mutation and DNA mismatch repair deficiency, while large panels are recommended for germline analyses, not only for inherited cancer predisposing syndrome, but also for metastatic PCa.ConclusionsFurther consensus aligning germline with somatic molecular analysis in metastatic PCa is required, including genomics scars, emergent immunohistochemistry, or functional pre‐screen imaging. With rapid advances in knowledge and technology in the field, continuous updating of guidelines to help the clinical management of these individuals, and well‐conducted studies to evaluate the benefits of genetic testing are needed.

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Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

“…BRCA1 cannot be considered as a strong driver of PCa. Germline and somatic BRCA1 mutations are found in <1% of metastatic PCas [5].…”

Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

Section: The Main Genetic Defects That Can Change Our Understanding O...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

et al. 2023

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“…Most patients are diagnosed with localized disease but a minority are diagnosed with metastatic disease or develop metastases later on [ 2 , 3 ]. Between 3 and 19% of patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a cancer predisposition gene [ 4 – 19 ]. The PVs in high-risk ( BRCA1 , BRCA2 , PALB2 ) or moderate-risk ( ATM , CHEK2 ) genes mainly associated with breast cancer in women follow an autosomal dominant inheritance pattern.…”

Section: Introductionmentioning

confidence: 99%

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives

Vlaming,

Ausems,

Schijven

et al. 2024

Familial Cancer

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Some patients with metastatic prostate cancer carry a pathogenic germline variant (PV) in a gene, that is mainly associated with an increased risk of breast cancer in women. If they test positive for such a PV, prostate cancer patients are encouraged to disclose the genetic test result to relatives who are at risk in case the carrier status changes the relatives’ medical care. Our study aimed to investigate how men who learned they carry a PV in BRCA1, BRCA2, PALB2, CHEK2 or ATM disclosed their carrier status to at-risk relatives and to assess the possible psychological burden for the carrier and their perception of the burden for relatives. In total, 23 men with metastatic prostate cancer carrying a PV completed the IRI questionnaire about family communication; 14 also participated in a semi-structured interview. Patients felt highly confident in discussing the genetic test result with relatives. The diagnosis of prostate cancer was experienced as a burden, whereas being informed about genetic testing results did in most cases not add to this burden. Two patients encountered negative experiences with family communication, as they considered the genetic test result to be more urgent than their relatives. This mixed-methods study shows that metastatic prostate cancer patients with a PV in genes mainly associated with increased risk of breast cancer feel well-equipped to communicate about this predisposition in their families. Carriers felt motivated to disclose their genetic test result to relatives. Most of them indicated that the disclosure was not experienced as a psychological burden.

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Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients

Cussenot,

Timms,

Perrot

et al. 2024

European Urology Oncology

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DNA damage repair gene germline profiling for metastatic prostate cancer patients of different ancestries

Cited by 4 publications

References 31 publications

Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

Aligning germline and somatic mutations in prostate cancer. Are genetics changing practice?

Men with metastatic prostate cancer carrying a pathogenic germline variant in breast cancer genes: disclosure of genetic test results to relatives

Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients

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