Acta Oncol. 2016 Jan;55(1):38-44. doi: 10.3109/0284186X.2015.1067714.
Increased risk of male cancer and identification of a potential prostate cancer cluster region in BRCA2.
Roed Nielsen H1, Petersen J2,3, Therkildsen C2, Skytte AB4, Nilbert M2,5.
- 1a Department of Clinical Genetics , Vejle Hospital , Denmark.
- 2b HNPCC Register, Clinical Research Center, Copenhagen University Hospital , Hvidovre , Denmark.
- 3c Department of Biostatistics , University of Copenhagen , Denmark.
- 4d Department of Clinical Genetics , Aarhus University Hospital , Denmark.
- 5e Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University , Lund , Sweden.
BACKGROUND: The risk of cancer in men from BRCA1 and BRCA2 families is relevant to define to motivate genetic testing and optimize recommendations for surveillance.
MATERIAL AND METHODS: We assessed the risk of cancer in male mutation carriers and their first-degree relatives in 290 BRCA1 and BRCA2 families with comparison to matched controls with the aim to motivate genetic testing and optimize recommendations for surveillance.
RESULTS: Mutation carriers in BRCA1 families were not at increased risk of cancer, whereas mutation carriers in BRCA2 families were at increased risk of male breast cancer and prostate cancer with cumulative risks of 12.5% and 18.8%, respectively. Breast cancer developed at a mean age of 59 years, typically as ER/PR positive ductal carcinomas. Prostate cancer developed at a mean age of 68 years, with Gleason scores ≥ 8 in 40% of the tumors. The hazard ratio for BRCA2-associated prostate cancer was 3.7 (p < 0.001) in mutation carriers and 3.1 (p = 0.001) in first-degree relatives. Of the 37 prostate cancers, 19 were linked to four BRCA2 mutations within a region defined by c.6373-c.6492. Individuals with mutations herein had a HR of 3.7 for prostate cancer compared to individuals with mutations outside of this region.
CONCLUSIONS: Male mutation carriers and first-degree relatives in BRCA2 families are at an increased risk of breast cancer and prostate cancer with a potential prostate cancer cluster region within exon 11 of BRCA2.
In families with a pathogenic mutation in the BRCA1 or BRCA2 gene risk of developing breast and ovarian cancer is increased. Male breast cancer, prostate cancer, pancreatic cancer, colon cancer and malignant melanoma have also been suggested to occur at increased incidences in these families. BRCA1 and BRCA2 mutations are inherited in an autosomal dominant manner. Male mutation carriers have been reported to have a decreased life expectancy. Despite these facts men in BRCA1 and BRCA2 families show a lower uptake on genetic testing than female family members. Primary motivational factors for genetic testing for male family members has been found to relate to an increased risk of cancer in their female relatives rather than to a personal risk of cancer.
In the general population male breast cancer is very rare and accounts for less than 1% of all male cancer cases. Compared to females with breast cancer, men do more often experience diagnostic delays and male survival rates are poorer. Male breast cancer most frequently affects BRCA2 mutation carriers with lifetime risks of 6–8% whereas the increased risk in BRCA1 mutation carriers is limited to risks around 1%. Prostate cancer represents the most common tumor type in men in the western world and is the second leading cause of cancer-related death in men. The relative risk of prostate cancer has been estimated to be 1.1–3.8 for BRCA1 mutation carriers and 4.7–8.6 for BRCA2 mutation carriers compared to the general population. One of the challenges in treating prostate cancer is to identify high-risk cancer and optimize the treatment strategy to reduce mortality and at the same time spare treatment and side-effects in individuals with low-risk tumors. Patients with low-risk tumors are generally advised active surveillance. Treatment options for intermediate and high-risk tumors include radical prostatectomy, radiotherapy and hormone therapy.
Genetic counseling of BRCA1 and BRCA2 families is based on broad risk estimates. Accurate risk estimates are needed to optimize and individualize genetic counseling and recommendations for surveillance. By analyzing data on male mutation carriers and first degree relatives to a mutation carrier from families with a BRCA1 or BRCA2 mutation we wanted to gain more knowledge on male family members’ cancer risk and to study the genotype–phenotype correlations.
To do that, we established a database of west Danish families with a known BRCA1/2 mutation and a control cohort with 5 controls per family member. Controls were matched by date of birth and sex. From the National Registry of Cancer and the Civil Registration system we collected data on cancer diagnosis, data on birth, death and emigration for all individuals. Complete data were available from 290 families, see Table 1
Table 1 Number of male mutation carriers and fist degree relative
In BRCA1 families we found that the overall risk of cancer compared to the control population was not increased in mutation carriers, but was increased in first-degree relatives (HR 1.5, 95% CI 1.1 – 2.0, p =0.01).
Breast cancer was diagnosed in two mutation carries at age 37 and 56, but did not show a significantly increased risk of breast cancer compared to controls. Prostate cancer was diagnosed in eight mutation carriers at a mean age of 63 years. The risk of prostate cancer was not increased in mutation carriers or first-degree relatives compared to controls, though mutation carriers showed a trend for an increased risk of prostate cancer development before age 65 years (HR 3.7, 95% CI 1.0 – 13.7, p=0.05).
In BRCA2 families the overall risk of cancer compared to the control population was increased in both mutation carriers and untested first degree relatives. The overall risk estimates were explained by increased risks for breast cancer and prostate cancer. In total, 15 male breast cancers and 37 prostate cancers developed. Male breast cancer developed in 13 mutation carriers, in one first-degree relative and in none of the controls. The cumulative incidence for male breast cancer at age 80 was 12.5% (95% CI 11.5 – 13.5). The male breast cancers developed at a mean age of 61years.
Prostate cancer developed in 17 mutation carriers and in 20 first-degree relatives, which corresponds to a HR of 3.7 (95% CI 1.9 – 7.2, p≤0.001) in mutation carriers and a HR of 3.1 (95% CI 1.6 – 5.7, p≤0.001) in first-degree relatives compared to their matched controls. The HR for prostate cancer before age 65 was 5.5 (95% CI 1.6 – 18.7, p= 0.01) for mutation carriers. The cumulative incidence for prostate cancer at age 80 was 18.8% (95% CI 16.6 – 21.9). The prostate cancers developed at a mean age of 67 years. Gleason scores ≥8 was found in 40% of the cases.
Genotype – phenotype correlations in the BRCA2 gene were analyzed in relation to male breast cancer and prostate cancer. The breast cancers did not show any association to specific genetic regions in the BRCA2 gene. We identify a potential prostate cancer cluster region, PCCR, based on 19/37 prostate cancers clustering to a region defined by c.6373-c.6492 in exon 11 of BRCA2. The c.6373delA mutation was found in 14 families with 10 cases of prostate cancer divided between six families. The c.6408_6414delAAATGGT mutation was identified in one family with four cases; the c.6486_6489delACAA mutation was seen in three families, each with one case of prostate cancer and one family with the c.6490_6492del/insGACT mutation contained two cases of prostate cancers Individuals who carried any of these four BRCA2 mutations had a HR of 3.7 (95% CI 1.35 – 9.33) p≤0.01 for development of prostate cancer compared with mutations in other parts of BRCA2. When the HR for prostate cancer development in individuals with mutations within the prostate cancer cluster region, PCCR was compared to controls, the HR was 9.7 (95% CI 4.0 – 23.7) p≤0.001 (Figure 1).
Figure 1 Risk of prostate cancer related to position of the mutation in BRCA2. PCCR: Prostate cancer cluster region defined as region c.6373-c.6492 in the BRCA2 gene.
The cumulative incidence of prostate cancer at age 80 was 35.6% for individuals with mutations within the PCCR and 10.6% for individuals with mutations outside of the PCCR. In the regions next to the PCCR only one case of prostate cancer was observed in 17 male mutation carries.
Estimates of genotype – phenotype effects are sensitive to cancer risk and penetrance and our observation needs validation in larger, prospective data sets to determine its clinical relevance.
We would like to acknowledge Prof. Ake Borg, Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, Sweden, Ass. Professor Mads Thomassen, Department of Clinical Genetics, Odense University Hospital, PhD Inge Søkilde Pedersen, Department of Molecular Diagnostics, Aalborg University Hospital and PhD Thomas van Overeem Hansen, Department of Genomic Medicine, Rigshospitalet, Copenhagen, Denmark for data on disease-predisposing mutations. The study was financially supported by the Aase and Einar Danielsens Fund, the Research Council, Vejle Hospital. No confl icts of interest apply for any of the authors. The authors alone are responsible for the content and writing of the paper.