The genetics of breast cancer

Breast cancer is the commonest cancer affecting women. A family history of breast cancer increases a woman’s lifetime risk of developing the disease. Most of the genetic risk is due to low-risk and moderate-risk susceptibility alleles rather than high-penetrance genes such as BRCA1 and BRCA2. Pathogenic variants in these two tumour suppressor genes only account for about 2% of all breast cancers. Female carriers of the BRCA gene pathogenic variants have a high lifetime risk of developing breast and ovarian cancer and male carriers have an increased risk of prostate and breast cancer.     

Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer

BackgroundTumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.ObjectiveTo determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.Design, setting, and participantsMen with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated.Outcome measurements and statistical analysisTumor and germline profiles were analyzed for pathogenic and likely pathogenic (“pathogenic”) variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability.Results and limitationsOf the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants.ConclusionsOf patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing.Patient summaryPatients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient’s prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome.     

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.     

Ethnic disparities among men with prostate cancer undergoing germline testing

BackgroundProstate cancer is among the most heritable cancers, and clinical testing for germline genetic variants based on ethnicity, disease features, and family history has recently become standard of care for men with advanced disease. It is not established whether prevalence of germline variants varies based on ethnicity or race.MethodsWe retrospectively examined germline genetic and clinical data of men reporting a diagnosis of prostate cancer referred to Color Genomics by a healthcare provider for testing of 30 genes associated with hereditary cancer risk. Variants were classified as pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign, or benign. P/LP and VUS prevalence was compared among subgroups classified by age at diagnosis, self-reported ethnicity, family history, and history of other cancer.ResultsWe identified 1,351 men reporting a diagnosis of prostate cancer of any stage who underwent germline testing. Overall, 78% of men were Caucasian, 11% Ashkenazi Jewish, 3% African-American/Canadian (AAC), 2% Hispanic, 2% Asian/Pacific Islander (API), and 4% Other (multiple, unknown, Native-American). One-hundred eighty-seven men (13.8%) carried a P/LP variant, and the most prevalent P/LP variants were in BRCA2 (3.4%), CHEK2 (2.8%), MUTYH (1.8%), and ATM (1.7%). Age at diagnosis, ethnicity, type of family member with prostate cancer, and type of second cancer were not associated with risk of carrying any P/LP variant. Ashkenazi Jewish men (6.7%) were more likely to carry P/LP BRCA2 variants than Caucasian men (2.8%) (P < 0.05). Two-hundred eighty-four men (21.0%) carried a VUS, and AAC (36.6%) and API (33.3%) men were most likely to carry a VUS (P < 0.01).ConclusionsP/LP germline variants are prevalent in men with prostate cancer. AAC, Hispanic, and API men with prostate cancer are under-represented in studies of germline testing, potentially contributing to higher rates of VUS relative to Caucasian and Ashkenazi Jewish men. Further studies in these groups will facilitate reclassification of VUS, increasing opportunities for early detection, cancer risk modification, and targeted therapeutics.     

Inherited Mutations in Breast Cancer Genes—Risk and Response

Germ-line mutations in BRCA1 and BRCA2 confer a high risk of developing breast cancer. They account, however, for only 40% of strongly familial breast cancer cases. Intensive genome-wide searches for other highly-penetrant BRCA genes that, individually account for a sizeable fraction of the remaining heritability has not identified any plausible candidates. The “missing heritability” is thought to be due to cumulative effects of susceptibility alleles associated with low to moderate penetrance, in accordance with a polygenic model of inheritance. In addition, a large number of individually very rare, highly penetrant variants could account for part of the gap. Meanwhile, an understanding of the function of BRCA1 and BRCA2 in the DNA damage response pathway has lead to the identification of a number of breast cancer susceptibility genes including PALB2, CHEK2, ATM and BRIP1, all of which interact directly or indirectly with BRCA1 or BRCA2. Knowledge of how BRCA1 and BRCA2 maintain genomic integrity has also led the development of novel targeted therapies. Here we summarize the recent advances made in the understanding of the functions of these two genes, as well as the risks and responses associated with mutations in these and other breast cancer susceptibility genes.     

The genetics of breast cancer

Breast cancer is the commonest cancer affecting women. A family history of breast cancer increases a woman's lifetime risk of developing the disease. Most of the genetic risk is due to low-risk and moderate-risk susceptibility alleles rather than high-penetrance genes such as BRCA1 and BRCA2. Mutations in these two tumour suppressor genes only account for about 2% of all breast cancers. Female carriers of BRCA gene mutations have a high lifetime risk of developing breast and ovarian cancer and male carriers have an increased risk of prostate and breast cancer.     

Management of breast cancer risk in BRCA1/2 mutation carriers who are unaffected with cancer

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk‐reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk‐reducing mastectomy decreases the risk of breast cancer development, and risk‐reducing salpingo‐oophorectomy decreases ovarian cancer‐specific as well as overall mortality, but controversy exists regarding its impact on breast cancer‐specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients’ goals may change.     

From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

BackgroundThere has been huge progress over the last 30 years in identifying the familial component of breast cancer.SummaryCurrently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace.Key-MessagesThere is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.     

Identification of twenty-nine novel germline unclassified variants of BRCA1 and BRCA2 genes in 1400 Italian individuals

ObjectivesBreast and/or ovarian cancers are complex multifactorial diseases caused by interaction of both genetic and non-genetic factors and characterized by predisposition to inheritance. BRCA1 and BRCA2 genes are the most clinically involved with these kinds of cancer and the spectrum of variants affecting these genes is very wide. In fact, point variants, large or small insertions/deletions, genomic rearrangements can be found in these patients, although a large number of variants with uncertain biological and clinical significance continues to be identified. Next-generation sequencing (NGS) technology is actually the most powerful tool for the discovering of causative mutations and novel disease genes, moreover it allows to make a rapid diagnosis of genetic variants giving fast, inexpensive and detailed genetic information.Material and methodsIn this study, we report the screening of BRCA1 and BRCA2 genes on 1400 consecutive Caucasian patients with breast and/or ovarian cancer history or family risk, attending the oncogenetic ambulatory at the Foundation Policlinico Agostino Gemelli in Rome.ResultsWe describe twenty-nine novel BRCA1 and BRCA2 variants detected in Italian individuals suffering from hereditary breast and ovarian cancer syndrome (HBOC).ConclusionData regarding novel variants can provide useful information not only at epidemiological but also at clinical level, allowing for the better managing of breast and ovarian cancer patients and their family members.     

Double Heterozygous Mutations in the BRCA2 and ATM Genes: A Case Report and Review of the Literature

IntroductionGermline mutations of the BRCA1 and BRCA2 genes are responsible for about a quarter of hereditary breast cancers (BCs). In this study, we aimed to determine the importance of rare double heterozygous (DH) pathogenic variant carriership in BRCA2and ATM genes in a patient diagnosed with BC and pancreas cancer (PC).Case ReportA 54-year-old female patient was diagnosed with BC at the age of 34 years and with PC at the age of 48 years. The multigene panel and next-generation sequencing technique were used to evaluate the status of the patient''s cancer susceptibility genes. Pathogenic variants c.537dup (p.Ile180Tyrfs*3) in the BRCA2 gene and c.5065C>T (p.Gln1689Ter) in the ATM gene were detected as DH in the patient. Co-segregation analysis was performed on the relatives of the patient using Sanger sequencing.Discussion/ConclusionMultiple primary malignant neoplasms can be encountered more frequently in DH pathogenic variant carriers, and the diagnosis of malignancies can be made at an earlier age through surveillance guided by genetic testing. In this rare case, more patient studies are needed to determine the contribution of DH in BRCA2 and ATM genes to the phenotype.     

Practical aspects of genetic counseling in breast cancer: Lights and shadows

In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10–30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention.     

Ovarian reserve of women with and without BRCA pathogenic variants: A systematic review and meta-analysis

IntroductionPreliminary clinical evidence suggests a detrimental effect of pathogenic variants of BRCA1 and 2 genes on fertility outcome. This meta-analysis evaluates whether women carrying BRCA mutations (BRCAm) have decreased ovarian reserve, in terms of Anti-Muellerian Hormone (AMH), compared to women without BRCAm (wild-type).Material and methodsSystematic searches of PubMed, Medline, Scopus, Embase, Science Direct and the Cochrane Library from inception until July 2020 were conducted. All studies comparing AMH level in fertile age women, with and without BRCA pathogenic variants were considered. Sub-analyses were performed according to age, presence of breast cancer, and type of mutation.ResultsAmong 64 studies, 10 series were included. For the entire cohort, a trend of reduced AMH level were found between BRCAm carriers and women without pathogenic variants. BRCAm carriers aged 41-years or younger had lower AMH levels compared to 41-years or younger wild type women (OR: 0.73 [95%CI-1.12;-0.35]; p = 0.0002). This finding was confirmed for BRCA1m carriers (OR: 1 [95%CI-1.96;-0.05]; p = 0.004) whereas no difference was observed between BRCA2m carriers and wild type women. The same analysis on breast cancer patients with and without BRCAm achieved the same results.ConclusionYoung BRCA1m carriers seem to have lower AMH level compared with wild type women and therefore a potential decreased ovarian reserve.     

Risk for breast cancer and management of unaffected individuals with non‐BRCA hereditary breast cancer

About 5%‐10% of breast cancer is hereditary with BRCA1 and BRCA2 being the most common genes associated with hereditary breast cancer (HBC). Several additional genes have recently been associated with HBC. These genes can be classified as highly or moderately penetrant genes with lifetime risk >30% or 17%‐30%, respectively. Highly penetrant genes associated with HBC include TP53, PTEN, CDH1, STK11, and PALB2. While, moderately penetrant genes include CHEK2, ATM, BARD1, BRIP1, NBN, NF1, RAD51D, and MSH6. Breast cancer risk and recommendations for screening and risk‐reduction vary by gene. In general, screening breast MRI is recommended for women at >20% lifetime risk, which includes women with mutations in highly penetrant genes and the majority (but not all) moderately penetrant genes. Consideration of chemoprevention is recommended for women with mutations in high and moderately penetrant genes. Risk‐reducing mastectomy does reduce the risk of breast cancer to the greatest extent and can be considered for women with highly penetrant genes. However, this procedure is associated with significant morbidities that should be considered, especially given the benefit of using screening breast MRI for high‐risk women. BSO is only recommended for women with mutations in genes associate with increased risk for ovarian cancer and not as a breast cancer risk‐reducing strategy. As more women undergo testing, additional genes may be identified and risk estimates for current genes and management recommendations may be modified.     

Nonsurgical Prevention Strategies in BRCA1 and BRCA2 Mutation Carriers

BackgroundFemale carriers of a BRCA1 or 2 germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.SummaryWhile endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, BRCA1-deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in BRCA1-deficient mouse models.Key MessageThe prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers.     

Genetic testing for breast cancer predisposition

The recent identification of the BRCA1 and BRCA2 genes has improved our understanding of the association between breast and ovarian cancers in certain families. Carriers of predisposing germline mutations must decide on different options for management, including close follow-up or prophylactic surgery. Further studies are needed to elucidate the optimal management of these patients and to identify the factors that modify their risk for developing breast cancer. Finally, we must work to prevent any form of discrimination against those who, following genetic testing, are found to be at increased risk for breast cancer.     

The prevalence of germline BRCA1 and BRCA2 mutations in young women with breast cancer undergoing breast-conservation therapy

BACKGROUND: Germline mutations of BRCA1 and BRCA2 increase the risk for breast cancer. Mutation carriers selecting breast-conservation therapy (BCT) for treatment of operable breast cancer experience a higher rate of new primary breast cancers. We sought to determine the frequency of BRCA1/BRCA2 mutations in women who underwent BCT. Genetic testing results were compared with the prior probability of mutations in either gene. METHODS: Eighty-nine patients age 39 or younger entered the study. Genetic testing was performed for BRCA1 and BRCA2 and the BRCAPRO model determined the probability of carrying a mutation. RESULTS: Eight mutations were discovered (prevalence, 9.0%). Twenty (22%) uncharacterized sequence variants were found. The prior probability of carrying a mutation was 14%. Mutation carriers had a higher prior probability (.49) compared with women with uncharacterized variants (.09) or with normal genes (.11). CONCLUSIONS: BRCA1 and BRCA2 mutations are common (9%) among unselected young breast cancer patients undergoing BCT.     

Clinical Management of Hereditary Breast Cancer Syndromes

Over the past 15 years there has been substantial improvement in the understanding of hereditary breast cancer. Germline genetic testing for mutations in BRCA1, BRCA2, PTEN and TP53 allows for the identification of individuals at increased risk for breast, ovarian and other cancers. Advances in screening, prevention and treatment have led to improved clinical management which is best defined for BRCA1 and BRCA2 mutation carriers. The addition of screening techniques such as breast magnetic resonance imaging has been shown to lead to earlier detection. Risk-reducing salpingo-oophorectomy leads to a reduction in the risk of both ovarian cancer and breast cancer and also is associated with an improvement in overall survival. BRCA1/2 mutation status may be applicable to systemic therapy decisions. Preclinical and early clinical research suggests that specific classes of chemotherapy may be more effective in mutation carriers. Finally, PARP inhibitors represent a novel therapeutic strategy that exploits the weaknesses of BRCA1/2-associated malignancies.     

Male breast cancer: history, epidemiology, genetic and histopathology

Breast carcinoma is a rare disease in men. The incidence is 1 per cent of the incidence in women. Relative hyperestrogenemia and environmental factors seem to be important for the development of the disease. In recent years, germline mutations have been observed in male breast carcinoma patients in several genes, BRCA2, the androgene receptor gene and PTEN. Suspected genetic factors include the cell-cycle checkpoint kinase (CHEK)2 protein truncating mutation 1100delC that has been shown to confer a 10-fold increase of breast cancer risk in men. The c.1-34T > C 5' promoter region polymorphism in cytochrome P450c17 (CYP17), a key enzyme in the biosynthesis of estrogen, has been associated with male breast cancer risk, hemochromatosis gene (HFE) mutations, the mismatch repair genes (hMSH2, hMLH1,hPMS1,hPMS2) and PTEN mutations (Cowden syndrome) are associated with male breast cancer. The majority of tumors is seen retromamillarly. Ductal carcinoma in situ comprises 5-10 % of all cancers. In case of invasive growth, 85-90 % are invasive ductal carcinomas (NOS), 2.5 % are papillary tumors; lobular cancers are exceptionally rare. About 3/4 of all cancers express estrogen and progesterone receptor with increasing positivity with increasing patient age. HER-2 / neu overexpression is seen in the same frequency as in female breast cancer. Poor prognostic factors are tumor size > 2 cm, poorly differentiated tumors, receptor negativity, axillary lymph node involvement and more than four affected nodes.     

Counseling for male BRCA mutation carriers: a review

BRCA mutations in women confer a high risk for breast and ovarian cancers. The risks to male carriers are poorly understood and risk management strategies undescribed. This review summarizes current evidence and gives recommendations for counseling male BRCA mutation carriers. Reported risks for breast, prostate, pancreatic, gastric and hematologic cancers are higher in male BRCA mutation carriers vs non-carriers. Especially in male BRCA2 mutation carriers under age 65 prostate and pancreatic cancer risks are increased. The risk increase for primary cancers of organs like the liver, bone and brain is difficult to assess as these organs are common sites for metastases. Reports on colorectal cancer and melanoma risks are inconclusive. On the current limited evidence available, male BRCA mutation carriers should be regarded as at high risk for breast, prostate, gastric, pancreatic and colorectal cancers; surveillance by appropriate investigations should start at age 40 years.