Cancer Risk In Mutation Carriers Research Articles

Reproductive and Hormonal Factors, and Ovarian Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Results from the International BRCA1/2 Carrier Cohort Study

Several reproductive and hormonal factors are known to be associated with ovarian cancer risk in the general population, including parity and oral contraceptive (OC) use. However, their effect on ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has only been investigated in a small number of studies. We used data on 2,281 BRCA1 carriers and 1,038 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study to evaluate the effect of reproductive and hormonal factors on ovarian cancer risk for mutation carriers. Data were analyzed within a weighted Cox proportional hazards framework. There were no significant differences in the risk of ovarian cancer between parous and nulliparous carriers. For parous BRCA1 mutation carriers, the risk of ovarian cancer was reduced with each additional full-term pregnancy (P trend = 0.002). BRCA1 carriers who had ever used OC were at a significantly reduced risk of developing ovarian cancer (hazard ratio, 0.52; 95% confidence intervals, 0.37-0.73; P = 0.0002) and increasing duration of OC use was associated with a reduced ovarian cancer risk (P trend = 0.0004). The protective effect of OC use for BRCA1 mutation carriers seemed to be greater among more recent users. Tubal ligation was associated with a reduced risk of ovarian cancer for BRCA1 carriers (hazard ratio, 0.42; 95% confidence intervals, 0.22-0.80; P = 0.008). The number of ovarian cancer cases in BRCA2 mutation carriers was too small to draw definitive conclusions. The results provide further confirmation that OC use, number of full-term pregnancies, and tubal ligation are associated with ovarian cancer risk in BRCA1 carriers to a similar relative extent as in the general population.

Colorectal cancer in HNPCC: cumulative lifetime incidence, survival and tumour distribution. A report of 121 families with proven mutations

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant condition caused by inactivating mutations of DNA mismatch repair (MMR) genes. An accurate estimation of colorectal cancer risk for mutation carriers is essential for counselling and rationalizing screening programmes. Families were referred on the basis of clinical criteria. Tumour immunohistochemistry and microsatellite testing were performed. Appropriate patients underwent sequencing of all relevant exons of the MMR genes. Proven and obligate mutation carriers and first-degree relatives (FDRs) with an HNPCC spectrum cancer were considered mutation carriers, as were a proportion of untested, unaffected FDRs based on the proportion of unaffected relatives testing positive in each age group. The cumulative lifetime risk was calculated by Kaplan-Meier analysis. Three hundred and forty-one colorectal cancers in 839 proven, obligate, or assumed mutation carriers were analysed. The cumulative risk to age 70 years for all mutation carriers combined was 50.4% (95% CI 47.8-52.9). The cumulative risk in males was 54.3% (95% CI 50.7-57.8), which was significantly higher than in females (log rank p = 0.02) who had a risk of 46.3% (95% CI 42.8-49.9). These penetrance estimates from HNPCC families attending high-risk clinics have been corrected for ascertainment bias and are appropriate risks for those referred to a high-risk clinic. Current colonoscopic screening guidelines are appropriate.

Smoking and risk of breast cancer in carriers of mutations in BRCA1 or BRCA2 aged less than 50 years

Cigarette smoke contains compounds that may damage DNA, and the repair of damage may be impaired in women with germline mutations in BRCA1 or BRCA2. However, the effect of cigarette smoking on breast cancer risk in mutation carriers is the subject of conflicting reports. We have examined the relation between smoking and breast cancer risk in non-Hispanic white women under the age of 50 years who carry a deleterious mutation in BRCA1 or BRCA2. We conducted a case-control study using data from carriers of mutations in BRCA1 (195 cases and 302 controls) and BRCA2 (128 cases and 179 controls). Personal information, including smoking history, was collected using a common structured questionnaire by eight recruitment sites in four countries. Odds-ratios (OR) for breast cancer risk according to smoking were adjusted for age, family history, parity, alcohol use, and recruitment site. Compared to non-smokers, the OR for risk of breast cancer for women with five or more pack-years of smoking was 2.3 (95% confidence interval 1.6-3.5) for BRCA1 carriers and 2.6 (1.8-3.9) for BRCA2 carriers. Risk increased 7% per pack-year (p<0.001) in both groups. These results indicate that smoking is associated with increased risk of breast cancer before age 50 years in BRCA1 and BRCA2 mutation carriers. If confirmed, they provide a practical way for carriers to reduce their risks. Previous studies in prevalent mutation carriers have not shown smoking to increase risk of breast cancer, but are subject to bias, because smoking decreases survival after breast cancer.

Breast Cancer Risk Assessment and Genetic Testing: Complexities, Conundrums, and Community

This special issue of Breast Disease is a testament to how far the field of genetic counseling for breast cancer susceptibility has advanced since the mid-1990s, following the cloning of two major breast (and ovarian) cancer susceptibility genes, BRCA1 and BRCA2. Although perhaps not fully appreciated at the time, individuals who pursued genetic testing shortly after it became available were truly pioneers. They were seeking important, indeed life-changing information, when in fact few specifics about several key issues could be provided. For example, the only available data regarding cancer risks in mutation carriers were derived from the highest risk families, most of which were not representative of the families seen in clinical practice. Then, largely due to the discovery of three founder mutations in Ashkenazi Jews, population-based data revealed a range of breast and ovarian cancer risks in carriers. Subsequently, additional information about mutation penetrance, genetic epidemiology, and risk modifiers, some of which is now integrated into routine clinical counseling, has also facilitated the development of elaborate models to predict the likelihood that an individual will test positive for a BRCA1/2 mutation. For women who test positive, several recent studies confirm what we suspected early on – namely that prophylactic mastectomy and oophorectomy confer significant protection against the development of breast and ovarian cancer. In premenopausal women, the benefits of oophorectomy are particularly significant, given the associated risk reduction for both breast and ovarian cancer. In addition, for those women who opt against prophylactic mastectomy, screening with a combination of mammography and magnetic resonance imaging appears to frequently detect breast cancer at an early stage. Effective screening strategies for ovarian cancer, however, remain elusive. Ongoing research to develop better screening measures for ovarian cancer is especially critical now given the substantial number of women who are identified by BRCA1/2 positive status as being at high risk for this disease – a risk not necessarily intuitive based on their family history, which often does not include ovarian cancer. Perhaps one of the most unanticipated findings subsequent to the identification of BRCA1 and BRCA2 was the number of high-risk families who do not harbor a detectable mutation in these genes. Recently, the availability of testing for large rearrangements in BRCA1 and BRCA2 has increased the sensitivity of commercial testing; however, the overall yield of deleterious mutations detected with this new method is small. In other high risk families, rare hereditary cancer syndromes may be implicated. Although these syndromes often have a distinct phenotype, they may be underrecognized by clinicians. In addition, we are learning more about other genetic contributions to familial breast cancer risk – including low penetrance gene mutations, SNPs (single nucleotide polymorphisms), and mutations in modifier genes. Given that no other ma-

Meta-Analysis of BRCA1 and BRCA2 Penetrance

Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis. We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach. Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years were as follows: breast cancer risk of 57% (95% CI, 47% to 66%) for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2 mutation carriers; and ovarian cancer risk of 40% (95% CI, 35% to 46%) for BRCA1 and 18% (95% CI, 13% to 23%) for BRCA2 mutation carriers. We also report the prospective risks of developing cancer for currently asymptomatic carriers. This article provides a set of risk estimates for BRCA1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study.

Hormone replacement therapy is more prevalent among Jewish BRCA1/2 mutation carriers

The aim of this study was to compare reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) in consecutive Jewish Ashkenazi breast cancer patients, with and without BRCA1/BRCA2 mutations. Jewish Israeli women with breast cancer (n=385) were genotyped for the three predominant Jewish mutations in BRCA1 and BRCA2, and data on reproductive factors, OC and HRT use, were analyzed using logistic regression analyses. Overall, 28/385 (7.3%) of participants were mutation carriers, the majority of whom were Ashkenazi (n=22; 78.6%) and were diagnosed with breast cancer at or under age 49 years (n=18; 64.3%). Mutation carriers were more likely than non-carriers to ever use OC (39.3% vs. 20.2%; P=0.053), HRT (35.7% vs. 13.7%; P=0.007), and have first menarche at or below 12 years of age (71.4% vs. 40.6%; P=0.03). Multivariate analysis showed that Ashkenazi women diagnosed with breast cancer under 40 years of age, with a family history of breast/ovarian cancer, who ever used HRT were more likely to be mutation carriers. This study has shown that HRT use is more prevalent among Jewish Ashkenazi mutation carriers, but its role in modifying breast cancer risk in mutation carriers remains unknown.

New Developments in Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Mismatch Repair Gene Testing

New Developments in Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Mismatch Repair Gene Testing

Colorectal cancer at a young age

Colorectal cancer at a young age

HNPCC-associated small bowel cancer: Clinical and molecular characteristics

The risk for small bowel cancer (SBC) is significantly increased in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC-associated SBCs are poorly characterized. Thirty-two SBCs were characterized according to clinical, pathologic, and germline mutation data. Histomorphologic characteristics, microsatellite instability (MSI) testing, mismatch repair (MMR) protein expression, and frameshift mutations of 7 coding mononucleotide repeats were investigated in 17 SBCs. Median age at diagnosis was 39 years. Fifty percent of SBCs were located in the duodenum. The Amsterdam criteria were fulfilled in 50% of patients; 45% of patients had no personal history of previous malignancies. Two patients had a positive family history for SBC. Pathogenic germline mutations were identified in 81%; high MSI was detected in 95% and loss of MMR protein expression in 89% of cases. TGFBR2 , BAX , MSH3 , MSH6 , ACVR2 , AIM2 , and SEC63 frameshift mutations were detected in 69%, 59%, 59%, 35%, 82%, 56%, and 56%, respectively. An expansive growth pattern of the tumor border and an intense intratumoral lymphocytic infiltrate were present in 75%, respectively. HNPCC-associated SBC often manifests at a young age and may be the first disease manifestation. Endoscopy may detect 50% of tumors. Considering recent data on gastric cancer, we propose endoscopic screening of mutation carriers starting at 30 years of age because clinical criteria cannot define a high-risk group. In addition, our study shows that histopathologic criteria, MSI, and MMR immunohistochemistry are often similar to these features in HNPCC.

Oral Contraceptive Use and Risk of Early-Onset Breast Cancer in Carriers and Noncarriers of BRCA1 and BRCA2 Mutations

Recent oral contraceptive use has been associated with a small increase in breast cancer risk and a substantial decrease in ovarian cancer risk. The effects on risks for women with germ line mutations in BRCA1 or BRCA2 are unclear. Subjects were population-based samples of Caucasian women that comprised 1,156 incident cases of invasive breast cancer diagnosed before age 40 (including 47 BRCA1 and 36 BRCA2 mutation carriers) and 815 controls from the San Francisco Bay area, California, Ontario, Canada, and Melbourne and Sydney, Australia. Relative risks by carrier status were estimated using unconditional logistic regression, comparing oral contraceptive use in case groups defined by mutation status with that in controls. After adjustment for potential confounders, oral contraceptive use for at least 12 months was associated with decreased breast cancer risk for BRCA1 mutation carriers [odds ratio (OR), 0.22; 95% confidence interval (CI), 0.10-0.49; P < 0.001], but not for BRCA2 mutation carriers (OR, 1.02; 95% CI, 0.34-3.09) or noncarriers (OR, 0.93; 95% CI, 0.69-1.24). First use during or before 1975 was associated with increased risk for noncarriers (OR, 1.52 per year of use before 1976; 95% CI, 1.22-1.91; P < 0.001). There was no evidence that use of current low-dose oral contraceptive formulations increases risk of early-onset breast cancer for mutation carriers, and there may be a reduced risk for BRCA1 mutation carriers. Because current formulations of oral contraceptives may reduce, or at least not exacerbate, ovarian cancer risk for mutation carriers, they should not be contraindicated for a woman with a germ line mutation in BRCA1 or BRCA2.

Germline mutations in DNA repair and cell cycle checkpoint genes: consequential somatic gene alterations and genome instability

Germline alterations in the BRCA1, BRCA2 and CHK2 genes were analysed in a series of breast cancer cases from the Icelandic population of 285,000 and risk was estimated. By screening 1172 cancer patients for the detected T59K sequence variant in the CHK2 gene, it was detected in a total of four breast cancer patients, two colon cancer patients, one stomach cancer patient and one ovary cancer patient, but not in 452 healthy individuals. The results suggest a tumor suppressor function for CHK2 in a small proportion of breast tumors and that the T59K CHK2 sequence variant is a low-penetrance allele with respect to tumor growth. A rare mutation was detected in the BRCA1 gene and a frequent mutation in the BRCA2 gene. The BRCA2 999del5 is classified as a founder mutation and the Icelandic population-based analysis gives an excellent opportunity to define the risk of this sequence variant for breast cancer and other cancer types. The BRCA2 999del5 mutation is present in 7% of unrelated breast cancer patients in Iceland, the prevalence increases with lower age of diagnosis and the estimated breast cancer risk in mutation carriers at the age of 70 years is 40%. A detailed analysis was done on the somatic events in tumors of 46 BRCA2 999del5 carriers with respect to genomic instability and gene alteration. Chromosome alterations were elevated and of specific architecture compared with sporadic cases, in line with the DNA/chromosome repair function of Brca2. An alternative mechanism of TP53 involvement seems to be specific to the pathogenesis of BRCA2 999del5 tumors. Furthermore, alterations at the FHIT gene located at the FRA3B locus with subsequent reduced expression seem to be of specific relevance in the BRCA2 tumors.

Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program.

Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.

The Li–Fraumeni syndrome

Li–Fraumeni syndrome (LFS) has been the most common terminology used for the syndrome. It is a rare familial dominantly inherited cancer syndrome characterized by a wide spectrum of neoplasms occurring in children and young adults. The canonical definition of LFS includes a proband diagnosed with sarcoma before 45 years of age, a first-degree relative with cancer before this same age and another first- or second-degree relative in the lineage with any cancer before this age or sarcoma at any age. Multiple studies have reported p53 germline mutations in LFS families in various parts of the world. As in sporadic tumors, loss of heterozygosity leading to the inactivation of the wild-type allele by deletion or mutation is observed in LFS tumors. Cancer-risk in mutation carriers has been estimated to be 73% in males and nearly 100% in females, the difference almost entirely explained by breast cancer. The identification of germline p53 mutations in rare cancer-prone families has given rise to the medical, counseling, psychological and ethical problems.

Genetic epidemiology of female breast cancer

Population-based studies of the genetic epidemiology of female breast cancer have shown that only a small proportion of familial aspects of the disease can be explained by what is currently known about its causes. These include mutations in the genes BRCA1 and BRCA2, associated with a 10- to 20-fold increased risk of developing breast cancer. There may be genetic or environmental factors that modify cancer risks in mutation carriers, not necessarily in the same way as they do in non-carriers. The ‘typical BRCA1/2 family’ consists of a ‘sporadic case’, not a multiple-case family. There are likely to be other dominantly- and even recessively-inherited genetic risks, including those influencing intermediate markers like mammographic densities. Unravelling all the causes of familial aggregation will be a major step in understanding the causes of female breast cancer.

Cancer risk in mutation carriers of DNA‐mismatch‐repair genes

Cancer risk in mutation carriers of DNA‐mismatch‐repair genes

Population-based study of risk of breast cancer in carriers of BRCA2 mutation

Estimates of an 80-90% risk of breast cancer for carriers of germline mutations in the BRCA1 and BRCA2 genes are based on studies of families at high risk of breast cancer. Risk estimates for a population are possible if the mutation status of a representative sample of that population can be assessed. In Iceland, one common founder BRCA2 mutation occurs in 0.6% of the population. Iceland has a population-based cancer registry and a large collection of pedigrees, and estimation of cancer risk in mutation carriers is therefore possible. We studied 575 breast-cancer patients, 541 women and 34 men unselected for family history of breast cancer. Data on cancer in first-degree relatives were available from the cancer registry. Risk of cancer was estimated by comparing the history of cancer in first-degree relatives of carriers and non-carriers. 56 (10.4%) of the 541 women and 13 (38%) of the 34 men carried the 999del5 mutation. The estimated risk of breast cancer at age 50 for all female carriers of the 999del5 mutation was 17.0% (95% CI 9.1-25.9) and 37.2% (22.4-53.9) at age 70. The results of our population-based study show that the mean risk of breast cancer in carriers of mutation in BRCA2 is lower than previously suggested. Individual risk assessment will, however, have to take account of family history.