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Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways appear largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects.
I collected data published in >30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data was extracted and used directly as published whenever possible with a minimum of statistical manipulation.
Although mutations target breast and ovary, a broader spectrum of cancers also occurs with statistically significant elevated frequencies. Risks for “all cancers except breast or ovary” are elevated, with some population subgroups differing in how often elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate and colon. The increased risk ranged from about 20-60% with the greatest increases in risk in stomach and pancreas.
The collected data shows BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.
Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Some female carriers of inherited mutations in BRCA1 or BRCA2 genes have lifetime risks for breast cancer exceeding 80%.
BRCA-related pathways safeguard genetic content and a very large fraction of human cancers have abnormal genetic content. BRCA1 and/or BRCA2 are involved in pathways important for DNA damage recognition, double strand break repair, checkpoint control, transcription regulation and chromatin remodeling. These functions are essential and important for all cell types. Despite the general nature of BRCA functions, tumors in mutation carriers predominantly target breast and ovary. A major problem is the broad theoretical importance of BRCA-related pathways conflicts with the specific targeting of cancers to breast and ovary. Some observational studies report elevations of the risk for certain cancers besides breast or ovarian cancer in BRCA1 or BRCA2 mutation carriers, but other studies conflict
Although mutations in BRCA related pathways may increase risk for sporadic or hereditary cancers other than breast or ovarian, the risks for these additional cancers may be smaller than those for breast or ovarian cancer; they may show wider variation; they may require large populations to measure; and they may involve proteins elsewhere in the pathways.
Carriers of mutations in BRCA1 and BRCA2 are relatively infrequent in the general population, and BRCA mutations are thought to be involved in at most 5% to 10% of all breast cancers. Mutations of genes encoding ATM and CHEK2 or mutations leading to EMSY amplification also affect BRCA pathways. These changes occur more frequently than BRCA1 or BRCA2 mutations in the general population, suggesting inactivation of BRCA-related pathways is probably associated with significantly higher percentages of cancers. Fortunately, data exist from many thousands of high-risk individuals who were not identified mutation carriers but who were eligible for mutation testing. These data would include all mutations that affect BRCA pathways, and some studies provide a built-in control because they also include those who were not eligible for mutation testing.
I collected data published in more than 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers or in large populations eligible for mutation testing. Results of meta analyses show that the loss of BRCA gene function provides growth or survival advantages to a broader spectrum of tumors, including stomach, pancreas, prostate and colon.
Thus BRCA pathways function at multiple sites throughout the body, not just in breast or ovary. This does much to resolve a major conflict between the mechanisms of BRCA pathways participation in tumor suppression and clinical observations. The data suggest increased clinical awareness for those with defects in BRCA related pathways. Identifying molecules that confer growth or survival advantages to tumors in those with BRCA pathway deficits may provide helpful targets for chemotherapy or chemoprevention.
Many PubMed searches were conducted. To search for possible effects between BRCA mutations and sporadic cancers, individual cancers were entered so the search read “BRCA1 and melanoma” then “BRCA2 and melanoma.” Initially the term “colon cancer and BRCA” was entered. Then all possible variants were entered such as “colorectal cancer and BRCA1.” An additional strategy was “hand searching” by consulting appropriate references in literature that seemed pertinent. A few searches of EMBASE were also done. Additional searches were conducted for incidence of cancers in high-risk groups, for second cancers after diagnosis of primary breast or ovarian cancer at young ages and for second cancers after diagnosis of male breast cancer.
More than 30 observational studies going back 20 years and including case histories from many thousands of mutation carriers or possible mutation carriers in high-risk populations were collected and intensively reviewed. Data representing a large number of mutation carriers was achieved by including several types of studies as follows. Population studies were used that tabulated cancer histories for known mutation carriers and for their first-degree relatives. Large populations enriched in mutation carriers, such as those eligible for BRCA gene mutation testing were also included. A third type of study measured incidences of second cancers after breast cancer in young women. The likely number of BRCA mutations was then estimated from data in the publication or from mutation incidence tables available at http://www.myriadgenetics.com. I also included studies that measured whether the frequency of BRCA gene mutations was elevated in patients presenting with certain cancers other than breast or ovarian.
The literature results were used directly as reported by the original authors. This enabled inclusion of data that were 10-20 years old in addition to the most recent studies. Goals were to use as little statistical manipulation as possible and to allow anyone to reproduce the results. Statistical calculations were by the summary method of meta-analysis using the StatsDirect Computer Program. StatsDirect calculates stratum weights as the inverse of the variance for the summary statistic (Y) supplied. The pooled estimate of Y is calculated as a weighted mean, i.e. the sum of weighted Y for each stratum divided by the sum of the weights. Meta-analyses based on approximate relative risk calculations were also run as a double check using available data in the original publications.
Studies were excluded in whole or in part if they did not present relative risks and confidence intervals or provide enough data to calculate missing information. Because of the close interactions of Fallopian tubes and ovaries and because data shows that Fallopian tubes are highly susceptible in BRCA mutation carriers, Fallopian tube cancer was considered to be a part of the breast/ovarian cancer syndrome.
Data from the studies included sample size, population, method, control population, method of expressing results (as relative risks, per cents, odds ratios, etc.) results, and 95% confidence interval.
I found no evidence for misdiagnosis of cancer and most studies reported histological verification in a high percentage of cases. It was necessary to make the assumption that cancers were diagnosed correctly.
Studies used are numbered and summarized in Table 1 and Table 2. Table 1 contains population studies (numbered 1-17) which include data on the incidence of cancers other than breast or ovarian cancer in BRCA mutation carriers or populations likely to be enriched in mutation carriers. Table 2 reports the measured incidence of BRCA1 or BRCA2 mutations in families of patients presenting with a particular cancer. (1-33)
Table 1 lists cancers that occurred at a statistically significant greater frequency relative to controls if BRCA function is impaired in at least some subgroups of mutation carriers within individual studies (column 6): Colon cancer, colorectal cancer, gall bladder/bile duct cancer, liver cancer, stomach cancer, malignant melanoma, esophageal cancer, myeloid leukemia, lung/bronchus cancer, laryngeal cancer, Hodgkin's disease, cancer of the uterine body and cervix, testicular cancer, cancer at multiple sites including pituitary and peritoneum, all cancers except breast ovary, non melanoma skin; all cancers in females other than breast, ovarian and non-melanoma skin; any second non-breast primary cancer, and unknown primary site cancer.
Figure 1A plots the statistically significant relative risks extracted from the 17 studies in Table 1. The plot shows that the increased incidences of cancers is not consistent among studies and vary in studies of different population subgroups. For example, 6 of 17 studies show statistically significant elevated risks for stomach cancers in some subgroups, and 4 studies show elevated risk for pancreatic cancer. Even different groups within the same study show variation. For example, comparisons of pancreatic cancer risks among different individual groups in the study of Bermejo and Hemminki(9) shows wide variation (Table 1), but their aggregated data includes 1 as part of the confidence interval. Increased risks for esophageal, lung, NHL, malignant melanoma, buccal cavity/pharynx, squamous skin and gallbladder/bile duct cancer are each represented in only 1 study. (Gallbladder/bile duct cancer was plotted near the results for liver cancer in Fig. 1A)
Eleven studies reported sufficient information to plot incidences of cancers lumped together in categories called “all cancers except breast, and ovarian” or “all cancers except breast, ovarian and non-melanoma skin cancer”. Figure 1B shows results for the reported incidences of cancers with statistically significant increases in relative risk of cancer at sites beyond breast or ovary. Results for different groups within each study were pooled together. Figure 1B shows that five of the studies do not include 1 in the confidence interval and relative risks from all of the studies are greater than 1 with p values <0.05. Combined risk was calculated as 1.52 (CI 1.21-1.93)
Most studies in Table 1 and Figs Figs1A1A and and1B1B find a statistically significant increased incidence for at least one cancer other than breast or ovarian cancer in BRCA gene carriers. This increased incidence crosses different methodologies and populations. This is consistent with the idea that the cancers occur sporadically but at moderately elevated frequency.
Figures 2A-D are forest plots of risks for stomach/gastric, pancreatic, prostate and colorectal cancer, respectively. These all show elevated relative risk. Surprisingly, the largest increase in relative risk was from stomach/gastric cancer (Fig 2A) RR=1.69 [1.21-2.38] followed closely by pancreatic cancer (Fig 2C) RR=1.62 [1.31-2.00]
In Table 1, studies 1-3 were from the Breast Cancer Linkage Consortium, a worldwide cooperative network of scientists and physicians with a major interest in inherited breast and ovarian cancer. Study 2 contains a listing of cancers as “all cancers except breast, ovary, non-melanoma skin and prostate cancer. ” The odds ratio for these other, presumably sporadic cancers is 1.90. Study 3 gives a relative risk of 1.34 [1.19-1.51] of all cancers except breast, ovary, non-melanoma skin, prostate and pancreatic cancer.
Study 2 examined data from a large number of BRCA1 carriers. Its increased statistical power detected moderate increases in numerous abdominal cancers (Table 1).
Brose and colleagues (Study 4, Table 1) found that colon, pancreatic, and gastric cancer occurred more frequently than in the general population(4). The cumulative age-adjusted risk of colorectal cancer in their study was a statistically significant twofold increase (P<.05). They also estimate a threefold increase in pancreatic cancer risk and a fourfold increase in gastric cancer risk. The cumulative age-adjusted lifetime risk of any cancer other than breast and ovarian diagnosis in this group of BRCA1 mutation carriers was 13.8% (95% CI 10.7% to 16.9%). Of note, the overall risk of cancers other than of the female breast and ovary was statistically significantly higher for men than women, with cumulative age-adjusted lifetime risks of 26.1% (95% CI 17.5% to 34.6%) and 10.3% (95% CI 7.2% to 13.3%), respectively. (4)
A study of families related to BRCA1 probands from Sweden (Table 1 Study 5) reported nearly 6 times the risk of gastric cancer in females. In a Japanese study (not listed in Table 1), a series of gastric cancer patients diagnosed before age 35 documented allelic losses flanking BRCA1 in 12 of 27 cases (44%), suggesting a possible mechanistic link between BRCA1 and the development of gastric cancer.(34)
Johansson and colleagues (Table 1 Study 5) also found about a 6 fold increase in squamous cell skin cancer in males from BRCA1 families. Invasive cervical cancer was increased in females from BRCA2 families and prostate cancer was of borderline significance. (Table 1 Study 5). Study 5 used expanded pedigrees based on mutation testing only for probands, so Study 5 would also include mutations elsewhere in BRCA pathways. Thus effects such as amplification of EMSY genes are automatically included. EMSY overexpression may occur at least as often BRCA mutations. A disadvantage of not typing mutations is that mutation carriers are still only a minority of the population and their risk values are diluted by including individuals with normal BRCA pathways. This makes it more difficult to show increased risks for other cancers
The work by Evans and colleagues (study 6, Table 1) also did not directly type BRCA gene mutations. Evans and colleagues used data from the Thames cancer registry to identify women under age 50 who had additional primary cancers after breast cancer. 32,799 women were diagnosed with breast cancer under the age of 50 between January 1, 1961 and December 31, 1995. Women were censored from the study at clear cut-off dates. The mean follow-up period was 7.5 years. 1448 cases had multiple additional tumors within the 9 sites monitored. 1389 had 2 tumors, 57 had 3 and 2 had 4 tumors. Based on Myriad Genetics tables, the odds that a woman related to one of these individuals would have a BRCA mutation is only 7.3%. 318 had multiple tumors under age 50 and were included in the study. The figure of about 7.3% is far above that for the general population but still omits those with mutations elsewhere in BRCA pathways.
The early age of onset of breast cancer is considered characteristic of inherited cancers. Evans and colleagues (6) also provide data for women older than 50 and this permits useful comparisons. Comparing women with breast cancer diagnosed under age 50 with those diagnosed over age 50, Evans and colleagues noted the younger age group had an increased risk of a second cancer at site other than breast. Table 1 and Figures Figures11 and and22 shows the risk for a number of second cancers is elevated and some of these rise to statistical significance.
Harvey and Brinton (Table 1, study 7) in a 1985 study listed primary cancers after a first breast cancer in Connecticut women under age 45. The authors noted a significant relationship between breast and subsequent colon cancer. Second cancers were much more numerous in this group of nearly 7000 younger women than in older women. They found a significant downward trend for risk of colon cancer (RR=1.6, 1.3, 1.1) and rectal cancer (RR=1.9,1.1,1.0) with age. This downward trend applied to ages<45, 45-54 and 55+. Similarly Teppo and colleagues (Table 1 study 8) found that colon cancer in women after breast cancer was diagnosed before age 50 occurred almost twice as often as it did in women diagnosed with breast cancer after age 70.
Bermejo and Hemminki used the Swedish Cancer Registry families to find families for which data existed for three generations. From these families, they selected individuals eligible for BRCA mutation testing. The results show an increased incidence of cancers in organs other than breast and ovary in a large population eligible for BRCA mutation testing. Cancers with increased standardized incidence ratios included prostate cancer, pancreatic cancer and pancreatic cancer before age 50. Perhaps eye cancer and stomach cancer by age 70 also achieved statistical significance (Table 1 Study 9.)
Including this study was not without complications. There was no follow-up after the first additional cancer so Bermejo and Hemminki would overlook slower growing cancers such as colorectal cancers in favor of ovarian cancer and other faster growing tumors. Ovarian and fallopian cancers were counted as an additional cancer, and the risk for these tumors varied from a few- to many-times greater than the risk for other cancers. In most groups, the odds were high that a diagnosis of ovarian cancer would have terminated follow-up, especially in the group defined by the presence of ovarian cancer in the family. Increased risk for stomach cancer did not rise to statistical significance until age 70 in one group. It is thus likely that including data of Bermejo and Hemminki leads to an underestimate of risk for other cancers, particularly slower growing tumors such as colon cancer. Although nothing was excluded, excluding even some of the data of Bermejo and Hemminki (such as the group with ovarian and breast cancer in the family) would markedly increase the risk for colon cancer.
Study 10 used a different population and methodology but still supports the increased incidence of other cancers in BRCA mutation carriers. Shih and colleagues (Study 10) found that 98 women with breast cancer who reported at least one other primary cancer in themselves or in a relative with breast cancer were twice as likely to be mutation carriers as women with breast cancer who did not report a second primary tumor. Their data support a general cancer susceptibility in those with BRCA1 and BRCA2 mutations and a heightened clinical awareness in dealing with mutation carriers (10).
Easton and colleagues(11) (Table 1, Study 11) studied 2 large breast cancer families with tumors linked to BRCA2 mutations. They found statistically significant increases in laryngeal cancer, prostate cancer and ocular cancer. In other studies, there are implications that ocular cancer is elevated, but the disease is so rare that it is difficult to achieve statistical significance.
Moslehi and colleagues(12) (Table 1, Study 12) found relatives of Ashkenazi Jewish female BRCA2 carriers to be at greater lifetime risk (to age 75) for cancer of any type than the relatives of the BRCA1 carriers (46.3% vs. 34.9%). In men younger than 65 years, the risk was significantly higher for cancer (21.4% vs. 4.4%;) and this was attributed largely to an excess of prostate, pancreatic, and colon cancers observed in male relatives of BRCA2 carriers at that age. In first degree relatives of Jewish ovarian cancer patients, greater risks for pancreatic cancer, prostate cancer and cancers in which the primary site was unknown were statistically significant.
In a population series of 649 women with ovarian cancer, Risch and colleagues(13) (Table 1, Study 13) examined BRCA2 mutation location relative to colorectal, stomach, pancreatic and prostate cancer in family members. For probands carrying BRCA2 mutations, colorectal cancer in family members occurred only when mutations were within the ovarian cancer cluster region of exon 11 of the BRCA2 gene (now defined as nucleotides 4075 to 6503). Statistically significant increases in risk for colorectal, stomach, pancreatic or prostate cancer (as well as for ovarian cancer) occurred for these mutations.
Aretini and colleagues(14) (Table 1, Study 14) as part of the Italian Consortium for Hereditary Breast and Ovarian Cancer found that cancers other than breast or ovarian were significantly elevated in mutation carriers. The presence of prostate or pancreatic cancer in a family was correlated with the presence of ovarian cancer in BRCA2 mutation carriers.
Colon cancer is highly age dependent, rising from an incidence of 0.23% at age 50 to 5.6% at age 80. Because it was a peripheral issue, the publication did not list data to estimate the rate of colon cancer in a control group, so colon cancer incidence data had to be excluded. Nonetheless the authors mentioned finding an increased incidence in BRCA families of pancreatic, prostate, and gastrointestinal cancers.
Streuwing and colleagues(15) (Table 1, Study 15) recruited over 5300 Jewish people in the Washington DC area and identified 120 carriers of one of the three BRCA founder mutations. The family histories of the carriers included increased percentages of numerous cancers other than breast or ovarian cancer. Even though the numbers of carriers were low, there were elevations in prostate, lung, multiple myeloma, and Hodgkins disease that reached sufficient statistical significance to warrant further investigation.
Goldgar and colleagues(16) (Table 1, study 16) found a highly significant statistical association between familial occurrences of breast, colon and prostate cancers and between breast and thyroid cancers. Berman and colleagues(17) in a small study (Table 1 study 17) noted significant cancer histories in 8 BRCA2 mutation carriers.
Mutations are prevalent in familial forms of both pancreatic and prostate cancers where multiple relatives are affected. Carriers of BRCA1 or BRCA2 mutations represent up to 4 to 7% of all unselected pancreatic cancer patients and 10% of those from Ashkenazi Jewish families. In the Swedish cancer registry study of probable BRCA mutation carriers, the incidence of early onset pancreatic cancer was elevated up to 6.54 fold(9).
With considerable variability, studies of patients presenting with pancreatic cancer or prostate cancer have concluded that BRCA1/BRCA2 mutation carriers are at increased risk for these cancers (Table 2, studies 18-20). The studies in Table 2 generally support those in Table 1. Because of the low percentages of mutation carriers in the general population, only low numbers of mutation carriers were involved in the studies in Table 2, ranging from a high of 64 to a low of 3 (See column 4).
Pancreatic cancer in BRCA2 mutation carriers is consistent with the possibility that BRCA2 loss sometimes promotes the malignant progression of existing lesions (Table 2). Familial pancreatic cancer marked by BRCA2 mutations occurs 8-10 years sooner than sporadic disease (9,18,33). One explanation for the higher prevalence of pancreatic carcinoma in families with >=2 affected first-degree BRCA2 mutation carriers is the early biallelic inactivation of the BRCA2 gene (35). The risk for sporadic pancreatic cancer in BRCA2 mutation carriers rises to 3.5 (18). Hahn and colleagues studied 64 patients (37 men and 27 women) with pancreatic cancer among 26 families. 4 families had 4 members with pancreatic cancer, 4 families had 3 affected members, and 18 families had 2 affected members. 3 families had 3 affected generations, 16 families had two affected generations, and 7 families had only one affected generation. No families were Ashkenazi Jews. (Table 2, Study 18)
Murphy and colleagues(19) (Table 2, Study 19) found increased risk of both sporadic and familial pancreatic cancer in BRCA2 mutation carriers. Within these kindreds, both Hahn and colleagues (18) and Murphy and colleagues (19) found a variety of additional cancers within the families they studied but risks were not calculated.
These two reports (18,19) suggest that some familial pancreatic cancers are caused by BRCA2 germ-line mutations. Of note, these pancreatic cancer families generally may not show an increased incidence of breast and ovarian cancer. Other pathways not mediated via BRCA proteins are also involved and apparently generate pancreatic cancers independent of BRCA proteins (33).
Kirchhoff and colleagues(21) (Table 2, Study 21) studied the incidence of 3 founder BRCA mutations in unselected prostate cancer patients. When results were stratified by gene, BRCA2 mutation carriers were at increased risk for developing prostate cancer (odds ratio 4.78; [1.87-12.25]. The risk of BRCA1 mutation carriers was not significantly increased. Vazina and colleagues (Study 23) found that the rate of founder BRCA1 mutations in Ashkenazi Jewish prostate cancer patients (2.3% and 3.3%) was greater than the rate of the general population (0.77% and 0.37%)(23). Mutation carriers had double the risk of the general Ashkenazi population. Only 1 of 5 carriers had prostate cancer detected early.
In the relatively homogenous Icelandic population, one of two Icelandic population studies found significant elevations in prostate cancer risk for BRCA2 mutation carriers (Table 2, studies 25 and 26)(25,26).
Several studies of ocular melanoma patients also found significant elevations in BRCA1/2 mutation carriers (e.g. Study 27)(27). The incidence of ocular melanoma appears to be 2-3% in BRCA mutation carriers, but there is insufficient data published to include them in relative risk plots in Figs Figs11 and and22.
Studies by Neill and colleagues(29) and Kirchoff and colleagues(30) do not exclude a small increase in risk for colon cancer. The two studies involved only a small number of mutation carriers (24 and 8 mutation carriers, respectively). Neill and colleagues found a modest elevation in colon cancer risk that did not rise to statistical significance: BRCA1 or BRCA2 mutation OR=1.47 [0.76 to 2.83)] adjusted OR 1.50 [0.77 to 2.95]. A graph of the risk of colon cancer vs. number of mutation carriers in all available studies (not shown) suggests that a much larger number of mutation carriers may be needed to demonstrate increased risk. Thiffault and colleagues(36) noted that it is not uncommon to find families with multiple cases of breast and colon cancer. They reported on one family with 10 cases of Breast or colon cancer among 26 first-, second- or third-degree relatives. The family had an apparent dual mutation in both BRCA2 and MSH2.
Hughes-Davies and colleagues reported that inhibition of BRCA function by EMSY amplification led to myelomas and liver cancer(37, 38). Relationships among BRCA- and Fanconi anemia proteins (35) indicate involvement with hematologic malignancies as well with a subgroup of solid tumors beyond breast and ovary.
The incidence of cancers other than breast or ovarian was a peripheral issue in most studies, but the high quality of the data makes the present analysis feasible. Although the sites that show increased risk for cancer may vary among studies, essentially all applicable studies support the idea that damage to BRCA-related pathways increases overall cancer risks beyond breast and ovarian (Table 1 and Figure 1). Figures Figures11 and and22 also show some specificity in the organs at risk because an increase in cancer susceptibility was found more frequently for the stomach, pancreas, prostate, and colon/rectum. The amount of the increase in risk ranges from about 20% to about 60%.
In comparison to breast and ovarian cancers, the frequencies of additional cancers associated with BRCA1 or BRCA2 pathway mutations are lower. These include some cancers that have a high incidence rate in the general population and are thus not unexpected in families with BRCA mutations. This makes it essential to review a large amount of data. Generally in comparing studies in Table 1 that included BRCA mutation testing, those studies which involved the greatest number of mutation carriers reported the largest number of different sites for cancers beyond breast and ovarian. The size of the effect can be debated in some tissues. But loss of BRCA-related pathways more generally favors tumor growth or improves survival of tumor cells in sites beyond breast and ovary. Moreover, BRCA related gene pathways function in numerous sites throughout the body, not just in breast or ovary.
Despite the interrelationships of BRCA1 and BRCA2 (35), different BRCA1/BRCA2 mutations could have different functional effects. Tables Tables11 and and22 and Figures Figures11 and and22 suggest that either mutation increases risk for a variety of cancers. Many studies tested only for BRCA1 or BRCA2 founder mutations and were unable to detect mutations of different types, which now make up a substantial minority of the total set. None of the studies tested for EMSY overexpression because EMSY was unknown at the time of the studies. In significant percentages of sporadic breast and ovarian cancers, overexpression of EMSY may be functionally equivalent to loss of BRCA genes. Heterozygous ATM mutations have also been associated with increased risk for breast cancer and potentially for other cancers as well.(39) Thus the risk for a variety of cancers can be evaluated by considering the whole BRCA pathway, not just BRCA1/2 genes. These arguments also justify this report's use of data not only from BRCA mutation carriers but also from people eligible for BRCA mutation testing. The percentages of the population with a defect in the BRCA pathway other than in BRCA genes may be significantly larger than the percentages of those with BRCA gene mutations. This implies that other components of BRCA pathways may be targeted in some sporadic cancers. This properly shifts the focus from an individual gene to the pathway or the local area of the network in which the gene resides.
Other inherited gene mutations including those in PTEN and p53 also predispose to breast cancer and would contribute to relative risks for other cancers. These mutations are rarer than those in BRCA genes and a case can be made and their pathways have some relationship to those involving BRCA1 and BRCA2.
A generalized susceptibility to a variety of additional tumors is consistent with current ideas of BRCA1 and BRCA2 functions. Figure 3 shows the evolving diagram of proposed functions and interactions among BRCA-mediated gene pathways. The figure summarizes published functional implications and models of DNA damage responses involving BRCA1 and BRCA2. Mechanisms that sense DNA damage activate protein kinases such as ATM or ATR, triggering a cascade of phosphorylation-dependent steps leading to cell-cycle checkpoint arrest, DNA repair, or apoptosis. BRCA1, BRCA2, and Fanconi anemia (FA) proteins are involved in these steps. The MRE-Rad50-Nbs1 complex indicated in the Figure also functions as a double strand break sensor that recruits ATM to broken DNA molecules.(40) Figure 3 stresses that BRCA1 and BRCA2 are involved in pathways that regulate DNA repair, cell-cycle progression, ubiquitylation, and apoptosis.
Inhibition of MYC action by interacting with BRCA1 may help explain why loss of BRCA function impacts some sporadic cancers. BRCA1-IRIS or unrecognized factors may participate in determining tissue specificity to limit BRCA influences in other tumors or they may significantly alter our current understanding. Moreover some relationships and interactions in Figure 3 are likely to occur only in specific physiological contexts. For example, MYC overexpression or BRCA mutation may have different effects depending on when in development they occur because the genomic background is different(38). Nonetheless the above considerations may be helpful in understanding involvement of BRCA related pathways in limiting tumors in organs other than breast or ovary. The above pathways and functional associations help explain the documented clinical associations.
It is possible that different populations in different geographical areas may have different susceptibilities. Sporadic cancers are sensitive to diet and environmental exposure and these cannot be controlled in any observational study. The possibility that chemotherapy for breast or ovarian cancers induces secondary tumors more readily in mutation carriers can not be excluded. Standard chemotherapy and radiation regimens for breast cancer would increase risks for leukemia and other cancers.(10) Risk for (myeloid) leukemia is statistically significantly elevated in the Evans study(6) but not in the Bermejo study(9). Goldgar and colleagues(16) and Harvey and Brinton(7) did not find an increased risk of leukemia associated with breast cancer.
One might expect that BRCA mutations would lower the age of onset of sporadic cancers. There is limited data on the age of onset of sporadic cancer vs. incidence of other cancers. Harvey and Brinton(7) found a significant downward trend for risk vs. age for colon cancer (RR=1.6, 1.3, 1.1) and rectal cancer (RR=1.9,1.1,1.0) for ages<45, 45-54 and 55+. This is consistent with BRCA mutations affecting the incidence/onset of colon cancer.
A lowered age at onset may be difficult to demonstrate more convincingly, particularly for slow-growing cancers such as colon cancer. It is likely that screening practices vary widely among population groups within individual studies. Patients usually have no symptoms or only nonspecific ones until their cancers reach a large size or spread to other organs. Current colon cancer screening misses many early cases,(41) up to almost 85% by fecal occult blood testing. Sigmoidoscopy may miss over 92% of advanced colorectal neoplasia in the proximal colon.(42) Screening for colon cancer is notorious for its poor compliance. BRCA mutations occur with comparatively high frequency in Israel; yet in 2000, almost half the Israeli population was unaware of colorectal cancer screening, and only 38% had any interest in participating. Thus, many cases of the disease are detected only at an advanced stage.(41) Colon cancer takes 20 to 40 years to develop with no intermediate endpoints to measure rate of development after transformation. Long follow-up was not frequently done in the studies reviewed so that slow-growing tumors might be missed.
Some cancers (such as prostate cancer) in BRCA mutation carriers or those eligible for mutation testing may not have distinct histopathology. Despite the BRCA-relationship, some routes of cancer evolution could still be abolished because some checkpoint mutations are lethal and limit diversity. The initiating oncogenic events may restrict ensuing pathways to limit the subsequent mutation profile of the cancers that occur, pruning disease entities so that the surviving tumors do not differ histologically from sporadic cancers.