BRCA1 and BRCA2 pathogenic sequence variants in women of African origin or ancestry
Abstract
BRCA1 and BRCA2 (BRCA1/2) pathogenic sequence variants (PSVs) confer elevated risks of multiple cancers. However, most BRCA1/2 PSVs reports focus on European ancestry individuals. Knowledge of the PSV distribution in African descent individuals is poorly understood. We undertook a systematic review of the published literature and publicly available databases reporting BRCA1/2 PSVs also accessed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) database to identify African or African descent individuals. Using these data, we inferred which of the BRCA PSVs were likely to be of African continental origin. Of the 43,817 BRCA1/2 PSV carriers in the CIMBA database, 469 (1%) were of African descent. Additional African descent individuals were identified in public databases (n = 291) and the literature (n = 601). We identified 164 unique BRCA1 and 173 unique BRCA2 PSVs in individuals of African ancestry. Of these, 83 BRCA1 and 91 BRCA2 PSVs are of likely or possible African origin. We observed numerous differences in the distribution of PSV type and function in African origin versus non-African origin PSVs. Research in populations of African ancestry with BRCA1/2 PSVs is needed to provide the information needed for clinical management and decision-making in African descent individuals worldwide.
1 INTRODUCTION
Many women benefit from genetic testing information that can guide their knowledge of cancer risks and help them to make informed prevention and medical management decisions if they have inherited pathogenic sequence variants (PSVs) in BRCA1 (GenBank reference sequence: NG_005905.2) or BRCA2 (GenBank reference sequence NG_012772.3; BRCA1/2). Knowledge of genetic risk is valuable because it can lead to the use of risk-reducing salpingo-oophorectomy or bilateral mastectomy, which significantly decrease breast and/or ovarian cancer risk and mortality BRCA1/2 PSV carriers (Domchek et al., 2006; Domchek et al., 2010; Domchek and Rebbeck, 2007; Domchek, Stopfer, and Rebbeck, 2006; Rebbeck, Kauff, and Domchek, 2008; T. R. Rebbeck et al., 2005; Rebbeck, Kauff, and Domchek, 2009). However, the vast majority of information about cancer risk and risk reduction has to date been conducted in Caucasian and Ashkenazi Jewish women (Rebbeck et al., 2018).
Because there has been limited capture of BRCA1/2 PSVs in more diverse race/ethnicity groups, we anticipate that a large number of PSVs have yet to be reported. Similarly, there is very limited information about cancer risks and the effect of prevention strategies in non-White/non-Jewish women. Therefore, a better understanding of PSVs and cancer risks in underrepresented populations is a critical unmet need in the BRCA1/2 field.
The BRCA1/2 International Diversity by Geography and Ethnicity (BRIDGE) Study has been developed to provide information about BRCA1/2 PSVs in populations who are currently underrepresented in research. We characterize PSVs in self-reported African ancestry (SRAA) individuals identifying commonly reported PSVs that may have had their origins on the African continent and identify potential African founder PSVs and PSV hot spots.
2 METHODS
The individuals included in this analysis were inferred to have African ancestry based on self-report or inference based on place of birth or residence. We included Africans from sub-Saharan Africa and Black South Africans. We also included those reporting African origins from North America, South America, the Caribbean, Europe, or Asia. We excluded White (Afrikaners) and Asian South Africans, mixed-race (colored) South Africans, and individuals who self-reported to be of other race/ethnicity groups whose ancestral origins were from outside Africa (e.g., Asian and Middle Eastern) and North Africans (Morocco, Tunisia, Algeria, Libya, and Egypt). In addition, this report only includes females with PSVs. In some cases, the basis of the race/ethnicity determination was not stated in the original research, and the assumption was made that the source of race/ethnicity information was by self-report or determined by the research team. None of the information about race or ethnicity was based on ancestral genomic information.
To characterize the distribution of PSVs in SRAA individuals, we evaluated a series of data sources (Figure 1). First, we undertook a systematic literature review of published studies reporting a deleterious BRCA1/2 PSV in an individual of SRAA, including sub-Saharan Africa, Caribbean, and African American. To identify reports of BRCA1/2 PSVs in SRAA individuals, we used the following keywords to search the medical literature: BRCA1 or BRCA2 and Africa or African (includes African American), or the Caribbean. Each paper was reviewed to determine if it described an independent study done in SRAA individuals and reported the presence of a disease-associated PSV in BRCA1/2. PSVs reported in other genes were excluded. Reports of PSV testing for BRCA1/2 that reported no disease-associated PSVs were not included in this report. Reports of variants of unknown significance were also excluded. All studies were included regardless of sampling design (e.g., family studies, population screening, genetic testing in clinical case series, etc.). In addition, a small number of papers or abstracts were identified from the citation list of the papers that were identified from the public literature search.
Summary of literature review used in this report for BRCA1 (GenBank reference sequence: NG_005905.2) or BRCA2 (GenBank reference sequence NG_012772.3)
Second, we obtained data from the CIMBA consortium (Chenevix-Trench et al., 2007) using the coded ethnicity variable for African American and countries in Sub-Saharan Africa, which included reports from Nigeria and South Africa only. White South Africans, Afrikaners, and mixed-race (colored) South Africans were excluded.
Third, we used publicly available data from the BIC (https://research.nhgri.nih.gov/bic/) database. A copy of the BIC database was downloaded on February 1, 2019 to identify reported BRCA1/2 PSV carriers. The ethnicity and nationality variables were searched for any notation of African descent individuals, African, African American, or the Caribbean.
Lastly, the NIH public database ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) was used as a check for PSV nomenclature and confirmation of the pathogenic status of each variant. CIMBA and BIC, among other sources, submitted their PSVs to ClinVar. The majority of sources did not contribute race/ethnicity information to ClinVar, so this database was determined not to be a useful data source for this report. Most PSVs reported here have been deposited into the ClinVar database.
PSVs were categorized according to type and function, including large deletion (DL), large duplication (DP), frameshift (FS), in-frame deletion (IFD), missense (MS), nonsense (NS), splice (SP), and individuals who carried multiple PSV types (including those listed above); No RNA, premature termination codon (PTC), nonsense-mediated decay (NMD), NMD with or without reinitiation; and mutation class (1, 2, or 3).
To establish the continental origin of BRCA1/2 PSVs that were reported in SRAA individuals, we identified PSVs reported in regions in which non-African admixture was likely (i.e., North America, Caribbean, South America, South Africa) and where non-African admixture was less likely (i.e., Sub-Saharan Africa excluding South Africa). Table S1 presents PSVs reported only in Sub-Saharan Africa and PSVs reported only in the Americas. In addition, we evaluated whether any of these PSVs were reported in non-African ancestry groups (e.g., Europeans or European Americans). We judged a PSV to be likely African origin if the PSV has only been reported in SRAA and never in a non-SRAA individual, and of possibly African origin if reported greater than 50% of the time in SRAA individuals. This inference was strengthened by the observation of a PSV reported in Africa. We judged the PSV to be likely non-African origin if it reported less than 50% of the time in SRAA individuals.
Collection of original data was undertaken under approved research and/or clinical human subjects protocols at each contributing center. Retrospective anonymized data analysis for the present research was undertaken under human subjects approvals at the Dana-Farber Cancer Institute.
3 RESULTS
3.1 African ancestry individuals with BRCA1/2 pathogenic sequence variants
The results of our literature search are shown in Figure 1. When more than one paper from a research group was found, we included the largest or most recent in the series. Studies that searched for but did not find any BRCA1/2 PSVs in SRAA women were excluded. Note that only 11 published studies were found that included male BRCA1/2 PSV carriers, but no additional BRCA1/2 PSVs were identified from these reports. Forty-eight studies were included in the present report: 16 studies of Sub-Saharan Africans (Awadelkarim et al., 2007; Biunno et al., 2014; Diez et al., 2011; Elimam et al., 2017; Fackenthal et al., 2005; Fackenthal et al., 2012; Francies et al., 2015; Gao et al., 2000; Luyeye Mvila et al., 2014; Stoppa-Lyonnet et al., 1997; van der Merwe et al., 2012; Zhang et al., 2009; Zhang et al., 2012; Zhang, Fackenthal, Huo, Zheng, & Olopade, 2010; Zheng et al., 2018; Zoure et al., 2018), 27 of African Americas (Arena et al., 1996; Arena et al., 1997; Arena et al., 1998; Castilla et al., 1994; Churpek et al., 2015; Dangel et al., 1999; Futreal et al., 1994; Ganguly, Dhulipala, Godmilow, & Ganguly, 1998; Q. Gao, Neuhausen, Cummings, Luce, & Olopade, 1997; Q. Gao, Sveen, Cummings, & Olopde, 1998; Q. Gao et al., 2000; Gayol et al., 1999; Haffty et al., 2009; Hall et al., 2009; John et al., 2007; Kanaan et al., 2003; Kedar-Barnes et al., 2000; Lynce et al., 2015; Martin et al., 2009; Miki et al., 1994; Nanda et al., 2005; Olopade et al., 2003; Pal et al., 2008; Pal et al., 2015; Pal, Permuth-Wey, Holtje, & Sutphen, 2004; Panguluri et al., 1999; Shen et al., 2000; Sutphen & Ferlita, 1999; Whitfield-Broome, Dunston, & Brody, 1999), and three of Afro-Caribbean populations (Akbari et al., 2014; Donenberg et al., 2011; Donenberg et al., 2016) and one study reporting SRAA of unspecified geography (Hall et al., 2009). From these papers, we identified 414 BRCA1 and 187 BRCA2 PSVs, and 108 unique BRCA1 and 103 unique BRCA2 PSVs.
The BIC database included 15,311 total submissions of BRCA1 PSVs, of which 8,564 were reported to be pathogenic. Of these, 206 (2.4%) were identified as SRAA. The BIC database included 14,914 total submissions of BRCA2 PSVs, of which 4,516 were deleterious. Of these, 85 (1.9%) identified as SRAA.
The CIMBA database consisted of 43,817 BRCA1/2 female PSV carriers. Of these, 382 (0.9%) were identified as African Americans and 269 (0.6%) were ascertained in Africa. Thirty-two of these carriers were from Nigeria and 237 were from South Africa. After excluding White South Africans, Afrikaaners, or mixed-race (Colored) South Africans, 11 Black South Africans were included. In total, 435 (1%) women of African descent were found in the CIMBA database. Of these 273 were BRCA1 and 162 were BRCA2. In addition, 34 African American carriers from the University of Illinois at Chicago, 14 BRCA1, and 20 BRCA2, not previously reported to CIMBA, were also included in the CIMBA dataset after consultation with the University of Illinois center.
3.2 BRCA1/2 PSVs in African ancestry individuals
Table s1 presents the complete list of all SRAA PSVs identified in this study and relevant characteristics according to PSV designation, type, and function as well as where and in what populations they have been reported. From our three primary data sources, a BRCA1 PSV in SRAA was reported 909 times: 404 (44.3%) in African Americans, 170 (18.6%) in Africans, 135 (14.8%) in the Caribbean, and 200 (21.9%) in SRAA of unknown or unreported geographic origin. From all data sources, we identified 164 unique BRCA1 PSVs. For BRCA2, a PSV in a woman of SRAA was reported 454 times, 262 (57.7%) in African Americans, 114 (25.1%) in Africans, 35 (7.7%) in the Caribbean, and 43 (9.5%) in SRAA of unknown origin. Of these, we identified 173 unique BRCA2 PSVs. We were not able to determine if an individual was included more than once in these data sources, so these figures do not represent the actual frequency of PSVs expected in SRAA.
The most commonly identified PSVs in BRCA1 and BRCA2 are presented in Table 1. Most of these PSVs have been reported in multiple geographical locations, and in particular, most have been reported in both the New and Old World. A small number of PSVs to date (n = 39) have been reported only in Africans residing in Africa.
| Gene | PSV | Total PSV in SRAA | All reported PSVs | % SRAA PSVs of total PSVs reported | Countries in which PSV has been reported in SRAA individuals | Continent on which PSV has been reported in non-SRAA individuals |
|---|---|---|---|---|---|---|
| BRCA1 | c.5324T>G | 103 | 125 | 82% | Bahamas, Nigeria, Trinidad, USA | North America, Europe |
| c.815_824dup | 100 | 155 | 65% | Senegal, Bahamas, Ivory Coast, France, USA, Spain, France | North America, Europe, South America | |
| c.4357+1G>A | 73 | 88 | 83% | Bahamas, USA | North America, Europe | |
| c.5177_5180del | 54 | 142 | 38% | USA, Canada, Trinidad, Nigeria | North America, Europe | |
| c.4986+6T>C | 35 | 45 | 78% | Bahamas, USA, Sudan | North America, Europe, South America | |
| c.68_69del | 34 | 4834 | 1% | Bahamas | North America, Europe, South America, Australia, Asia | |
| c.303T>G | 26 | 34 | 76% | Nigeria | North America, Europe | |
| c.190T>G | 19 | 30 | 63% | USA | North America, Europe | |
| c.5467+1G>A | 16 | 25 | 64% | USA | North America, Europe, Asia | |
| c.5251C>T | 15 | 188 | 8% | USA | North America, Europe, South America, Australia, Asia | |
| BRCA2 | c.1310_1313del | 26 | 192 | 14% | Bahamas, Nigeria, Trinidad, USA | North America, Europe, Australia, Asia |
| c.9382C>T | 23 | 205 | 11% | Trinidad, USA | North America, Europe, Caribbean, Australia, Asia | |
| c.2808_2811del | 22 | 646 | 3% | Nigeria, Brazil, USA | North America, Europe, South America, Australia, Asia | |
| c.5616_5620del | 18 | 23 | 78% | USA | North America, Europe | |
| c.658_659del | 12 | 217 | 6% | USA | North America, Europe, Caribbean, Australia, Asia | |
| c.4552del | 11 | 12 | 92% | USA | North America | |
| c.9253dup | 10 | 69 | 14% | USA | North America, Europe, Asia | |
| c.5771_5774del | 9 | 18 | 50% | South Africa | North America, Europe | |
| c.2402_2412del | 7* | 7 | 100% | Nigeria | ||
| c.2957_2958insG | 7* | 8 | 88% | USA, Nigeria | North America | |
| c.6405_6409del | 7* | 131 | 5% | USA, Brazil, Nigeria | North America, Europe, South America, Australia, Asia |
In order to identify PSVs that were most likely to be of African origin, we characterized PSVs according to the number of times they were reported in individuals of African and non-African descent (Table 2). We characterized those being reported only in SRAA populations and/or only in Africa as being of likely African origin (n = 115), those reported >50–99% as possibly African origin (n = 59), those 25–50% as probably non-African (n = 35), and those reported <25% of the time in SRAA individuals as likely non-African origin (n = 128). For BRCA1, 50 (30.5%) PSVs are likely to be of African origin, 33 (20.1%) possibly of African origin, 19 (11.6%) probably non-African, and 62 (37.8%) likely of non-African origin. For BRCA2, 65 (37.6%) PSVs are likely to be of African origin, 26 (15.0%) possibly of African origin, 16 (9.2%) probably non-African, and 66 (38.2%) likely of non-African origin. The list of these PSVs and their corresponding designations is presented in Table S1. Thus, about half of PSVs identified in SRAA can be inferred to be of likely or possibly African origin.
| BRCA1 | BRCA2 | ||||
|---|---|---|---|---|---|
| Determination | n | % | n | % | Total |
| Likely African | 50 | 30.5% | 65 | 37.6% | 115 |
| Possibly African | 33 | 20.1% | 26 | 15.0% | 59 |
| Unlikely African | 19 | 11.6% | 16 | 9.2% | 35 |
| Likely non-African | 62 | 37.8% | 66 | 38.7% | 128 |
| Total | 164 | 100% | 173 | 100% | 337 |
- Abbreviations: PSV, pathogenic sequence variant; SRAA, self-reported African ancestry.
Figures 2 and 3 display the frequency and distribution of likely or possible African origin PSVs across the span of each gene. For BRCA1, two common PSVs (c.5324T>G and c.4357+1G>A) were observed in multiple populations of African descent. Among those identified as unlikely to be of African origin include the c.68_69del Jewish founder PSV, as well as PSVs that have been reported as common or founder PSVs in European populations (e.g., c.211A>G in Spain and c.5251C>T in Greece (Janavičius, 2010) or in the CIMBA database (e.g., c.1504_1509del in Asians in Australia and c.5177_5180del in French Caucasians). Notably, the c.68_69del PSV was found in an African population in Burkina Faso (Zoure et al., 2018) as well as many other populations in Europe, the Middle East, and North Africa. In BRCA2, c.5616_5620del was observed in multiple African descent populations. As with BRCA1, the most common PSVs that were inferred as unlikely to be of African origin have been reported as common or founder PSVs in European populations (e.g., c.2808_2811del in Spain and c.1310_1313del in Denmark, or in the CIMBA database (e.g., c.658_699del in Germany and c.9382C>T globally, including Japan and in the CIMBA database in Europe; Arai et al., 2018; Janavičius, 2010).
BRCA1 (GenBank reference sequence: NG_005905.2) pathogenic sequence variants (PSVs) by determination of African origin and self-identification. (a) Likely or possible African origin and (b) unlikely African origin
BRCA2 (GenBank reference sequence NG_012772.3) PSVs by determination of African origin and self-identification. (a) Likely or possible African origin and (b) unlikely African origin. PSV, pathogenic sequence variant
Using the SRAA CIMBA PSV carriers, we were also able to characterize the distribution of PSVs by type and effect (Tables 3 and 4). FS, PTC, and NMD were less common in SRAA than in CIMBA overall for both BRCA1 and BRCA2. IFD was more common in BRCA1 SRAA (but this included very few PSVs), and PSV class was different between SRAA and non-SRAA in BRCA2. For BRCA1, large deletions and duplications were not significantly different in frequency in CIMBA SRAA versus the previously reported CIMBA distribution (T. R. Rebbeck et al., 2018). There was also no significant difference for splice variants, PSV class, or lack of NMD with reinitiation, and marginally significant differences with missense PSVs, nonsense PSVs, no RNA, or reinitiation. Other PSV types or functions included frameshift, in-frame deletions, PSVs of multiple types, premature termination codon, and NMD. There were also significant differences in the number of PSVs with unknown PSV effect. There were approximately twice as many SRAA PSVs of an unknown effect than in other groups.
| n = 1,650 CIMBA PSVs (All ethnicities) | n = 164 likely or possibly African PSVs | |||||
|---|---|---|---|---|---|---|
| n | % | n | % | p-value* | ||
| Large deletion (DL) | 130 | 7.9 | 10 | 6.1 | .749 | |
| Large duplication (DP) | 27 | 1.6 | 2 | 1.2 | >.999 | |
| Frameshift (FS) | 948 | 57.5 | 66 | 40.2 | <.0001 | |
| PSV type | In-frame deletion (IFD) | 1 | <0.1 | 4 | 2.4 | <.0001 |
| Missense (MS) | 46 | 2.8 | 9 | 5.5 | .078 | |
| Nonsense (NS) | 313 | 19.0 | 40 | 24.4 | .081 | |
| Splice (SP) | 166 | 10.1 | 20 | 12.2 | .259 | |
| Multiple types (including those listed above)/Unknown | 20 | 1.1 | 13 | 7.9 | <.0001 | |
| PSV effect | No RNA | 21 | 1.3 | 5 | 3.0 | .055 |
| Premature termination codon (PTC) | 1,331 | 81.0 | 95 | 57.9 | <.0001 | |
| Unknown/Other | 298 | 18.0 | 64 | 39.0 | <.0001 | |
| Nonsense-mediated decay (NMD)** | 1,213 | 73.9 | 84 | 51.2 | <.0001 | |
| No NMD | 58 | 3.5 | 2 | 1.2 | .229 | |
| Reinitiation | 4 | 0.2 | 2 | 1.2 | .080 | |
| NMD/Reinitiation | 60 | 3.7 | 8 | 4.9 | .492 | |
| Unknown/Other | 294 | 17.8 | 68 | 41.5 | <.0001 | |
| PSV class | 1 | 1,298 | 78.6 | 99 | 60.6 | .756 |
| 2 | 112 | 6.8 | 10 | 6.1 | ||
| 3 | 240 | 14.6 | 19 | 11.6 | ||
| Unknown | 36 | 22.0 | ||||
- Abbreviations: PSV, pathogenic sequence variant; SRAA, self-reported African ancestry.
- * p-values from Fisher's exact test reflect the comparison of all ethnicities versus likely or possible African PSVs, for the specific mutation group versus all other mutations.
- ** References (Anczukow et al., 2008; Buisson, Anczukow, Zetoune, Ware, & Mazoyer, 2006; Mikaelsdottir, Valgeirsdottir, Eyfjord, & Rafnar, 2004; Perrin-Vidoz, Sinilnikova, Stoppa-Lyonnet, Lenoir, & Mazoyer, 2002; Ware et al., 2006).
| n = 1,731 CIMBA PSVs (All ethnicities) | n = 173 likely or possibly African PSVs | |||||
|---|---|---|---|---|---|---|
| n | % | n | % | p-value* | ||
| Large deletion (DL) | 34 | 1.9 | 1 | 0.01 | .003 | |
| Large duplication (DP) | 11 | 0.6 | 0 | 0.0 | NE | |
| Frameshift (FS) | 1,141 | 65.9 | 106 | 61.3 | <.0001 | |
| PSV type | In-frame deletion (IFD) | 2 | 0.1 | 0 | 0.0 | NE |
| Missense (MS) | 13 | 0.8 | 1 | 0.01 | NE | |
| Nonsense (NS) | 380 | 22.0 | 47 | 27.2 | .617 | |
| Splice (SP) | 131 | 7.6 | 8 | 4.6 | .062 | |
| Multiple types (including those listed above) | 19 | 1.1 | 10 | 5.8 | <.0001 | |
| PSV effect | No RNA | 6 | 0.3 | 0 | 0.0 | NE |
| Premature termination codon (PTC) | 1,542 | 89.0 | 132 | 76.3 | <.0001 | |
| Unknown/Other | 183 | 10.6 | 41 | 23.7 | <.0001 | |
| Nonsense-mediated decay (NMD)** | 1,523 | 88.0 | 132 | 76.3 | <.0001 | |
| No NMD | 16 | 0.9 | 0 | 0 | NE | |
| Reinitiation | 0 | 0.0 | 0 | 0 | NE | |
| NMD/Reinitiation | 0 | 0.0 | 0 | 0 | NE | |
| Unknown/Other | 187 | 10.7 | 41 | 23.7 | <.0001 | |
| PSV class | 1 | 1,529 | 88.3 | 131 | 75.7 | <.0001 |
| 2 | 36 | 2.1 | 0 | 0 | ||
| 3 | 167 | 9.6 | 6 | 3.5 | ||
| Unknown | 36 | 20.8 | ||||
- Abbreviations: NE, not estimable; PSV, pathogenic sequence variant; SRAA, self-reported African ancestry.
- * p-values from Fisher's exact test reflect the comparison of all ethnicities versus likely or possible African PSVs, for the specific mutation group versus all other mutations.
- ** References (Anczukow et al., 2008; Buisson et al., 2006; Mikaelsdottir et al., 2004; Perrin-Vidoz et al., 2002; Ware et al., 2006).
For BRCA2, there were significant differences between SRAA and the published CIMBA PSV distribution for large deletions, frameshift, in-frame deletions, missense, and multiple PSV types. There were also statistically significant differences for all PSV effects including premature termination codon PSVs, NMD, and PSV class. Again, the proportion of PSVs of unknown effect was significantly higher in SRAA than CIMBA as a whole.
4 DISCUSSION
Despite the availability of substantial information regarding cancer risks in BRCA1/2 PSV carriers, the amount of information available to women of African ancestry is extremely limited. The worldwide CIMBA database containing over 30,000 families with BRCA1/2 PSVs includes less than 1% of individuals of African ancestry (T. R. Rebbeck et al., 2016). This very limited capture of PSVs in women of African ancestry presents a number of important limitations for the clinical implementation and decision-making for African ancestry women (Olopade et al., 2003; Oluwagbemiga, Oluwole, & Kayode, 2012).
We summarize all reported PSVs found in SRAA individuals and infer which of these PSVs may be of African origin. Approximately half of PSVs reported in SRAA are likely or possibly of African origin. A number of individuals who are SRAA have inherited PSVs of European origin. These PSVs were observed primarily in individuals in North America or the Caribbean and likely reflect recent European admixture. However, the c.68_69del PSV was also commonly observed in all SRAA populations. Haplotype analyses suggest that this PSV arose no more than 1500 years ago, suggesting that it was transmitted from the middle east to Africa, and did not arise there before the original migration of individuals out of Africa (Laitman et al., 2013). However, this PSV has been reported in native Africans (Zoure et al., 2018) and has arisen in multiple populations independently, so it is not known whether this PSV is a new PSV at a locus that demonstrates high mutation rates, or if it is the common Jewish founder PSV, which has been observed in Middle Eastern or North African populations (Laitman et al., 2013; Slaoui et al., 2014; Zoure et al., 2018).
We also report that the distribution of PSV type or effect differs for some PSV groups between SRAA and the CIMBA population as a whole. It is well established that African women, as well as African American women, have an earlier average age of diagnosis and a higher proportion of hormone receptor negative and triple negative tumors than women of other ethnicities (American Cancer Society, 2016; Vanderpuye et al., 2017). It is not clear how much of this phenotypic pattern in African descent women could be explained by PSVs in BRCA1/2, but it is possible that, at least in Africa, a substantial proportion of breast cancer may be hereditary in nature. To the degree this is true, the observation in this report that the distribution of PSV type or effect may be different in African descent populations compared with other populations could have clinical implications for assessing cancer risk in women of SRAA. It is also possible that the penetrance associated with mutations in SRAA is different than that of non-SRAA populations. However, the currently available data do not allow us to evaluate the relationship of PSVs in BRCA1/2, as well as specific types of PSVs, in cancer susceptibility. Reports in the literature do not provide consistent information about individual women and their cancer status that would be required to undertake association studies. Such associations could be undertaken in the CIMBA study, but the sample size of SRAA in the CIMBA dataset remains underpowered for these analyses. In addition, the relatively larger proportion of PSVs that could not be characterized with respect to their effect compared with all PSV carriers suggests that additional research is required to understand the phenotypic consequences of BRCA1/2 PSVs in SRAA.
We have also made initial ad hoc inferences about the likelihood that each PSV reported in SRAA is of African origin. We used a value of 50% of PSVs being observed in SRAA to suggest that the PSV was of African origin. However, given that the number of individuals tested for BRCA1/2 is much higher in non-Africans, it is possible this number is too conservative. If a PSV exists in both African women and non-African women regardless of percentage, the PSV may have arisen prior to the initiation of migration out of African 200,000–300,000 years ago. Mutations found only in SRAA women may represent new mutations that arose in Africa (i.e., since the migration out of Africa) or arose in populations that did not migrate out of Africa. In the future, the estimation of haplotype backgrounds and PSV age will be important to further characterize the origin of PSV with respect to African versus non-African origin.
It is clear from our findings that there is a great need for increased participation among currently underserved populations in BRCA1/2 research. Large-scale genomic studies of BRCA1/2 in Africa have yet to be undertaken, although initiatives such as H3Africa (https://h3africa.orginitiative) may provide relevant data in the future if BRCA1/2 testing is undertaken by participating groups. Participation of these groups in BRCA1/2 research will provide a more comprehensive evaluation of PSVs in non-European descent populations and improve risk assessment and an understanding of risk modifiers. It will be critical to evaluate in these groups the complete PSV spectrum, common/founder PSVs (that may aid in developing efficient genetic testing panels) and understand the origins of these PSVs through population/evolutionary genetics research. Additional research will be required to understand cancer risk and risk modifiers so that cancer prevention and treatment can be optimized in these populations.
ACKNOWLEDGMENTS
All the families and clinicians who contribute to the studies; Sue Healey, in particular taking on the task of mutation classification with the late Olga Sinilnikova; Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis; members and participants in the New York site of the Breast Cancer Family Registry; members and participants in the Ontario Familial Breast Cancer Registry; Vilius Rudaitis and Laimonas Griškevičius; Drs Janis Eglitis, Anna Krilova and Aivars Stengrevics; Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management; Bent Ejlertsen and Anne-Marie Gerdes for the recruitment and genetic counseling of participants; Alicia Barroso, Rosario Alonso and Guillermo Pita; Manoukian Siranoush, Bernard Peissel, Cristina Zanzottera, Milena Mariani, Daniela Zaffaroni, Bernardo Bonanni, Monica Barile, Irene Feroce, Mariarosaria Calvello, Alessandra Viel, Riccardo Dolcetti, Laura Ottini, Giuseppe Giannini, Laura Papi, Gabriele Lorenzo Capone, Liliana Varesco, Viviana Gismondi, Maria Grazia Tibiletti, Daniela Furlan, Antonella Savarese, Aline Martayan, Stefania Tommasi, Brunella Pilato; the personnel of the Cogentech Cancer Genetic Test Laboratory, Milan, Italy. Ms. JoEllen Weaver and Dr. Betsy Bove; Marta Santamariña, Ana Blanco, Miguel Aguado, Uxía Esperón and Belinda Rodríguez; IFE - Leipzig Research Centre for Civilization Diseases (Markus Loeffler, Joachim Thiery, Matthias Nüchter, Ronny Baber); We thank all participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to the DKFZ study and the collaborating groups in Lahore, Pakistan (Muhammad U. Rashid, Noor Muhammad, Sidra Gull, Seerat Bajwa, Faiz Ali Khan, Humaira Naeemi, Saima Faisal, Asif Loya, Mohammed Aasim Yusuf) and Bogota, Colombia (Diana Torres, Ignacio Briceno, Fabian Gil). Genetic Modifiers of Cancer Risk in BRCA1/2 Mutation Carriers (GEMO) study is a study from the National Cancer Genetics Network UNICANCER Genetic Group, France. We wish to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014. The team in Lyon (Olga Sinilnikova, Mélanie Léoné, Laure Barjhoux, Carole Verny-Pierre, Sylvie Mazoyer, Francesca Damiola, Valérie Sornin) managed the GEMO samples until the biological resource centre was transferred to Paris in December 2015 (Noura Mebirouk, Fabienne Lesueur, Dominique Stoppa-Lyonnet). We want to thank all the GEMO collaborating groups for their contribution to this study: Coordinating Centre, Service de Génétique, Institut Curie, Paris, France: Muriel Belotti, Ophélie Bertrand, Anne-Marie Birot, Bruno Buecher, Sandrine Caputo, Anaïs Dupré, Emmanuelle Fourme, Marion Gauthier-Villars, Lisa Golmard, Claude Houdayer, Marine Le Mentec, Virginie Moncoutier, Antoine de Pauw, Claire Saule, Dominique Stoppa-Lyonnet, and Inserm U900, Institut Curie, Paris, France: Fabienn e Lesueur, Noura Mebirouk. Contributing Centres: Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France: Nadia Boutry-Kryza, Alain Calendar, Sophie Giraud, Mélanie Léone. Institut Gustave Roussy, Villejuif, France: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont–Ferrand, France: Yves-Jean Bignon, Nancy Uhrhammer. Centre Léon Bérard, Lyon, France: Valérie Bonadona, Christine Lasset. Centre François Baclesse, Caen, France: Pascaline Berthet, Laurent Castera, Dominique Vaur. Institut Paoli Calmettes, Marseille, France: Violaine Bourdon, Catherine Noguès, Tetsuro Noguchi, Cornel Popovici, Audrey Remenieras, Hagay Sobol. CHU Arnaud-de-Villeneuve, Montpellier, France: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille, France: Claude Adenis, Aurélie Dumont, Françoise Révillion. Centre Paul Strauss, Strasbourg, France: Danièle Muller. Institut Bergonié, Bordeaux, France: Emmanuelle Barouk-Simonet, Françoise Bonnet, Virginie Bubien, Michel Longy, Nicolas Sevenet, Institut Claudius Regaud, Toulouse, France: Laurence Gladieff, Rosine Guimbaud, Viviane Feillel, Christine Toulas. CHU Grenoble, France: Hélène Dreyfus, Christine Dominique Leroux, Magalie Peysselon, Rebischung. CHU Dijon, France: Amandine Baurand, Geoffrey Bertolone, Fanny Coron, Laurence Faivre, Caroline Jacquot, Sarab Lizard. CHU St-Etienne, France: Caroline Kientz, Marine Lebrun, Fabienne Prieur. Hôtel Dieu Centre Hospitalier, Chambéry, France: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice, France: Véronique Mari. CHU Limoges, France: Laurence Vénat-Bouvet. CHU Nantes, France: Stéphane Bézieau, Capucine Delnatte. CHU B retonneau, Tours and Centre Hospitalier de Bourges France: Isabelle Mortemousque. Groupe Hospitalier Pitié-Salpétrière, Paris, France: Chrystelle Colas, Florence Coulet, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy, France: Myriam Bronner, Johanna Sokolowska. CHU Besançon, France: Marie-Agnès Collonge-Rame, Alexandre Damette. CHU Poitiers, Centre Hospitalier d’Angoulême and Centre Hospitalier de Niort, France: Paul Gesta. Centre Hospitalier de La Rochelle: Hakima Lallaoui. CHU Nîmes Carémeau, France: Jean Chiesa. CHI Poissy, France: Denise Molina-Gomes. CHU Angers, France: Olivier Ingster; Ilse Coene en Brecht Crombez; Ilse Coene and Brecht Crombez; Alicia Tosar and Paula Diaque; Drs.Sofia Khan, Taru A. Muranen, Carl Blomqvist, Irja Erkkilä and Virpi Palola; The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, D.J. Jenner; Erasmus Medical Center, Rotterdam, NL: J.M. Collée, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C.J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gómez-Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek; Hong Kong Sanatorium and Hospital; the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Aniko Bozsik, Timea Pocza, Zoltan Matrai, Miklos Kasler, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study; the Oncogenetics Group (VHIO) and the High Risk and Cancer Prevention Unit of the University Hospital Vall d’Hebron, and the Cellex Foundation for providing research facilities and equipment; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella; Dr Martine Dumont for sample management and skillful assistance; Ana Peixoto, Catarina Santos and Pedro Pinto; members of the Center of Molecular Diagnosis, Oncogenetics Department and Molecular Oncology Research Center of Barretos Cancer Hospital; Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab; the KOBRA Study Group; Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic); Anne Lincoln, Lauren Jacobs; the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev; the investigators of the Australia New Zealand NRG Oncology group; members and participants in the Ontario Cancer Genetics Network; Leigha Senter, Kevin Sweet, Caroline Craven, Julia Cooper, and Michelle O'Conor; Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation, Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively; the Meirav Comprehensive breast cancer center team at the Sheba Medical Center; Christina Selkirk; Åke Borg, Håkan Olsson, Helena Jernström, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Öfverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Umeå University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellström Pigg, Richard Rosenquist; from Linköping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren; Cecilia Zvocec, Qun Niu; Joyce Seldon and Lorna Kwan; Dr. Robert Nussbaum, Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad and Salina Chan; Simon Gayther, Susan Ramus, Paul Pharoah, Carole Pye, Patricia Harrington and Eva Wozniak; Geoffrey Lindeman, Marion Harris, Martin Delatycki, Sarah Sawyer, Rebecca Driessen, and Ella Thompson for performing all DNA amplification.
FUNDING INFORMATION
CIMBA: The CIMBA data management and data analysis were supported by Cancer Research – UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research -UK Senior Cancer Research Fellow. GCT and ABS are NHMRC Research Fellows. iCOGS: the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The PERSPECTIVE project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy, Science, and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation.
BCFR: UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR. BFBOCC: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. BIDMC: Breast Cancer Research Foundation. BMBSA: Cancer Association of South Africa (PI Elizabeth J. van Rensburg). CNIO: Spanish Ministry of Health PI16/00440 supported by FEDER funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare Diseases (CIBERER). COH-CCGCRN: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under grant number R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. CONSIT: Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 no.15547) to P. Radice. Italian Association for Cancer Research (AIRC; grant no.16933) to L. Ottini. Associazione Italiana Ricerca sul Cancro (AIRC; IG2015 no.16732) to P. Peterlongo. Jacopo Azzollini is supported by funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000′). Dana-Farber Cancer Institute: NIH 5U54CA156732-07. DEMOKRITOS: European Union (European Social Fund – ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. DFKZ: German Cancer Research Center. EMBRACE: Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. FCCC: The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by R0 1CA140323, R01 CA214545, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship. FPGMX: FISPI05/2275 and Mutua Madrileña Foundation (FMMA). GC-HBOC: German Cancer Aid (grant no 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE - Leipzig Research Centre for Civilization Diseases, project numbers 713-241202, 713-241202, 14505/2470, 14575/2470). GEMO: Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa). GEORGETOWN: the Nontherapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. G-FAST: Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. HCSC: Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. HEBCS: Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBON: the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the BBMRI grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. HRBCP: Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. HUNBOCS: Hungarian Research Grants KTIA-OTKA CK-80745 and OTKA K-112228. ICO: The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “Fondo Europeo de Desarrollo Regional (FEDER), una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). IHCC: PBZ_KBN_122/P05/2004. ILUH: Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INHERIT: Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program – grant # CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade – grant # PSR-SIIRI-701. IOVHBOCS: Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. IPOBCS: Liga Portuguesa Contra o Cancro. kConFab: The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. MAYO: NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. MCGILL: Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). MODSQUAD: MH CZ - DRO (MMCI, 00209805), MEYS - NPS I - LO1413 to LF and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ). MSKCC: the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). NAROD: 1R01 CA149429-01. NCI: the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. NICCC: Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. NNPIO: the Russian Federation for Basic Research (grants 15-04-01744, 16-54-00055 and 17-54-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. OSUCCG: Ohio State University Comprehensive Cancer Center. PBCS: Italian Association of Cancer Research (AIRC) [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. SEABASS: Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. SMC: the Israeli Cancer Association. SWE-BRCA: the Swedish Cancer Society. UCHICAGO: NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer Research Foundation. OIO is an ACS Clinical Research Professor. UCLA: Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. UCSF: UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UKFOCR: Cancer Research UK UPENN: National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. UPITT/MWH: Hackers for Hope Pittsburgh. VFCTG: Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. WCP: Dr. Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06–258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124.
