The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers

This review focuses on the association of mutations in BRCA1/2 with carcinoma of the prostate, pancreas and stomach and screening for BRCA1/2 gene mutations. It is evident from the reviewed literature that the pancreas and
prostate were the two most important sites for males who possess a BRCA1/2 mutation.

The impact of BRCA1/2 mutations for prostate cancer

When BRCA1/2 mutations were discovered it was extensively reported that these mutations played
a role in the development of breast and ovarian cancer. Since this advancement, considerable
research has investigated whether BRCA1/2 mutations bestow risk of prostate cancer. Familial aggregation of prostate cancer
has been described and the germline mutation of BRCA1/2 genes has been implicated in some research studies 13]. To date, many have reported on the association of both BRCA1/2 mutations and some findings have indicated extensively lower rates of survival and
more aggressive disease patterns 14], 15].

It is recognised that some prostate cancer diagnoses have a poor prognosis and this
has been connected with hereditary factors 16]. The association between prostate cancer and BRCA2 is consistent within research. Several studies indicate that male carriers of BRCA2 are at an increased risk of developing prostate cancer 13], 17] while men with a BRCA1 mutation are believed to have a slightly higher risk of developing prostate cancer
than those who possess no BRCA1/2 mutations. Early studies reported BRCA1 mutation carriers to have a significant increased relative risk of developing prostate
cancer 18]. Men who carry a mutated BRCA2 gene are reported to be seven times more likely to develop prostate cancer than men
who do not possess the mutation 19], 20]

BRCA2 is a multisite cancer gene that not only affects women, but also increases a man’s
risk of developing cancer 17]. There is a recognised association of breast cancer with prostate cancer within some
families which has been highlighted within several epidemiological studies 21]–23]. Agalliu et al. 24] found that risk of developing prostate cancer was particularly increased in participants
who possessed a mutated BRCA1 gene and had a first-degree relative with prostate, breast or ovarian cancer. Nonetheless,
their findings showed that associations between founder mutations and prostate cancer
were strong in men with no first-degree relative with breast or ovarian cancer and
were unaffected by family history of prostate cancer 24]. Another study showed that two of 290 participants with prostate cancer possessed
germline protein-truncating BRCA2 mutations, giving an overall prevalence of 0.69 %. Only one of these participants
reported a first-degree relative with prostate cancer and neither of the two participants
reported a family history of breast or ovarian cancer 25].

Bermejo and Hemminki 26] demonstrated that families with bi-lateral breast cancer diagnosed before aged 50 years
presented increased standard incidence ratios for prostate cancers. Edwards et al.
27] found that 18 % of participants in their study had a first-degree relative with prostate
cancer. It was calculated that BRCA2 mutations amount for approximately 6 % of the increased familial risk of prostate
cancer. This suggests that while associations have been established, the overall contribution
of BRCA2 mutations to the familial aggregation of prostate cancer is small.

Prostate cancer risk and age at diagnosis

It is frequently hypothesised that the risk of prostate cancer associated with mutations
in BRCA1/2 varies by age at diagnosis. Previously, an increased incidence was reported in men
with BRCA2 mutations and prostate cancer that were diagnosed before 65 years 20]. In some studies the risk of prostate cancer associated with BRCA1/2 mutations is reported higher in men diagnosed at an older age 24]. Some studies also suggest that men with prostate cancer who harbour BRCA1/2 mutations are believed to develop the disease at an early age. In the study by Agalliu
et al. 24] participants were stratified into two groups: cases at age of diagnosis 65 and 65 years
of age. Their findings demonstrated no associations of the founder mutations in the
65 year age group. They also showed a statistically significant result between the
age group 65 years at prostate diagnosis and BRCA1. Edwards et al. 27] used the average of the estimated prevalence (0.12 and 0.07 %) of disease associated
BRCA2 mutations within the general UK population. It was reported that 50 % of the six
prostate cancer patients carrying BRCA2 mutations were diagnosed before aged 50 years. Similarly Agalliu et al. 25] reported the existence of aggressive prostate tumours developing at an early-onset,
less than 55 years. This implies that screening may be required at a younger age among
BRCA1/2 mutation carriers.

Most often, the association between BRCA1/2 mutations is assessed according to clinical features. In a study by Agalliu et al.
24] it was established that carriers of any of the three founder mutations in BRCA1/2 were associated with an increased risk in developing high grade prostate cancer.
Results showed that BRCA2 mutation carriers had a 3.2-fold increased risk of high grade prostate cancer. In
analysis by Edwards et al. 11] a loss of heterozygosity was evident in the five available prostate cancer tumours
from group one which indicated a relationship between BRCA2 germline mutations and predisposition to prostate cancer in these individuals.

BRCA1/2 mutations and prostate cancer survival rate

Within the research it appears evident that a poorer survival rate is greatly associated
with BRCA2 germline mutations. Narod et al. 17] compared the survival of men with a BRCA1 mutation with prostate cancer with that of men with a BRCA2 mutation and prostate cancer and found a significant difference in results. The median
survival from diagnosis for BRCA1 was 8.0 years compared to BRCA2 which was 4.0 years. A similar prevalence was detected in the cohort study by Edwards
et al. 11] where the median survival of prostate cancer patients with a BRCA2 mutation was 4.8 years whereas the median survival in controls was 8.5 years.

Edwards et al. 27] found that five of their six participants carrying BRCA2 mutations had no family history of prostate cancer and four participants had no family
history of breast cancer. This suggests BRCA2 may be a high risk prostate cancer susceptibility gene. The results also have potential
implications for the management of early-onset prostate cancer. It would be reasonable
to suggest that such individuals should be offered referral to screening programmes.
Utilising this cohort study by Edwards et al. 27], further research was undertaken by the group 11] comparing this cohort with a clinical set from Manchester, UK, of known BRCA2 mutation carriers with prostate cancer. A small sample of men who possessed a BRCA2 mutation and were diagnosed with prostate cancer at less than 55 years were compared
with men diagnosed at a similar age but without a mutated BRCA2 gene. Findings concluded that germline mutations in BRCA2 are an independent prognostic factor for survival in prostate cancer. Such results
highlight the importance of developing targeted chemotherapies to treat prostate cancer
in men with BRCA2 mutations 17]. This may be an important factor to consider for future research into treatment.

BRCA1/2 mutations in pancreatic cancer

Pancreatic cancer is a disease with poor prognosis and low survival rates worldwide.
Its mortality compares strikingly with its incidence. In the UK in 2011, there were
8,773 diagnosed cases and a mortality rate of 8,320 28]. Through analysis of the literature it was found that both BRCA1 and BRCA2 mutations are associated with the incidence of pancreatic cancer and that BRCA2 mutation poses an increased risk for developing pancreatic cancer 29]. Furthermore environmental and genetic factors have been proposed as causes of the
pancreatic cancer with the genetic factor of particular importance believed to be
the BRCA2 gene 30].

It has been reported that pancreatic cancer is the third most common cancer associated
with BRCA1/2 mutations 31]. The risk of pancreatic cancer increases in the individual who has a close relative
with the disease. Approximately 5-10 % of pancreatic cancer cases are believed to
show familial clustering 32]. As with prostate cancer incidence 27], it has been suggested that patients with pancreatic cancer and germline BRCA2 mutations tend to be of Ashkenazi Jewish decent and have a younger than average age
of onset 33]. Recently, evidence of a strong family history of pancreatic cancer was reported
in a study among 211 Ashkenazi Jewish probands. Within the sample, 31 % had a first-degree
relative with pancreatic cancer, 53 % had a second-degree relative and 16 % had a
third-degree relative diagnosed with the disease; furthermore 26 of the 211 probands
had more than one relative diagnosed with pancreatic cancer 29]. It is important to acknowledge that the study participants are of Ashkenazi Jewish
decent therefore, it would be reasonable to assume that BRCA1/2 mutation prevalence may be increased among this sample.

It is clear that BRCA1/2 mutations are evident in many familial breast-pancreas cancer families and that carriers
of the BRCA2 mutation have an increased risk of developing pancreatic cancer 29]. Nonetheless, the degree to which family history of pancreatic cancer influences
the likelihood of detecting a BRCA1/2 mutation in an individual with breast cancer is less clear 29]. Perhaps, differences in population samples can account for conflicting results within
studies making it difficult to make a connection. Furthermore, the use of different
analysis models within studies can lead to variations in mutation prevalence.

Pancreatic cancer has been regarded as a component of the breast-ovarian cancer syndrome
29]. In a study by Axilbund et al. 34] over half the study population reported a family history of breast and/or ovarian
cancer in addition to pancreatic cancer. The study findings suggest that BRCA1 mutations are not a substantial cause of breast cancer in familial pancreatic cancer
kinships as none of the participants were found to possess a BRCA1 mutation from DNA sequencing.

Stadler et al. 29] demonstrated that 70 families had more than two relatives diagnosed with breast cancer
within the same pedigree as the family history of pancreatic cancer and 31 probands
had a relative with ovarian cancer within the same family tree. Axilbund et al. 34] showed that from a sample of 66 pancreatic cancer patients, four reported having
had breast cancer prior to being diagnosed with pancreatic cancer. Conversely, in
a cohort study by Tulinius et al. 35] no familial risk due to BRCA2 gene mutations was found for pancreatic cancer among breast cancer patients, yet,
it was evident for cancers of the stomach, prostate and kidneys. These results could
suggest that specific regions of BRCA1/2 genes may have increased associations with particular cancers.

Kim et al. 36] reviewed the pedigrees of 1312 families tested for a BRCA1/2 mutation; 219 families were positive for BRCA1 mutations and 156 families had BRCA2 mutations. Results showed that 11 % of the 219 BRCA1 positive families had at least one relative with pancreatic cancer and 2.7 % had
more than one relative with pancreatic cancer. Stadler et al. 29] identified 14.2 % BRCA1/2 mutations among the sample of 211 Ashkenazi Jews who reported a personal history
of breast cancer and a family history of pancreatic cancer. Furthermore, Bermejo and
Hemminki 26] demonstrated that families of patients with breast cancer diagnosed before aged 35 years
presented significant standard incidence ratios (a ratio that allows comparison of
incidence rates among different populations) for pancreatic cancers. However, this
standard incidence ratio was reported to be indicative of some association of early-onset
breast cancer and pancreatic cancer through causes unrelated to BRCA1 mutations, although no other proposed causes were suggested.

The findings from the Stadler study 29] demonstrated that approximately 64 % of the relatives with pancreatic cancer were
female and 24 % of these women also had a previous diagnosis of breast cancer. Two
male relatives, one from a BRCA1 positive family and one from a BRCA2 positive family, were diagnosed with both breast and pancreatic cancer. However,
the findings from this study suggest that the distribution of BRCA1 (47 %) and BRCA2 (53 %) mutations is nearly equal in Ashkenazi Jewish breast-pancreas cancer families
who possess a mutation. Conversely, in the study by Axilbund et al. 34], BRCA1 mutations were not identified despite over half of the pancreatic cancer probands
reporting a family history of breast and ovarian cancer. Since the prevalence of BRCA1/2 gene mutations in the general population is small not all familial clustering of
cancers can be associated with mutations in these genes. A strong family history could
be attributed to other inheritable factors or lifestyle choices within families.

As with prostate cancer 25], it has been suggested that pancreatic cancer patients who possess a mutated BRCA2 gene have a younger age of onset 20]. Kim et al. 36] reported the mean age of diagnosis of pancreatic cancer within BRCA1 positive families was 62.9 years. The median age for males among this group was 59 years
and 68 years in females. Within BRCA2 positive families the mean age at diagnosis was also 62.9 years, while the median
age in males was 67 years and 59 years in females. These results support the findings
by Stadler et al. 29] where the mean age for diagnosis of pancreatic cancer among the relatives was 67.4 years.
This is typically older than the average age at which BRCA1/2-related breast and ovarian cancers occur. However, 24 % of the females previously
had breast cancer before developing pancreatic cancer.

BRCA1/2 mutations in stomach cancer

Stomach cancer represents a significant global cancer burden and BRCA1/2 mutations have been reported to increase the lifetime risk of developing stomach
cancer by as much as 6-fold greater among first-degree relatives of BRCA1/2 mutation carriers 20], 37]. The risk is reported to be 4-fold greater in BRCA1 mutation carriers 38] and at least 2-fold greater in BRCA2 mutation carriers 35].

As with pancreatic cancer 26], familial aggregations of breast cancer and stomach cancer have been highlighted.
In a Polish study evaluating the importance of a family history of stomach cancer
in predicting the presence of a BRCA2 mutation in patients with ovarian cancer, findings showed that 8 of 34 women with
ovarian cancer and a family history of stomach cancer were found to carry a BRCA2 mutation versus 3 of 75 women with ovarian cancer and a family history of ovarian
cancer but not stomach cancer 39]. In a further study, Jakubowska et al. 40] analysed DNA to determine the frequency and nature of BRCA2 germline mutations in Polish families where there was a clear aggregation of breast
and male stomach cancers occurring at an early age. 29 families with an aggregation
of at least one female diagnosed with breast cancer before aged 50 years and one male
diagnosed with stomach cancer before aged 55 years participated in the study. They
demonstrated that in 12 of 28 families, stomach cancer was diagnosed in a first-degree
relative of an early-onset breast cancer proband 40]. This highlights the importance of family history in surveillance.

Tulinius et al. 35] conducted a cohort study using record linkage of breast cancer families to estimate
the risk of malignant diseases in families of probands with the same BRCA2 mutation. Of the 995 probands in the study, 887 were tested for the mutation. 797
tested negative for the BRCA2 mutation and 90 (10.1 %) tested positive. The relative risk of stomach cancer was
significantly increased among the BRCA2 mutation positive cohort and was reported to be 2.40-fold for first-degree relatives
and 1.91-fold for second-degree relatives. Similarly, Bermejo and Hemminki 26] demonstrated that the incidence of individuals affected with stomach cancer before
aged 70 years in families with breast and ovarian cancer was 1.88 %, which is significantly
higher than in the general population.

Schlebusch et al. 41] demonstrated that stomach cancer prevalence was significantly increased in BRCA2 mutation families compared to the general population. However, previous to this,
van Asperen et al. 42] reported no significant increased risk of developing stomach cancer in their study
on cancer risks in Dutch BRCA2 families. However, Ashkenazi Jews represented 15.5 % of the sample in the Schlebusch
study 41] which may have implications for their increased prevalence yet many of their participants
were reported to be of Dutch decent. It has been suggested that the frequency of stomach
cancer appears greater among Polish families with BRCA2 mutations 40] but again this could be due to a higher proportion of participants of Jewish decent.
The findings from this previous study showed that in the occurrence of breast and
stomach cancer among first-degree relatives, BRCA2 mutations were detected in 16.7 %. Findings from the Jakubowska study 39] suggest the presence of a germline BRCA2 mutation among these families given the incidence of ovarian and stomach cancer among
families in the Polish population. It also confirms stomach cancer is among the range
of diseases attributable to BRCA2 mutations. Figer et al. 43] previously reported the frequency of BRCA2 mutations among 70 consecutive Ashkenazi Jewish patients with stomach cancer was
5.7 %, approximately five times higher than the general population. Furthermore, Jakubowska
et al. 40] showed that BRCA2 abnormalities were detected in 16.7 % in families where breast and stomach cancers
occurred among first-degree relatives and BRCA2 mutations were identified among 23.5 % in families where stomach cancer occurred
among second-degree relatives.

It has previously been suggested that the increased frequency of stomach cancers in
BRCA2 carriers may be sex related as it has been reported to occur primarily in males 20]. In the population based study by Bermejo and Hemminki 26] almost all the individuals diagnosed with stomach cancer in families with breast
and ovarian cancers were males. Findings showed that 23 families with breast, ovarian
and stomach cancers included 23 men and 1 woman with stomach cancer 26]. It could be argued that as BRCA1/2 mutations in women can lead to early-onset breast cancer, individuals who develop
breast or ovarian cancers early in life may not survive to develop stomach cancer
in later life.

The findings from the Polish study by Jakubowska et al. 39] highlight the need for future research to establish if there is a region on the BRCA2 gene associated with a particularly high risk of stomach cancer. However, a major
weakness of these findings is that when constructing pedigrees, cancers in relatives
were based on patient recall and pathological confirmation was generally not available.
Therefore, it is possible that the risk of stomach cancer in this study may be overestimated
or underestimated.

Impact of BRCA1/2 mutations in other associated cancers

Previous studies have highlighted an association with BRCA1/2 gene mutations and an increased risk of developing cancer in sites other than the
breast and ovary. The association of BRCA1/2 gene mutations with cancer of the prostate, pancreas and stomach has been demonstrated
in a number of studies as discussed in this review. However, carcinomas of the colon
and kidneys, as well as malignant melanoma, have also been reported to be linked with
mutations in the BRCA1/2 genes 20], 44]. Nonetheless, the absolute risks for cancer developing at these other sites are small
19]. The strengths of the associations may be difficult to estimate due to the lower
reported incidence of these cancers in mutation carriers.

Screening for BRCA1/2 mutations

After the discovery of mutations in BRCA1/2 genes, widespread interest in genetic testing developed among women at risk of
harbouring a disease-associated mutation 45]. Screening and genetic testing has the potential to cause unease within a family
as the impact of receiving a positive BRCA mutation diagnosis not only has implications
for the carrier, but all family members. Additionally, in some countries, screening
for BRCA1/2 mutations can result in implications for health and life insurances.

Implications for male BRCA1/2 mutation carriers

Kim et al. 36] report that in most BRCA1/2 testing programmes less than 10 % of the individuals tested are men, yet there is
an equal gender distribution in the population of male and female BRCA1/2 mutation carriers. It is argued that BRCA1/2 mutation screening may be of greater relevance to females as the risks of cancer
are greatly elevated in female BRCA1/2 mutation carriers compared to male 37], however the findings of this review highlight that there are cancer risks for male
carriers of BRCA1/2 mutations therefore screening has relevance for men in their own right, rather than
just to inform risk for relatives.

Several motivation factors prompt individuals to undergo genetic screening. In a study
by Daly et al. 45] 23 of 26 participants cited concern for their offspring as their main motivation
to undergo screening. Concerns about transmitting a mutated gene to daughters appeared
to be a major motivating factor. Results reported by Hallowell et al. 46] generated similar findings and found that all men underwent genetic testing with
the intention of providing information for their children.