Introduction: There is some evidence suggesting a link between BRCA1/2 germline mutations and increased risk of gastric cancer. Methods: Endoscopic screening for stomach malignancies was performed in 120 BRCA1 mutation carriers in order to evaluate the probability of detecting the tumor disease. Results: No instances of gastric cancer were revealed at the first visit. The analysis of atrophic changes performed by OLGA (Operative Link for Gastritis Assessment) criteria revealed that OLGA stages I–IV alterations were observed in 26 of 41 (63%) subjects aged >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ2 test). One BRCA1 mutation carrier developed gastric cancer 4 years after the first visit for endoscopic examination. We performed next-generation sequencing analysis for this tumor and additional 4 archival gastric cancers obtained from BRCA1/2 mutation carriers. Somatic loss of the remaining BRCA1/2 allele was observed in 3 out of 5 tumors analyzed; all of these carcinomas, but none of the malignancies with the retained BRCA1/2 copy, showed chromosomal instability. Conclusion: Taken together, these data justify further studies on the relationships between the BRCA1/2 and gastric cancer.

BRCA1/2 germline mutations significantly increase the lifetime risk of breast and ovarian cancer; therefore, carriers of BRCA1/2 pathogenic alleles are advised to undergo a number of diagnostic and preventive procedures. There is a preponderance of evidence suggesting that inherited BRCA1/2 heterozygosity is associated with an elevated probability of some other tumor types; however, these data are significantly less systematic than the ones obtained for breast and ovarian malignancies [1, 2].

We have recently reported instances of BRCA1 germline mutations in consecutive patients with gastric cancer. Importantly, BRCA1-associated stomach tumors demonstrated somatic loss of the remaining BRCA1 allele, thus supporting the role of inherited BRCA1 defect in predisposition to stomach malignancies [3]. There are some other studies suggesting that gastric cancer is a part of BRCA1/2 syndrome [4-6]. It is essential to recognize that the incidence of stomach carcinomas varies worldwide, depending on the diet, alcohol consumption, hygienic standard, and other factors. Russia is characterized by a significantly higher incidence of stomach cancers as compared to some European countries and the USA [7, 8]. It is possible that the penetrance of BRCA1/2 germline mutations relative to gastric malignancies depends on the aforementioned non-genetic factors. If this is the case, the link between BRCA1/2 heterozygosity and elevated stomach cancer risk would be observed in some but not other regions across the world, which could explain the inconsistency of observed gene-disease associations.

Endoscopic screening is an efficient tool for early gastric cancer diagnosis, which is already applied to healthy populations in countries like Japan [9]. We reasoned that there is sufficient preliminary evidence to justify investigational endoscopic surveillance among BRCA1 germline mutation carriers in order to assess the feasibility of this effort [3-6].

Here, we report the first results of ongoing endoscopic screening for BRCA1 germline mutation carriers, which was launched in the N.N. Petrov Institute of Oncology (St. Petersburg, Russia) and City Cancer Center (St. Petersburg, Russia) in the year 2014. This report describes 120 BRCA1 consecutive germline mutation carriers (median age: 46.5 years; range 19–74; interquartile range [IQR]: 17 [37—54] years; 112 women and 8 men), who were recruited prospectively within the years 2014–2019. These subjects were offered endoscopic examination at their regular visits to their mammologist, gynecologist, or clinical geneticist. Ninety-five patients had a history of breast or ovarian cancer, while 25 subjects remained cancer-free. None of these subjects reported alcohol abuse. All study participants provided informed consent.

The stomach surface was visually examined by an endoscopist for the presence of preneoplastic and neoplastic lesions. Given that atrophic gastritis is the main risk factor for gastric cancer, all patients were also analyzed by the OLGA (Operative Link for Gastritis Assessment) system. Briefly, 5 biopsies from each patient were taken from distinct anatomic regions of the stomach (the greater and lesser curvatures [i.e., mucus-secreting mucosa]; the lesser curvature at the incisura angularis; and the anterior and posterior walls of the proximal corpus [i.e., oxyntic mucosa]). Gastric atrophy was scored in each sample by a four-tiered scale (no atrophy; mild; moderate; severe) depending on the proportion of abnormal glands. OLGA stages (0, I, II, III, IV) were assigned based on the severity of atrophy and the extent of involved anatomic regions of the stomach. Further details on the OLGA system are given in Rugge et al. [10].

BRCA1 somatic loss-of-heterozygosity (LOH) was analyzed in atrophic or tumor samples by digital-droplet PCR as described in Preobrazhenskaya et al. [11]. High-grade gastric dysplasia and gastric carcinoma observed in the same BRCA1 mutation carrier were investigated by whole-exome sequencing (WES) using the methodology described in Sokolenko et al. [12]. We also added to molecular profiling analysis 4 archival gastric cancers, which were identified in BRCA1/2 heterozygotes; 2 of these cases were taken from the study by Moiseyenko et al. [3], while the remaining 2 carcinomas were identified upon routine BRCA1/2 diagnostic testing. One tumor obtained from a BRCA2 carrier was analyzed by WES, whereas 3 additional tumors from BRCA1 carriers were subjected to multigene targeted next-generation sequencing (NGS) for 180 cancer-related genes (see the list in online suppl. Material S1; see www.karger.com/doi/10.1159/000511323for all online suppl. material). DNA libraries for targeted sequencing were prepared using Kapa HyperPlus Kit (Roche, USA). The enrichment was performed by SeqCap EZ Prime Choice Probes (Roche, USA). Somatic mutations in tumor tissues were identified with the MuTect2 tool (https://software.broadinstitute.org/gatk/documentation/tooldocs/3.8-0/org_broadinstitute_gatk_tools_walkers_cancer_m2_MuTect2.php) [13]. Chromosomal instability (CIN), which is a hallmark of the BRCAness phenotype and is manifested by multiple copy number variations spread across the genome, was determined according to the procedure described in Sokolenko et al. [12]. The examples of NGS-based analysis of the copy number variations are given in online supplementary Figure S1.

Primary endoscopic screening for gastric cancer in 120 BRCA1 germline mutation carriers revealed no instances of gastric cancer. Gastric mucosa was analyzed for the presence of atrophic gastritis. BRCA1 carriers demonstrated a correlation between gastric atrophy and older patient age (Spearman’s coefficient = 0.337, p < 0.001). In particular, OLGA stage I–IV mucosal alterations were observed in 26 of 41 (63%) BRCA1 germline mutation carriers >50 years as compared to 29 of 79 (37%) in younger subjects (p = 0.007, χ2 test; Table 1).

Table 1.

Frequency of OLGA atrophy in BRCA1 carriers (n = 120)

Frequency of OLGA atrophy in BRCA1 carriers (n = 120)
Frequency of OLGA atrophy in BRCA1 carriers (n = 120)

Gastric cancer in BRCA1 mutation carriers may develop via somatic inactivation of the remaining BRCA1 allele [3]. We investigated whether atrophic mucosa samples, which were obtained from BRCA1 heterozygous subjects, carry this abnormality. Eleven biopsies with atrophic changes in >40% of gastric glands were subjected to the LOH analysis; no instances of LOH were detected (data not shown).

Subjects with stage IV atrophic gastritis were invited for annual endoscopic examination in order to provide proper gastric cancer surveillance. Three BRCA1 carriers attended this procedure after the initial diagnosis of severe stomach atrophy and did not show evidence of gastric cancer at the follow-up visit.

One BRCA1 germline mutation carrier, who was diagnosed with OLGA stage I atrophy during the screening, requested gastric endoscopy 3 years later due to anxiety. She was diagnosed with antral low-grade intraepithelial neoplasia upon this first follow-up visit. The lesion was removed; however, antral high-grade intraepithelial neoplasia was detected again 1 year later. Four months later, this patient was diagnosed with another epithelial neoplasia in the body of the stomach; however, histological examination of the removed lesion revealed invasive, poorly differentiated gastric adenocarcinoma (Fig. 1). High-grade gastric dysplasia and gastric carcinoma were subjected to BRCA1 LOH analysis and WES. Both lesions retained the remaining BRCA1 allele. The dysplastic sample demonstrated biallelic inactivation of APC gene and 1p36 loss. The adenocarcinoma sample had an intact APC gene but carried a CDH1 frameshift mutation. No evidence for CIN was seen in these samples. This patient previously underwent treatment for ovarian cancer. The ovarian tumor showed BRCA1 LOH, carried Y220C mutation in TP53 oncogene, and had a high frequency of chromosomal imbalances (Table 2).

Table 2.

LOH analysis and driver somatic mutations observed in gastric samples

LOH analysis and driver somatic mutations observed in gastric samples
LOH analysis and driver somatic mutations observed in gastric samples
Fig. 1.

Development of gastric cancer in an ovarian cancer patient carrying a BRCA1 germline mutation (patient GA54). a Endoscopic signs of mucosal atrophy in the antrum: thinning of the mucosa and visible vascular pattern in the submucosa, disappearance of gastric folds, discoloration. b Morphological appearance of intestinal metaplasia (hematoxylin and eosin staining; Alcian blue staining). c Natural history of cancer disease in patient GA54. d Gastric mucosa lesions: atrophic changes in 2015, low-grade dysplasia in 2018, high-grade dysplasia in 2019. e Adenocarcinoma G3 with PAS-positive cells. ACT, adjuvant chemotherapy; EGD, esophagogastroduodenoscopy; EMR, endoscopic mucosal resection; GC, gastric cancer; GIN, glandular intraepithelial neoplasia; HGSOC, high-grade serous ovarian carcinoma; MP, mitomycin + cisplatin; OC, ovarian cancer; P, cisplatin; PDS, primary debulking surgery.

Fig. 1.

Development of gastric cancer in an ovarian cancer patient carrying a BRCA1 germline mutation (patient GA54). a Endoscopic signs of mucosal atrophy in the antrum: thinning of the mucosa and visible vascular pattern in the submucosa, disappearance of gastric folds, discoloration. b Morphological appearance of intestinal metaplasia (hematoxylin and eosin staining; Alcian blue staining). c Natural history of cancer disease in patient GA54. d Gastric mucosa lesions: atrophic changes in 2015, low-grade dysplasia in 2018, high-grade dysplasia in 2019. e Adenocarcinoma G3 with PAS-positive cells. ACT, adjuvant chemotherapy; EGD, esophagogastroduodenoscopy; EMR, endoscopic mucosal resection; GC, gastric cancer; GIN, glandular intraepithelial neoplasia; HGSOC, high-grade serous ovarian carcinoma; MP, mitomycin + cisplatin; OC, ovarian cancer; P, cisplatin; PDS, primary debulking surgery.

Close modal

We examined our registry and identified 4 additional gastric cancers diagnosed in BRCA1/2 mutation carriers (BRCA1: n = 4, including the tumor described above; BRCA2: n = 1; Table 2). All these stomach carcinomas were available for molecular analysis. Loss of the remaining BRCA1/2 allele was detected in 3 of these tumors. Strikingly, all tumors with BRCA1/2 somatic loss showed a high frequency of allelic imbalances, while cancers with the retained BRCA1/2 function had a stable chromosomal status (Table 2).

This study considered 120 BRCA1 germline mutation carriers. None of the invited subjects manifested with gastric cancer at the first visit; however, one woman was diagnosed with stomach malignancy during follow-up. It is difficult to conclude from these preliminary data whether BRCA1 mutation carriers require specific efforts for gastric cancer detection. Indeed, the probability of detecting gastric cancer in an adult individual at the first screening visit approaches approximately 0.1% [14]. Even if we assume that the presence of BRCA1 mutation increases the risk of stomach malignancy by several-fold, it will require a significantly larger study to evaluate the probability of detecting gastric cancer in BRCA1 heterozygotes.

There are several important limitations related to this investigation. Endoscopic examination is currently the only available tool for efficient diagnosis of early gastric cancer. Therefore, in contrast to other screening procedures for BRCA1 mutation carriers, which rely mainly on imaging analysis, proper examination of the stomach requires a semi-invasive intervention. Endoscopic examination, being an unpleasant procedure, is also associated with some risk of complications [9]. Therefore, it is difficult to organize large-scale systematic clinical investigations involving gastric endoscopy. The lack of a proper control group is a critical but unavoidable drawback of this study. The recruitment of healthy individuals for this type of investigation is impossible in Russia, given that endoscopy may be offered only to subjects who have a clinical indication for this diagnostic procedure.

This study paid specific attention to the efficient detection of atrophic gastritis, given the fact that stomach atrophy is a well-established risk factor for gastric cancer [10]. Although this statement is certainly true for the general population, it is not at all self-evident that the development of gastric cancer in BRCA1 germline mutation carriers occurs via visually detectable preneoplastic changes such as mucosal atrophy. Furthermore, comparison with literature data is complicated as well, as the majority of published studies recruited patients with some stomach-related symptoms (Table 3). In addition, interobserver variability may contribute to some interstudy variations. Therefore, the direct numerical comparison of distribution of OLGA stages between various data sets is complicated [19].

Table 3.

OLGA distribution in different studies

OLGA distribution in different studies
OLGA distribution in different studies

There are multiple confounding factors affecting the probability of gastric cancer detection. We invited all adult BRCA1 germline mutation carriers to receive stomach examinations. Some of these subjects were younger than 25 years (n = 8; 7 healthy subjects and 1 woman with breast cancer), that is, belonged to the age group with a very low incidence of gastric cancer. Ninety-five BRCA1 mutation carriers were diagnosed with breast or ovarian cancer 0–7 years before endoscopic examination and received neoadjuvant or adjuvant cytotoxic therapy. BRCA1-driven cancers are known to be sensitive to chemotherapy [23]; therefore, one could expect that preceding systemic treatment could have resulted in the regression of small BRCA1-driven tumors. The protective effect of some chemotherapeutic regimens on the development of subsequent tumors is well known from breast cancer studies [24].

It is worth acknowledging that BRCA1 mutation carriers demonstrated a clear age-related increase in the frequency of atrophy. One may speculate that BRCA1 haploinsufficiency predisposes to gastric atrophy in aged individuals; however, it is of notice that systematic analysis of atrophic mucosal specimens in BRCA1 mutation carriers revealed no instances of somatic loss of the remaining BRCA1 allele. There are also several studies suggesting an age-related increase of gastric abnormalities determined by the OLGA system [17, 20].

It is also important to comment that we could not collect a critical mass of BRCA2 mutation carriers because BRCA2 pathogenic alleles are rare in Russians. BRCA2 has a distinct repertoire of associated tumors compared to BRCA1: in addition to breast and ovarian cancers, it also predisposes to prostate and pancreatic malignancies [25-27]. It is unclear, whether BRCA1 and BRCA2 demonstrate differences with regard to the risk of stomach cancer or gastric atrophy.

The molecular analysis of gastric cancers arising in BRCA1/2 mutation carriers reveals 2 clearly distinct categories of tumors. Some tumors develop via the loss of the remaining BRCA1/2 allele and demonstrate evident CIN. They resemble “canonical” BRCA1/2-driven carcinomas and are likely to be responsive to platinum agents and PARP inhibitors [2, 15]. Overall, these tumors demonstrate a clear causal relationship with the presence of a BRCA1 germline defect. On the other hand, there are gastric tumors which retain BRCA1 function and remain chromosomally stable. These molecular features are characteristic for some non-breast/ovarian tumors which develop in BRCA1/2 heterozygotes [2]. It is unclear whether inheritance of a BRCA1 mutation played a role in the pathogenesis of these cancers and what is the mechanism of predisposition to this type of neoplasm.

Taken together, our data provide justification for further studies on stomach health in BRCA1/2 mutation carriers. It would be feasible to collect available data on the results of endoscopic examination of BRCA1/2-mutated individuals with regard to the incidence of gastric atrophy and cancer. Meticulous registration and analysis of non-breast/ovarian cancers arising in BRCA1/2 heterozygotes continues to be important. There is also a need to collect and investigate instances of combined occurrence of breast/ovarian and gastric cancer within individuals or families. The available data are sufficient to conclude that BRCA1/2 germline mutations contribute to the development of a subset of stomach cancers; however, the extent of this contribution and the feasibility of medical consideration of this relationship remain to be determined.

This study was approved by the local Ethics Committee. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

The authors have no conflicts of interest to declare.

Patient selection, endoscopic screening, morphological analysis, and whole-exome sequencing were supported by the Russian Science Foundation (grant number 19-15-00168). Targeted NGS analysis was supported by the Russian Foundation for Basic Research (grant number 18-29-09090).

A.A.A. and E.N.I.: conceptualization. A.A.A., A.O.I., A.P.S., and E.N.I.: methodology. A.O.I., M.A.K., M.A.M., I.V.B., G.A.R., K.V.S., T.V.G., A.A.B., E.I.A., O.A.V., A.A.R., V.I.N., R.V.B., O.B.T., and A.M.S.: formal analysis and investigation. A.A.A., A.P.S., A.J.W., and E.N.I.: writing – original draft preparation. All authors: writing – review and editing. A.P.S.: funding acquisition.

1.
Cavanagh
H
,
Rogers
KM
.
The role of BRCA1 and BRCA2 mutations in prostate, pancreatic and stomach cancers
.
Hered Cancer Clin Pract
.
2015
Aug
;
13
(
1
):
16
.
[PubMed]
1731-2302
2.
Jonsson
P
,
Bandlamudi
C
,
Cheng
ML
,
Srinivasan
P
,
Chavan
SS
,
Friedman
ND
, et al
Tumour lineage shapes BRCA-mediated phenotypes
.
Nature
.
2019
Jul
;
571
(
7766
):
576
9
.
[PubMed]
0028-0836
3.
Moiseyenko
VM
,
Volkov
NM
,
Suspistin
EN
,
Yanus
GA
,
Iyevleva
AG
,
Kuligina
ES
, et al
Evidence for predictive role of BRCA1 and bTUBIII in gastric cancer
.
Med Oncol
.
2013
Jun
;
30
(
2
):
545
.
[PubMed]
1357-0560
4.
Sahasrabudhe
R
,
Lott
P
,
Bohorquez
M
,
Toal
T
,
Estrada
AP
,
Suarez
JJ
, et al;
Latin American Gastric Cancer Genetics Collaborative Group
.
Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer
.
Gastroenterology
.
2017
Apr
;
152
(
5
):
983
986.e6
.
[PubMed]
0016-5085
5.
Ichikawa
H
,
Wakai
T
,
Nagahashi
M
,
Shimada
Y
,
Hanyu
T
,
Kano
Y
, et al
Pathogenic germline BRCA1/2 mutations and familial predisposition to gastric cancer
.
JCO Precis Oncol
.
2018
;
2
(
2
):
1
8
.
[PubMed]
2473-4284
6.
Kim
H
,
Choi
DH
,
Park
W
,
Im
YH
,
Ahn
JS
,
Park
YH
, et al
The association between non-breast and ovary cancers and BRCA mutation in first- and second-degree relatives of high-risk breast cancer patients: a large-scale study of Koreans
.
Hered Cancer Clin Pract
.
2019
Jan
;
17
(
1
):
1
.
[PubMed]
1731-2302
7.
Bertuccio
P
,
Chatenoud
L
,
Levi
F
,
Praud
D
,
Ferlay
J
,
Negri
E
, et al
Recent patterns in gastric cancer: a global overview
.
Int J Cancer
.
2009
Aug
;
125
(
3
):
666
73
.
[PubMed]
0020-7136
8.
Ferro
A
,
Peleteiro
B
,
Malvezzi
M
,
Bosetti
C
,
Bertuccio
P
,
Levi
F
, et al
Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype
.
Eur J Cancer
.
2014
May
;
50
(
7
):
1330
44
.
[PubMed]
0959-8049
9.
Hamashima
C
;
Systematic Review Group and Guideline Development Group for Gastric Cancer Screening Guidelines
.
Update version of the Japanese Guidelines for Gastric Cancer Screening
.
Jpn J Clin Oncol
.
2018
Jul
;
48
(
7
):
673
83
.
[PubMed]
0368-2811
10.
Rugge
M
,
Correa
P
,
Di Mario
F
,
El-Omar
E
,
Fiocca
R
,
Geboes
K
, et al
OLGA staging for gastritis: a tutorial
.
Dig Liver Dis
.
2008
Aug
;
40
(
8
):
650
8
.
[PubMed]
1590-8658
11.
Preobrazhenskaya
EV
,
Bizin
IV
,
Kuligina
ES
,
Shleykina
AY
,
Suspitsin
EN
,
Zaytseva
OA
, et al
Detection of BRCA1 gross rearrangements by droplet digital PCR
.
Breast Cancer Res Treat
.
2017
Oct
;
165
(
3
):
765
70
.
[PubMed]
0167-6806
12.
Sokolenko
AP
,
Bizin
IV
,
Preobrazhenskaya
EV
,
Gorodnova
TV
,
Ivantsov
AO
,
Iyevleva
AG
, et al
Molecular profiles of BRCA1-associated ovarian cancer treated by platinum-based therapy: analysis of primary, residual and relapsed tumors
.
Int J Cancer
.
2020
Apr
;
146
(
7
):
1879
88
.
[PubMed]
0020-7136
13.
Van der Auwera
GA
,
Carneiro
M
,
Hartl
C
,
Poplin
R
,
Del Angel
G
,
Levy-Moonshine
A
, et al
From FastQ Data to High-Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline. Current protocols in bioinformatics.
2013
;43(1110):11.10.1-11.10.33.
14.
Park
YM
,
Kim
JH
,
Baik
SJ
,
Park
JJ
,
Youn
YH
,
Park
H
.
Clinical risk assessment for gastric cancer in asymptomatic population after a health check-up: an individualized consideration of the risk factors
.
Medicine (Baltimore)
.
2016
Nov
;
95
(
44
):
e5351
.
[PubMed]
0025-7974
15.
Rugge
M
,
de Boni
M
,
Pennelli
G
,
de Bona
M
,
Giacomelli
L
,
Fassan
M
, et al
Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study
.
Aliment Pharmacol Ther
.
2010
May
;
31
(
10
):
1104
11
.
[PubMed]
0269-2813
16.
Rugge
M
,
Fassan
M
,
Pizzi
M
,
Farinati
F
,
Sturniolo
GC
,
Plebani
M
, et al
Operative link for gastritis assessment vs operative link on intestinal metaplasia assessment
.
World J Gastroenterol
.
2011
Nov
;
17
(
41
):
4596
601
.
[PubMed]
1007-9327
17.
Rugge
M
,
Meggio
A
,
Pravadelli
C
,
Barbareschi
M
,
Fassan
M
,
Gentilini
M
, et al
Gastritis staging in the endoscopic follow-up for the secondary prevention of gastric cancer: a 5-year prospective study of 1755 patients
.
Gut
.
2019
Jan
;
68
(
1
):
11
7
.
[PubMed]
0017-5749
18.
Rugge
M
,
Genta
RM
,
Fassan
M
,
Valentini
E
,
Coati
I
,
Guzzinati
S
, et al
OLGA Gastritis Staging for the Prediction of Gastric Cancer Risk: A Long-term Follow-up Study of 7436 Patients
.
Am J Gastroenterol
.
2018
Nov
;
113
(
11
):
1621
8
.
[PubMed]
0002-9270
19.
Isajevs
S
,
Liepniece-Karele
I
,
Janciauskas
D
,
Moisejevs
G
,
Putnins
V
,
Funka
K
, et al
Gastritis staging: interobserver agreement by applying OLGA and OLGIM systems
.
Virchows Arch
.
2014
Apr
;
464
(
4
):
403
7
.
[PubMed]
0945-6317
20.
Nam
JH
,
Choi
IJ
,
Kook
MC
,
Lee
JY
,
Cho
SJ
,
Nam
SY
, et al
OLGA and OLGIM stage distribution according to age and Helicobacter pylori status in the Korean population
.
Helicobacter
.
2014
Apr
;
19
(
2
):
81
9
.
[PubMed]
1083-4389
21.
Zhou
Y
,
Li
HY
,
Zhang
JJ
,
Chen
XY
,
Ge
ZZ
,
Li
XB
.
Operative link on gastritis assessment stage is an appropriate predictor of early gastric cancer
.
World J Gastroenterol
.
2016
Apr
;
22
(
13
):
3670
8
.
[PubMed]
1007-9327
22.
Zhang
M
,
Liu
S
,
Hu
Y
,
Bao
HB
,
Meng
LN
,
Wang
XT
, et al
Biopsy strategies for endoscopic screening of pre-malignant gastric lesions
.
Sci Rep
.
2019
Oct
;
9
(
1
):
14909
.
[PubMed]
2045-2322
23.
Iyevleva
AG
,
Imyanitov
EN
.
Cytotoxic and targeted therapy for hereditary cancers
.
Hered Cancer Clin Pract
.
2016
Aug
;
14
(
1
):
17
.
[PubMed]
1731-2302
24.
Kramer
I
,
Schaapveld
M
,
Oldenburg
HS
,
Sonke
GS
,
McCool
D
,
van Leeuwen
FE
, et al
The influence of adjuvant systemic regimens on contralateral breast cancer risk and receptor subtype
.
J Natl Cancer Inst
.
2019
Jul
;
111
(
7
):
709
18
.
[PubMed]
0027-8874
25.
van Asperen
CJ
,
Brohet
RM
,
Meijers-Heijboer
EJ
,
Hoogerbrugge
N
,
Verhoef
S
,
Vasen
HF
, et al;
Netherlands Collaborative Group on Hereditary Breast Cancer (HEBON)
.
Cancer risks in BRCA2 families: estimates for sites other than breast and ovary
.
J Med Genet
.
2005
Sep
;
42
(
9
):
711
9
.
[PubMed]
0022-2593
26.
Page
EC
,
Bancroft
EK
,
Brook
MN
,
Assel
M
,
Hassan Al Battat
M
,
Thomas
S
, et al;
IMPACT Study Collaborators
.
Interim Results from the IMPACT Study: Evidence for Prostate-specific Antigen Screening in BRCA2 Mutation Carriers
.
Eur Urol
.
2019
Dec
;
76
(
6
):
831
42
.
[PubMed]
0302-2838
27.
Breast Cancer Linkage Consortium
T
;
Breast Cancer Linkage Consortium
.
Cancer risks in BRCA2 mutation carriers
.
J Natl Cancer Inst
.
1999
Aug
;
91
(
15
):
1310
6
.
[PubMed]
0027-8874
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