Expanding the Phenotypic Spectrum of BRCA1-Associated HBOC: Gastric Cancer and a Salivary Gland Tumor in a Colombian Family

doi:10.21203/rs.3.rs-4714352/v1

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Case Report

Expanding the Phenotypic Spectrum of BRCA1-Associated HBOC: Gastric Cancer and a Salivary Gland Tumor in a Colombian Family

https://doi.org/10.21203/rs.3.rs-4714352/v1

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Objective

This study aims to broaden the understanding of the BRCA1-associated Hereditary Breast and Ovarian Cancer (HBOC) syndrome by highlighting its link to non-traditional cancer types such as gastric and salivary gland tumors in a Colombian family.

Case Presentation:

We present the case of a 61-year-old woman with mucoepidermoid carcinoma of the salivary gland who underwent significant surgical treatment. The family history revealed a diverse cancer pattern, including gastric, breast, and colorectal cancers across four generations in the paternal lineage. Genetic testing confirmed a BRCA1: p.Gln1111Asnfs*5, diverging from the common breast or ovarian cancer manifestations of HBOC syndrome.

Conclusion

The study underscores the necessity of including gastrointestinal and salivary gland cancers in the spectrum of HBOC syndrome associated with BRCA1 variants. It advocates for extensive genetic counseling and testing for families displaying a broad range of cancer types. This contribution supports the diversification of associated cancer types with BRCA1 and encourages further research into precise therapies and management approaches for affected individuals.

BRCA1

Salivary Gland Tumor

Gastric Cancer

HBOC

The widespread use of sequencing technologies has deepened our understanding of genetic variability related to breast (BC) and ovarian cancer (OC) risk. Besides BRCA1/2, other genes such as PALB2, PTEN, TP53, ATM, CDH1, STK11, and CHEK2 also contribute to clinical risk with varying penetrance levels [1, 2, 3]. Pathogenic and Likely Pathogenic (P/LP) variants in these genes may result in pleiotropic tumor syndromes, with BC being one of several manifestations [4].

P/LP variants in BRCA1/2 genes, traditionally associated with BC and OC, have also been linked to prostate and melanoma cancers, expanding the phenotypic spectrum of Hereditary Breast and Ovarian Cancer Syndrome (HBOC) [5, 6]. Recent evidence includes less frequent tumors like gastric cancer (GC) and gastrointestinal stromal tumors (GIST) as part of the HBOC spectrum [6, 7]. Shen et al. suggest that families with HBOC linked to BRCA genes may be more susceptible to salivary gland tumors (SGTs) [8]. Additionally, case reports describe patients with BRCA1 variants developing head and neck tumors, indicating a broader phenotypic spectrum [9].

This report presents a comprehensive case of a large Colombian family segregating a BRCA1 pathogenic variant: c.3331_3334delCAAG, p.Gln1111Asnfs*5. This family demonstrates co-segregation of the variant with occurrences of GC and SGTs, malignancies not traditionally associated with the HBOC phenotype.

Case Description

The proband is a 61-year-old female referred to the Head and Neck Surgery Unit at the National Institute of Cancerology due to a progressively enlarging left parotid mass. This mass was associated with ipsilateral otalgia, limited mouth opening, and weight loss over five months. A paranasal sinus computed tomography (CT) scan localized the mass within the left parotid gland, involving adjacent subcutaneous and submandibular tissues, and identified suspicious lymph node enlargement in the ipsilateral region without bony infiltration (Fig. 1a).

A biopsy revealed a high-grade carcinoma with squamous differentiation (Fig. 1c, d). Immunohistochemistry showed positivity for cytokeratin (CK) A1/AE3, epithelial membrane antigen (EMA), CK5/6, P63, and CK7 markers, with focal CEA expression. CK20 and androgen receptors were negative. The Ki-67 proliferation index was high at 80%, confirming a diagnosis of high-grade mucoepidermoid carcinoma of the parotid gland.

The patient underwent extensive surgery, including partial parotidectomy, segmental mandibulectomy, lateral hypopharyngectomy, left-sided neck dissection, and tracheostomy, with reconstruction achieved using a fibula flap (Fig. 1b). The surgery was completed without complications.

Family History

The proband's significant family history of cancer prompted a referral for genetic counseling. Her family, from both maternal and paternal lineages, originates from southwestern Colombia, specifically the Andean region (Huila). Analysis of the family pedigree (Fig. 2) revealed an informative paternal lineage due to several relatives with various malignancies. In total, 16 members across four generations in the paternal lineage (Fig. 2), including siblings and nieces, were affected by cancers such as colorectal (3/16), GC (5/16), thyroid (2/16), and BC (6/16), as well as one unspecified cancer (Table 1). Notably, two members were affected by metachronous tumors.

Table 1

Distribution of Cancer Types and Clinical Presentation in Paternal Lineage Relatives of the Proband
ID	Type Cancer	Age to Onset	BRCA1 variant	Relation to Proband
Proband	SCG	62	+	-
III12	Breast	52	+	1st degree (sister)
III12	Colorectal	66	+	1st degree (sister)
III13	Breast	65	-	1st degree (sister)
III14	Gastric	82	-	1st degree (sister)
II4	Gastric	72	-	1st degree (father)
IV	Thyroid	51	-	2d degree
IV7	Breast (Bilateral)	57	-	2d degree
II1	Colorectal	60–70*	-	3rd degree
II2	Gastric	50–60*	-	3rd degree
III1	Cancer non-specified	> 50*	-	4th degree
III2	Gastric	40	-	4th degree
III5	Gastric	48	+	4th degree
III5	Breast	50	+	4th degree
III6	Breast	> 50*	-	4th degree
III7	Breast	> 50*	-	4th degree
III8	Thyroid	70	-	4th degree
IV1	Colorectal	37	-	5th degree
(+) Variant carrier identified by germline molecular testing; (-) Not tested or not identified as a carrier. *Unclear information provided.

The paternal cousin of the proband, individual III-5, was diagnosed with metachronous cancer, presenting with GC at 48 years and unilateral breast carcinoma at 50 years. Due to this presentation, the MyRisk® Hereditary Cancer Test was performed, identifying a germline heterozygous BRCA1 pathogenic frameshift variant c.3331_3334delCAAG, p.Gln1111Asnfs*5. This was the first case where this variant established a diagnosis of HBOC syndrome in the paternal lineage. The second confirmed case of the same BRCA1 variant was one of the proband's sisters, who was diagnosed with unilateral breast carcinoma at 52 years and colorectal cancer at 66 years.

Considering the comprehensive family history and the identification of the BRCA1: p.Gln1111Asnfs*5, in a close relative, the proband underwent next-generation sequencing (NGS) multi-cancer panel testing, including BRCA1, BRCA2, and PALB2 genes. This confirmed the presence of the BRCA1 variant c.3331_3334delCAAG, p.Gln1111Asnfs*5, thereby establishing a diagnosis of HBOC syndrome.

Through this diagnosis, genetic counseling provided the patient with essential information and a personalized follow-up plan. This included a gastroenterology consultation due to the family's history of gastrointestinal cancers, which are not typically associated with HBOC. Cascade screening in relatives was recommended, and it identified additional carriers IV5 and IV7. The latter was diagnosed with bilateral BC during follow-up. Importantly, after two years of follow-up, the proband has not developed any other cancers related to HBOC or the broader spectrum of family-associated cancers.

The concept of a broader phenotypic spectrum for HBOC syndrome was first proposed in 1994 by Ford et al., who identified patients with P/LP BRCA1 variants at an increased risk for cancers beyond BC and OC, including colorectal and prostate cancers [10]. Large-scale studies have since supported this notion, showing that individuals with P/LP BRCA1 variants have an elevated risk of various cancers, particularly GC [6, 11, 12]. Variability in cancer presentation in HBOC syndrome has been linked to the specific gene involved (BRCA1 or BRCA2), the location and type of the variant within the gene [13, 14], ancestry, and the geographic distribution of carriers due to environmental factors or genetic ancestral backgrounds [14, 15].

Here, we present the phenotypic oncological spectrum of a large Colombian family carrying the BRCA1: c.3331_3334del, p.Gln1111Asnfs*5 (rs80357903) pathogenic variant in exon 10, which is predicted to undergo NMD (Nonsense Mediated Decay) mechanism. This variant corresponds to a founder mutation in the Andean region, originating from Iberia and introduced to Colombia during the American colonization [16–20]. It has been associated with the typical spectrum of cancers linked to P/LP BRCA1 variants, such as BC and OC. Notably, this variant has also been identified in families with GC and colorectal cancers [18, 19, 21, 22]. Torres et al. [18] reported five families segregating this variant, with three showing members with GC and two with colorectal cancer. Sahasrabudhe et al [21]. reported two cases with this variant and diffuse GC.

The association between BRCA genes and GC risk has been extensively studied (Table 2). The first population study to identify this association was conducted by the Breast Cancer Linkage Consortium in 1999, confirming a significant risk for BRCA2 carriers (RR 2.59, CI 1.46–4.61) [23]. Subsequent studies have supported these findings. Differences in cancer presentation by age have also been reported: at 50 years (0.15%, CI 0.04–0.39) and 70 years (1.88%, CI 1.05–3.12) [24]. Momozawa et al. (2022) highlighted significant odds ratios for both BRCA1 (OR 5.2, CI 2.6–10.5) and BRCA2 (OR 4.7, CI 1.8–30), noting different peak ages of cancer presentation for BRCA1 (30–39 years) and BRCA2 (60–69 years) [6]. The age of GC onset in P/LP BRCA variants carriers typically aligns with known patterns: women with BRCA1 variants have a higher risk of developing BC rapidly until about age 30–40, while BRCA2 diagnosis increases until about age 40–50 [25].

Table 2

Studies Reporting the Association between *BRCA1/2* Mutations and Increased Risk of Gastric and Salivary Gland Cancers
Cancer Type	Year	Gene	Estimated Incidence	Estimated Risk	Risk Association	Clinical information	Ref
Gastric	1994	BRCA1	1 observed case vs 0.76 expected cases	RR 1.11 (p > 0.05)	Not significant	-	Ford et al. [10]
	1999	BRCA2	-	RR 2.59 (CI 1.46–4.61)	Confirmed	-	Breast Cancer Linkage Consortium [23]
	2001	BRCA1/2	(BRCA1) 4.9%; (BRCA2) 1.8%	(BRCA1) RR 6.2 (CI 2.0–19); (BRCA2) RR 2.3 (CI 0.30–18)	Confirmed	-	Risch et al. [36]
	2004	BRCA1/2	1.88% (CI 1.05–3.12%) vs 0.92%	-	Confirmed	Study for both genes, risk calculated by age: 50 years (0.15%, CI 0.04–0.39); 70 years (1.88%, CI 1.05–3.12).	Bermejo et al. [24]
	2012	BRCA1/2	Family GC incidence 24.7% vs 20.5%	RR 0.947 (CI 0.288–1.091)	Not significant	-	Noh et al. [37]
	2019	BRCA1/2	Family GC incidence 13.8% vs 7.4%	OR 1.666 (CI 1.183–2.345)	Confirmed	-	Kim et al. [11]
	2020	BRCA1/2	Family GC incidence 11.9% vs 5.5%	p > 0.001	Confirmed	Squamous cell tumor	Sun et al. [12]
	2021	BRCA1/2	-	BRCA1: RR 1.70 (CI 0.93–3.09); BRCA2: RR 2.15 (CI 1.98–2.33)	Confirmed	Only BRCA2	Lee et al. [38]
	2022	BRCA1/2	-	BRCA1: OR 5.2 (CI 2.6–10.5); BRCA2: OR 4.7 (CI 1.8–30)	Confirmed	For BRCA1, the most frequent age of gastric cancer presentation is 30–39 years, and for BRCA2 it is 60–69 years.	Momozawa et al. [6]
Salivary gland	2014	BRCA1/2	3 out of 5754 (0.052%); incidence 0.003%	p < 0.001	Confirmed	Non-Clinical Characterization	Shen et al. [8]
	2020	BRCA1	Case report	-	Suggested	Diagnosis at 55 years. Genetic testing identified: BRCA1: p.Ser157fs*1.	De Barros et al. [9]
	2021	BRCA1	Case Series (5 families).	-	Suggested	Only two cases (Diagnosis at 55 and 65 years) with genetic testing identified: BRCA1: p.Ser267Lysfs19 and BRCA2: p.Lys3161.	Ripamonti et al. [7]
(-) No additional information reported.

Interestingly, reported cases of GC onset for BRCA1: p.Gln1111Asnfs*5 carriers are usually above 50 years (range 50–70) [18]. In our family, GC was diagnosed in members ranging from 40 to 82 years, with a mean age of 60 years (Table 1). This suggests that this variant may be associated with GC at an advanced age, possibly related to a strong interaction between BRCA1 carriers and environmental factors.

The relationship between BRCA1 and environmental factors, particularly Helicobacter pylori infection, has been extensively studied. Usui et al. suggest that H. pylori infection can significantly increase GC risk, especially in individuals carrying P/LP variants in the Homologous Recombination Repair (HRR) pathway, which includes BRCA1 [26]. Families carrying P/LP variants in HRR genes often share the same H. pylori strains, potentially amplifying the risk [26]. This study found a significantly higher prevalence of BRCA1/2 and ATM variants in Japanese GC patients with H. pylori infection compared to those without infection (OR 20.25 vs. 5.76), suggesting an additive effect where H. pylori-induced genomic instability may further elevate GC risk in BRCA1 variants carriers. Identifying such high-risk populations could be crucial for early detection and prevention strategies.

Salivary gland tumors are considered rare entities, accounting for 3–10% of all head and neck tumors [27]. They are mostly sporadic and not typically related to hereditary cancer syndromes [28]. However, similarities between salivary glands and mammary glands have suggested possible similarities in their carcinogenesis. Both salivary and mammary glands are exocrine tissues, sharing a similar embryological origin as tubuloacinar exocrine glands, and their tumors often exhibit overlapping morphological and immunohistochemical features [29, 30]. Salivary duct carcinomas share similar structures and histologic features with certain forms of BC, including overexpression of ERBB2 and the presence of estrogen or progesterone receptors. They also exhibit pathologic features, such as sclerosing polycystic adenosis, which resembles fibrocystic changes in the breast [28]. Additionally, ERBB2-positive salivary duct carcinomas have been reported to respond well to trastuzumab, a treatment also used for HER2-positive BC [31]. These observations have supported potential genetic links, particularly with BRCA genes [7, 9, 32].

Though evidence is limited (Table 2), the association between BRCA genes and salivary gland cancer began to be explored by Shen et al. (2014) [8], who identified an incidence of 0.052% of salivary gland cancers among 5754 carriers of BRCA1/2 variants (p < 0.001). Since then, only a few studies have reported associations between pathogenic/likely pathogenic variants in BRCA genes and salivary gland cancers. De Barros et al. [9] reported a case of a Brazilian female diagnosed with metachronous tumors, including bilateral BC (first at 33 years), primary papillary thyroid carcinoma (53 years), and primary mucoepidermoid carcinoma in the right parotid (55 years), carrying a pathogenic BRCA1 variant: c.470_471delCT, p.Ser157fs*1, found in exon 7 and predicted to lead to NMD. Although segregation of the variant was not proven, the authors described four relatives with untested BRCA1, including one case of non-smoking-related lung cancer, two cases of smoking-related laryngeal cancer, and a paternal aunt with GC diagnosed at 50 years old.

Ripamonti et al. [7] described a case series of five families from the Istituto Nazionale Tumori of Milan carrying BRCA variants and salivary gland cancers. Although only two cases were well characterized and lacked detailed family descriptions, the first case involved a 56-year-old man with a parotid myoepithelial carcinoma with lung and bone metastases. Genetic testing revealed a BRCA1 variant: c.798_799delTT, p.Ser267Lysfs19, in exon 10, predicted to undergo NMD. The second case involved a 66-year-old male diagnosed with submandibular papillary cystadenocarcinoma, with genetic testing showing a nonsense variant BRCA2: c.9481A > T, p.Lys3161, also predicted to undergo NMD.

Our case is the first well-characterized large family with a diverse oncologic spectrum, including SGCs, segregating a BRCA1 variant. All reported cases, including ours, identified BRCA1 frameshift variants in exons not typically considered hotspots, particularly exon 10, usually a “cold spot” [33, 34]. These BRCAs variants generate null alleles and undergo NMD. HBOC presentation varies by variant type and location; BC is more associated with NMD variants, while OC is linked to non-NMD variants [14, 15]. This pattern matches our family, which has no OC cases, and the case reported by De Barros et al. [9]. Like GC, SGCs in BRCA1 carriers are often diagnosed after 50 years, indicating a specific presentation in these individuals. However, further research is needed to understand the clinical, pathological, and molecular patterns described in this family and the particularities of the association of SGC and GC in BRCA-related HBOC. Genotype-phenotype family characterization is a valid approach to understanding the expanded spectrum of hereditary cancer syndromes like HBOC, enhancing personalized follow-up and treatment.

More importantly, considering the introduction of PARP inhibitors (PARPi), which improve progression-free and distant disease-free survival in individuals with germline and somatic P/LP variants in HRR pathway genes, particularly BRCA1/2 [35], recognizing the expanded spectrum of BRCA1 oncological phenotypes could broaden the benefits of PARPi treatment to patients with tumors beyond the classic HBOC spectrum who harbor BRCA1 mutations. Thus, we suggest that clinicians consider BRCA1 mutation screening in patients with SGTs and GC, especially those with a family history suggestive of HBOC.

Here, we present the largest family characterization of a family segregating a BRCA1 pathogenic variant and SCG. This report highlights the broader phenotypic spectrum of HBOC syndrome associated with the BRCA1: p.Gln1111Asnfs*5 mutation, with GC being the most common tumor after BC. The findings emphasize the importance of comprehensive genetic counseling and screening for diverse cancer types in families with BRCA1 mutations. Additionally, environmental factors like Helicobacter pylori infection may further elevate GC risk. This underscores the need to characterize BRCA1-carrying families for personalized follow-ups and potential directed treatments for a wider range of BRCA1-associated cancers.

Ethics approval and consent to participate: The Institutional Review Board of the National Cancer Institute of Colombia approved the carrying out of this case report.

Consent for publication: Informed consent was obtained from the proband, who also accepted the publication of this report.

Availability of data and materials: Not applicable

Competing interests: Not applicable

Funding: Not applicable

Authors' contributions: WT and JCRM contributed equally to structuring and writing final manuscript, collecting information, and designing and creating tables and images. EV contributed to structuring the paper, collecting and organizing information, and writing the manuscript. DFB, RPM, and EC collected information and contributed to the general writing of the manuscript discussion. All authors read and approved the final manuscript.

Acknowledgements: Not applicable

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No competing interests reported.

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Expanding the Phenotypic Spectrum of BRCA1-Associated HBOC: Gastric Cancer and a Salivary Gland Tumor in a Colombian Family

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Objective

Case Presentation:

Conclusion

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Introduction

Case Presentation and Family History

Case Description

Family History

Discussion

Conclusion

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References

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