Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

Dana Farengo Clark, Scott T Michalski, Rashmi Tondon, Bita Nehoray, Jessica Ebrahimzadeh, Sarah Kate Hughes, Emily R Soper, Susan M Domchek, Anil K Rustgi, Daniel Pineda-Alvarez, Michael J Anderson, Bryson W Katona, Dana Farengo Clark, Scott T Michalski, Rashmi Tondon, Bita Nehoray, Jessica Ebrahimzadeh, Sarah Kate Hughes, Emily R Soper, Susan M Domchek, Anil K Rustgi, Daniel Pineda-Alvarez, Michael J Anderson, Bryson W Katona

Abstract

Purpose: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied.

Methods: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers.

Results: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers.

Conclusion: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Keywords: CTNNA1; breast cancer; cancer risk assessment; diffuse gastric cancer; multigene panel testing.

Conflict of interest statement

The following conflicts of interest are reported: B.N.: advisory board (Invitae); S.T.M., D.P.-A., M.J.A.: employment (Invitae), Shareholder (Invitae); S.M.D.: honoraria (AstraZeneca, Clovis, Bristol-Myers Squibb); B.W.K.: consulting (Exact Sciences), travel (Janssen). The other authors declare no conflicts of interest.

Figures

Fig. 1. Individuals undergoing CTNNA1 sequencing.
Fig. 1. Individuals undergoing CTNNA1 sequencing.
Flow chart showing prior cancer history of all individuals undergoing CTNNA1 sequencing between October 2015 and July 2019, as well as delineation of the CTNNA1 sequencing results. LOF loss of function, VUS variant of uncertain significance.
Fig. 2. CTNNA1 family 13.
Fig. 2. CTNNA1 family 13.
a Pedigree of family 13. Red = gastric cancer, yellow = breast cancer and lobular carcinoma in situ (LCIS), gray = other cancers. (b, c) Hematoxylin & eosin (H&E) staining and α-E-catenin immunohistochemistry (IHC) of endoscopic biopsies of the family 13 proband’s diffuse signet-ring cell gastric adenocarcinoma (b) and the proband’s unaffected normal gastric mucosa (c). Images obtained at 20×.
Fig. 3. CTNNA1 family 14.
Fig. 3. CTNNA1 family 14.
a Pedigree of family 14. Red = gastric cancer, gray = other cancers. b Hematoxylin & eosin (H&E) staining and α-E-catenin immunohistochemistry (IHC) of a lymph node metastasis of the family 14 proband’s diffuse signet-ring cell gastric adenocarcinoma. Images obtained at 20×.
Fig. 4. CTNNA1 family 15.
Fig. 4. CTNNA1 family 15.
Pedigree of family 15. Yellow = breast cancer, gray = other cancers.

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