Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer

Megan Ren,Boyang Cao,Anaseidy Albanez,Megan Frone,Lilian Barreda,Michael Dean,Anali Orozco,Jeremy Ortiz,Dongjing Wu,Lisa Garland,Sergio Ralon,Eduardo Gharzouzi,Roberto Orozco,Victor Argueta,Lusheng Wang,Jiahui Wang,Charles C Chung,Christian S Alvarez,Kang Shao

doi:10.1007/s10549-021-06305-5

Abstract

PurposeMutations in hereditary breast cancer genes play an important role in the risk for cancer.MethodsCancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome.ResultsA total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001).ConclusionsHereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.

Highlights

Breast cancer is the most commonly diagnosed cancer among women worldwide
We found that 77% of patients with pathogenic variants in high or moderate penetrance breast cancer genes met National Comprehensive Cancer Network (NCCN) criteria for genetic screening compared to 59% of all others (Table 1)
We found 11% (73/664) carry pathogenic variants in high and moderate penetrance breast cancer susceptibility genes

Summary

Introduction

In Latin America and the Caribbean, breast cancer accounted for 15% of all cancer cases among women in 2018 [1]. Genetic testing for germline mutations in breast cancer susceptibility genes can identify individuals with a higher risk of developing breast cancer. Still there is limited information on the mutation profile of many Latin American populations [2, 3]. A study conducted in Latin American women referred for genetic testing showed that they have equal or higher rates of BRCA1 and BRCA2 mutations (15%) as other groups [4]. The frequency of hereditary cancer gene mutations has been described for other Latin American populations and U.S Hispanics, but only one previous study included 19 patients from Guatemala[5,6,7,8]

Methods

Results

Conclusion