Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan

Fizza Akbar, Zahraa Siddiqui, Muhammad Talha Waheed, Lubaina Ehsan, Syed Ibaad Ali, Hajra Wiquar, Azmina Tajuddin Valimohammed, Shaista Khan, Lubna Vohra, Sana Zeeshan, Yasmin Rashid, Munira Moosajee, Adnan Abdul Jabbar, Muhammad Nauman Zahir, Naila Zahid, Rufina Soomro, Najeeb Niamat Ullah, Imran Ahmad, Ghulam Haider, Uzair Ansari, Arjumand Rizvi, Arif Mehboobali, Abida Sattar, Salman Kirmani, Fizza Akbar, Zahraa Siddiqui, Muhammad Talha Waheed, Lubaina Ehsan, Syed Ibaad Ali, Hajra Wiquar, Azmina Tajuddin Valimohammed, Shaista Khan, Lubna Vohra, Sana Zeeshan, Yasmin Rashid, Munira Moosajee, Adnan Abdul Jabbar, Muhammad Nauman Zahir, Naila Zahid, Rufina Soomro, Najeeb Niamat Ullah, Imran Ahmad, Ghulam Haider, Uzair Ansari, Arjumand Rizvi, Arif Mehboobali, Abida Sattar, Salman Kirmani

Abstract

Background: Breast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally. Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5-10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored.

Methods: Retrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020. Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher's exact, Pearson's chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05.

Results: Out of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5-48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42-5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers.

Conclusions: In our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase.

Keywords: Consensus guidelines; Genetic counseling; Genetic services manuscript; Genetic testing; Germline pathogenic variant; Hereditary breast Cancer.

Conflict of interest statement

The authors claim no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
The spectrum of the identified variants is summarized, showing 45% of the positive results are attributed to non BRCA1/2 genes
Fig. 2
Fig. 2
A Patient characteristics of the study participants (flow chart). B Patient Disease characteristics and triage framework of the study

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