Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan

Rashid, Muhammad Usman; Khan, Faiz Ali; Muhammad, Noor; Loya, Asif; Hamann, Ute

doi:10.4143/crt.2018.356

Cited by 11 publications

(9 citation statements)

References 53 publications

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“…The present study included 302 early-onset and familial breast cancer patients with ER positive and/or PR positive tumors. All study participants were tested negative for pathogenic variants in BRCA1, BRCA2 [17,18] and about 60% for pathogenic variants in PALB2 (n = 187), TP53 (n = 180), CHEK2 (n = 168), and RAD51C (n = 168) [13][14][15][16] (Muhammad U. Rashid, unpublished TP53 data). We categorized study participants into four risk groups based on age at cancer diagnosis or family history of breast and/or ovarian cancer (Table 1) [17].…”

Section: Study Subjectsmentioning

confidence: 99%

“…umd.be/HSF3/), GeneSplicer (http://ccb.jhu.edu/software/ genesplicer/), and SpliceSiteFinder-like (http://www.umd. be/searchSpliceSite.html) for splice-site and intronic variants [14]. In case of any disagreement between clinical and functional evidence, the clinical evidence was considered more convincing.…”

Section: Variant Classificationmentioning

confidence: 99%

“…The burden of breast cancer in terms of estimated age-standardised incidence and mortality rates is 43.9 and 23.2 per 100,000, respectively [12]. Pathogenic variants in high-and moderate-penetrance breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, RAD51C, and PALB2) account for about 27% of early-onset and familial breast cancers in Pakistan [13][14][15][16][17], leaving a substantial proportion of cases unexplained. In the present study, we determined the contribution of pathogenic RECQL variants to hereditary breast cancer in 302 early-onset and familial BRCA1 and BRCA2 negative patients with ER positive and/or PR positive breast cancer in a South Asian population from Pakistan.…”

Section: Introductionmentioning

confidence: 99%

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Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

Rashid

Muhammad

Khan

et al. 2020

Hered Cancer Clin Pract

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Background The RecQ Like Helicase (RECQL) gene has previously been shown to predispose to breast cancer mainly in European populations, in particular to estrogen receptor (ER) and/or progesterone receptor (PR) positive tumor. Here, we investigated the contribution of pathogenic RECQL germline variants to hereditary breast cancer in early-onset and familial breast cancer patients from Pakistan. Methods Comprehensive RECQL variant analysis was performed in 302 BRCA1 and BRCA2 negative patients with ER and/or PR positive breast tumors using denaturing high-performance liquid chromatography followed by DNA sequencing. Novel variants were classified using Sherloc guidelines. Results One novel pathogenic protein-truncating variant (p.W75*) was identified in a 37-year-old familial breast cancer patient. The pathogenic variant frequencies were 0.3% (1/302) in early-onset and familial breast cancer patients and 0.8% (1/133) in familial patients. Further, three novel variants of unknown significance, p.I141F, p.S182S, and p.C475C, were identified in familial breast cancer patients at the age of 47, 68, and 47 respectively. All variants were absent in 250 controls. Conclusions Our data suggest that the RECQL gene plays a negligible role in breast cancer predisposition in Pakistan.

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Section: Study Subjectsmentioning

confidence: 99%

Section: Variant Classificationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

Rashid

Muhammad

Khan

et al. 2020

Hered Cancer Clin Pract

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“…In contrast to these two sets of genes, PALB2 (15%) and RAD51C (8%) showed significantly higher proportions than previous findings for young women with breast cancer carrying positive mutations (1%) [8]. Recent studies have reported that PALB2 represents 1%-4% [15][16][17] of total mutations in early-onset breast cancer. Our study found that, overall, PALB2 accounted for 2% and RAD51C for 1% of the germline pathogenic variants.…”

Section: Pathogenic Variants In Young Women With Breast Cancermentioning

confidence: 57%

Clinically Relevant Germline Mutations in a Cohort of Young Women with Breast Cancer: A Comprehensive Analysis of Hereditary-Cancer Genes from Whole-Exome Sequencing

Gomez-Flores-Ramos¹,

Dean²,

Jones³

et al. 2020

Preprint

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Young women with breast cancer represent 15% of cancer cases in Latin America. Genomic studies have found that early-onset breast-cancer cases exhibit a higher genetic susceptibility and a specific genomic signature as compared to their older counterparts. The aim of this study was to describe clinically relevant germline mutations in a cohort of young women with breast cancer. To achieve this, we analyzed hereditary-cancer genes from whole-exome sequencing data in 108 unrelated women with an extreme phenotype of breast cancer (≤40 years of age), diagnosed and treated at the National Cancer Institute of Mexico; 11% of the patients carried a pathogenic variant. BRCA2 comprised 46% of the mutations, followed by BRCA1 with 23%; PALB2 with 15%; and TP53 and RAD51C with 8 % each. This article describes a novel pathogenic mutation in RAD51C c.519dupT. The median age at diagnosis was 35 years overall; however, it was six years younger in patients with mutations. Age at diagnosis (OR=0.82, CI 95% 0.71-0.94; P= 0.008) and first-degree family history of cancer (OR=8.26, CI95% 1.35-50; P= 0.022) were the only epidemiological variables associated with mutational status. We found no differences in disease-free survival (p=0.403) or overall survival (p=0.735) among mutational status subgroups.

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“…Indeed, germline mutations in BRCA1 and BRCA2 are the most important risk factors for hereditary breast and ovarian cancer and contribute to 5%-10% of breast cancers, being inherited in an autosomal dominant manner (Shih et al, 2002;Skol, Sasaki, & Onel, 2016). Besides BRCA1/2 genes, other cancer predisposition genes (ATM,PALB2,TP53,BARD1,CHEK2) are also implicated in hereditary breast cancer (Elledge & Allred., 1998;Meijers-Heijboer et al, 2002;Usman, Khan, Muhammad, Loya, & Hamann, 2018;Walsh & King., 2007).…”

Section: Introductionmentioning

confidence: 99%

MICA‐129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population

Ouni

Chaaben

Ayari

et al. 2020

Int J Immunogenetics

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Identification of candidate genes associated with susceptibility of breast cancer can have a significant impact at a cancer management national healthcare systems level, making genetic testing more affordable and cost‐effective. We have previously shown that the major histocompatibility complex class I‐related chain A (MICA) was related to breast cancer and plays an important role in modulating immune response mechanisms through NKG2D receptor activation. Compared to our previous study, in this work, we recruited a new cohort composed of 354 unrelated Tunisian women affected by breast cancer and 380 age‐matched women as controls, all genotyped for MICA‐129 Met/Val (rs 1051792). Subsequently, we exanimated the distribution of this polymorphism in ten families. As a result, an association was found between the Val allele and Val/Val genotype and the risk of breast cancer (p = 2.5 × 10–15; OR = 2.40; p = 6.5 × 10–13; OR = 3.03, respectively). Stratified analysis with age and family history of cancer revealed an association between the Val/Val genotype and younger patients <40 years (p = .003; OR = 2.03). Among those patients having a family history of cancer, 68% had a Val/Val genotype (p = .02; OR = 1.82). In the family study, an analyse of pedigrees revealed that the majority of families showed the development of breast cancer at a young age. Moreover, all patients diagnosed with early‐onset breast cancer had a Val/Val genotype. Our results lead us to propose that this polymorphism may be an inherited genetic biomarker contributing to an increased breast cancer risk in Tunisian women.

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Prevalence of PALB2 Germline Mutations in Early-onset and Familial Breast/Ovarian Cancer Patients from Pakistan

Cited by 11 publications

References 53 publications

Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

Prevalence of RECQL germline variants in Pakistani early-onset and familial breast cancer patients

Clinically Relevant Germline Mutations in a Cohort of Young Women with Breast Cancer: A Comprehensive Analysis of Hereditary-Cancer Genes from Whole-Exome Sequencing

MICA‐129 Met/Val polymorphism could be a genetic biomarker for Familial Breast Cancer in the Tunisian population

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