Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations

Deb, Siddhartha; Wong, Stephen Q.; Li, Jason; Do, Hongdo; Weiss, Jonathan M.; Byrne, David; Bosma, Trent J.; Fellowes, Andrew; Dobrovic, Alexander; Fox, Stephen B.

doi:10.1038/bjc.2014.511

Cited by 21 publications

(20 citation statements)

References 35 publications

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“…We reported the occurrence of PIK3CA amplification at higher frequency than that previously reported in MBC [26]. The frequency of PIK3CA amplification found in our study is consistent with that reported in FBC [27–29].…”

Section: Discussionsupporting

confidence: 92%

Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers

et al. 2016

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Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from its largely known female counterpart. We aimed at investigating whether MBC cases harbor somatic alterations of genes known as prognostic biomarkers and molecular therapeutic targets in female breast cancer.We examined 103 MBC cases, all characterized for germ-line BRCA1/2 mutations, for somatic alterations in PIK3CA, EGFR, ESR1 and CCND1 genes.Pathogenic mutations of PIK3CA were detected in 2% of MBCs. No pathogenic mutations were identified in ESR1 and EGFR. Gene copy number variations (CNVs) analysis showed amplification of PIK3CA in 8.1%, EGFR in 6.8% and CCND1 in 16% of MBCs, whereas deletion of ESR1 was detected in 15% of MBCs. Somatic mutations and gene amplification were found only in BRCA1/2 mutation negative MBCs.Significant associations emerged between EGFR amplification and large tumor size (T4), ER-negative and HER2-positive status, between CCND1 amplification and HER2-positive and MIB1-positive status, and between ESR1 deletion and ER-negative status.Our results show that amplification of targetable oncogenes is frequent in BRCA1/2 mutation negative MBCs and may identify MBC subsets characterized by aggressive phenotype that may benefit from potential targeted therapeutic approaches.

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Section: Discussionsupporting

confidence: 92%

Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers

et al. 2016

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“…Somatic HRAS‐ activating PVs are frequently found in salivary gland, urinary tract, upper aerodigestive tract and cervical cancer, but are rarely observed in breast cancer (< 1%) . Moreover, duplications of HRAS have only been found in tumors of male breast cancer patients carrying a pathogenic germline BRCA2 variant . It is unknown whether or not the observed HRAS duplication has a dosage effect or if aberrant HRAS expression influences tumor development at all.…”

Section: Discussionmentioning

confidence: 99%

“…35,36 Moreover, duplications of HRAS have only been found in tumors of male breast cancer patients carrying a pathogenic germline BRCA2 variant. 37 It is unknown whether or not the observed HRAS duplication has a dosage effect or if aberrant HRAS expression influences tumor development at all. To the best of our knowledge, this is the first report of a germline HRAS duplication identified in HBOC patients.…”

Section: Discussionmentioning

confidence: 99%

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

Schubert

Luttikhuizen

Auber

et al. 2019

Intl Journal of Cancer

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NGS‐based multiple gene panel resequencing in combination with a high resolution CGH‐array was used to identify genetic risk factors for hereditary breast and/or ovarian cancer in 237 high risk patients who were previously tested negative for pathogenic BRCA1/2 variants. All patients were screened for pathogenic variants in 94 different cancer predisposing genes. We identified 32 pathogenic variants in 14 different genes (ATM, BLM, BRCA1, CDH1, CHEK2, FANCG, FANCM, FH, HRAS, PALB2, PMS2, PTEN, RAD51C and NBN) in 30 patients (12.7%). Two pathogenic BRCA1 variants that were previously undetected due to less comprehensive and sensitive methods were found. Five pathogenic variants are novel, three of which occur in genes yet unrelated to hereditary breast and/or ovarian cancer (FANCG, FH and HRAS). In our cohort we discovered a remarkably high frequency of truncating variants in FANCM (2.1%), which has recently been suggested as a susceptibility gene for hereditary breast cancer. Two patients of our cohort carried two different pathogenic variants each and 10 other patients in whom a pathogenic variant was confirmed also harbored a variant of unknown significance in a breast and ovarian cancer susceptibility gene. We were able to identify pathogenic variants predisposing for tumor formation in 12.3% of BRCA1/2 negative breast and/or ovarian cancer patients.

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“…In The Cancer Genome Atlas (TCGA) project, six MaBCs were included, of which all were of luminal subtype, two harbored PIK3CA somatic mutations and none had TP53 mutations (13). The repertoire of genetic alterations affecting 48 common cancer genes has been analyzed in familial MaBCs (BRCA1, BRCA2 and BRCAX patients) (14); these tumors were found to display a mutational landscape similar to that of luminal A FBCs, with PIK3CA being the most commonly mutated gene (17%) in addition to infrequent TP53 and PTEN mutations (4% and 2%, respectively) (14). Substantial differences were detected, however, between BRCA2 and ‘BRCAX’ patients.…”

Section: Introductionmentioning

confidence: 99%

“…Substantial differences were detected, however, between BRCA2 and ‘BRCAX’ patients. Whilst TP53 mutations were only found in BRCA2 cases (14), PIK3CA mutations were significantly more prevalent in BRCAX patients (15), suggesting that BRCA2-associated MaBCs may have distinct genomic features, possibly due to the DNA repair defect caused by BRCA2 mutations.…”

Section: Introductionmentioning

confidence: 99%

The Genomic Landscape of Male Breast Cancers

Piscuoglio

Murray

et al. 2016

Clinical Cancer Research

131

129

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Purpose Male breast cancer (MaBC) is rare and its genomic landscape has yet to be fully characterized. Lacking studies in men, treatment of MaBC patients is extrapolated from results in females with the disease (FBC). We sought to define whether MaBCs harbor somatic genetic alterations in genes frequently altered in FBCs. Experimental Design All MaBCs were estrogen receptor-positive and all but two were HER2 negative. 59 MaBCs were subtyped by immunohistochemistry and tumor-normal pairs were microdissected and subjected to massively parallel sequencing targeting all exons of 241 genes frequently mutated in FBCs or DNA-repair related. The repertoires of somatic mutations and copy number alterations of MaBCs were compared to that of subtype-matched FBCs. Results 29% and 71% of MaBCs were immunohistochemically classified as luminal A-like or luminal B-like, respectively. MaBCs displayed a heterogeneous repertoire of somatic genetic alterations that to some extent recapitulated that of estrogen receptor (ER)-positive/HER2-negative FBCs, including recurrent mutations affecting PIK3CA (20%) and GATA3 (15%). ER-positive/HER2-negative MaBCs, however, less frequently harbored 16q losses, and PIK3CA and TP53 mutations than ER-positive/HER2-negative FBCs. In addition, MaBCs were found to be significantly enriched for mutations affecting DNA repair-related genes. Conclusion MaBCs less frequently harbor somatic genetic alterations typical of ER-positive/HER2-negative FBCs, such as PIK3CA and TP53 mutations and losses of 16q, suggesting that at least a subset of MaBCs are driven by a distinct repertoire of somatic changes. Given the genomic differences, caution may be needed in the application of biological and therapeutic findings from studies of FBCs to MaBCs.

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Mutational profiling of familial male breast cancers reveals similarities with luminal A female breast cancer with rare TP53 mutations

Cited by 21 publications

References 35 publications

Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers

Somatic alterations of targetable oncogenes are frequently observed in BRCA1/2 mutation negative male breast cancers

The identification of pathogenic variants in BRCA1/2 negative, high risk, hereditary breast and/or ovarian cancer patients: High frequency of FANCM pathogenic variants

The Genomic Landscape of Male Breast Cancers

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