The Genomic Landscape of Mucinous Breast Cancer

Pareja, Fresia; Lee, Ju Youn; Brown, David; Piscuoglio, Salvatore; Gularte‐Mérida, Rodrigo; Selenica, Pier; Paula, Arnaud Da Cruz; Arunachalam, Sasi; Kumar, Rahul; Geyer, Felipe C.; Silveira, Catarina; Silva, Edaise M. da; Li, Anqi; Marchiò, Caterina; Ng, Charlotte K.Y.; Mariani, Odette; Fuhrmann, Laetitia; Wen, Hannah Y.; Norton, Larry; Vincent‐Salomon, Anne; Brogi, Edi; Reis‐Filho, Jorge S.; Weigelt, Britta

doi:10.1093/jnci/djy216

Cited by 68 publications

(106 citation statements)

References 18 publications

(16 reference statements)

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“…Akin to the morphology and behaviour of MPMCs, which are intermediate between those of mucinous carcinomas and micropapillary carcinomas, our analyses revealed that some MPMCs had similarities with micropapillary carcinomas, such as a complex pattern of copy number alterations and 16q losses, whereas others showed simple copy number profiles and lacked concurrent 1q gains and 16q losses, like mucinous carcinomas . Moreover, we did not identify mutations affecting TP53 and PIK3CA or any other significantly mutated gene in breast cancer, akin to mucinous carcinomas, which harbour a lower frequency of TP53 and PIK3CA mutations than common forms of ER‐positive breast cancer . Nonetheless, we identified a frameshift mutation affecting the happloinsufficient gene CUX1 in a pure MPMC (MPMC14), which also showed a 16q loss.…”

Section: Discussionmentioning

confidence: 67%

“…MPMCs feature a hybrid morphology that is intermediate between that of mucinous carcinomas and micropapillary carcinomas . We and others have shown that mucinous carcinomas differ from common forms of ER‐positive breast cancer at the molecular level . Mucinous carcinomas of the breast have a lower rate of mutations affecting PIK3CA and TP53 , which are genes that are commonly mutated in ER‐positive disease.…”

Section: Discussionmentioning

confidence: 98%

“…Mucinous carcinomas of the breast have a lower rate of mutations affecting PIK3CA and TP53 , which are genes that are commonly mutated in ER‐positive disease. Moreover, pure mucinous carcinomas have been shown to lack concurrent 1q gains and 16q losses, which are detected in the majority of common forms of ER‐positive breast cancer . In contrast to mucinous carcinomas, micropapillary carcinomas harbour frequent mutations in PIK3CA and TP53 , and show complex copy number profiles, with recurrent gains of 8q …”

Section: Discussionmentioning

confidence: 99%

“…Whilst the genomic landscape of breast mucinous carcinomas and micropapillary carcinomas has been well characterised, little is known about the genetic alterations of MPMCs. Here, we sought to determine the genetic alterations underpinning MPMCs, and to define whether they overlap with those of mucinous carcinomas and/or micropapillary carcinomas.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 Work by our group and others has led to the identification of pathognomonic genetic alterations in rare breast cancers, such as the MYB-NFIB fusion gene or MYBL1 rearrangements in adenoid cystic carcinoma, 6-10 the IDH2 R172 hotspot or TET2 mutations concurrently with PIK3CA or PIK3R1 mutations in solid papillary carcinomas with reverse polarity, 11,12 and HRAS Q61 hotspot mutations concurrently with PIK3CA mutations in ER-negative adenomyoepitheliomas. 13 The analyses of mucinous carcinomas, [14][15][16] however, have not resulted in the identification of a pathognomonic genetic alteration; rather, these studies have demonstrated that mucinous carcinomas lack PIK3CA mutations, concurrent 16q losses and 1q gains, which are characteristic features of common forms of ER-positive breast cancers. Likewise, breast micropapillary carcinomas have been shown to have genomic features similar to those of luminal B ER-positive invasive ductal carcinomas of no special type.…”

Section: Introductionmentioning

confidence: 99%

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Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma

et al. 2019

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Aims Micropapillary variant of mucinous carcinoma of the breast (MPMC) is a rare histological form of oestrogen receptor (ER)‐positive invasive carcinoma that is characterised by micropapillary clusters of tumour cells in lakes of extracellular mucin. The aims of this study were to determine the genetic alterations underpinning MPMCs, and to determine whether they overlap with those of mucinous carcinomas and/or invasive micropapillary carcinomas. Methods and results DNA from five MPMCs was subjected to whole‐exome sequencing. Somatic mutations, copy number alterations and mutational signatures were determined with state‐of‐the‐art bioinformatics methods. No mutations in genes significantly mutated in breast cancer, including TP53, PIK3CA, GATA3, and MAP3K1, were detected. We identified copy number alterations that have been reported in invasive micropapillary carcinomas, such as recurrent gains in 1q, 6p, 8q, and 10q, and recurrent losses in 16q, 11q, and 13q, as well as a recurrent 8p12–8p11.2 amplification encompassing FGFR1. Like mucinous carcinomas, three of the five MPMCs analysed lacked PIK3CA mutations, 1q gains, and 16q losses, which are the hallmark genetic alterations of ER‐positive breast cancers, whereas two MPMCs harboured 16q losses and/or a complex pattern of copy number alterations similar to those found in breast‐invasive micropapillary carcinomas. Conclusions MPMCs are heterogeneous at the genetic level; some tumours show a pattern of somatic genetic alterations similar to those of mucinous carcinomas, whereas others resemble invasive micropapillary carcinomas at the genetic level. These findings suggest that MPMCs may not constitute one histological subtype, but rather a convergent phenotype that can stem from mucinous carcinomas or invasive micropapillary carcinomas.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma

et al. 2019

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Genomic characterization of small cell carcinomas of the uterine cervix

et al. 2021

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Small cell carcinoma (SCC) of the uterine cervix is a rare and aggressive form of neuroendocrine carcinoma, which resembles small cell lung cancer (SCLC) in its histology and poor survival rate.Here we sought to define the genetic underpinning of SCCs of the uterine cervix and compare their mutational profiles with those of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas, HPV-positive cervical carcinomas and SCLCs using publicly available data. Using a combination of whole-exome and targeted massively parallel sequencing, we found that the nine uterine cervix SCCs, which were HPV18-positive (n=8) or HPV16-positive (n=1), harbored a low mutation burden, few copy number alterations and other than TP53 in two cases no recurrently mutated genes. The majority of mutations were likely passenger missense mutations, and only few affected previously described cancer-related genes. Using RNA-Sequencing, we identified putative viral integration sites on 18q12.3 and on 8p22 in two SCCs of the uterine cervix. The overall nonsilent mutation rate of uterine cervix SCCs was significantly lower than those described for SCLCs, HPV-driven cervical adeno-and squamous cell carcinomas or HPV-positive head and neck squamous cell carcinomas. Unlike SCLCs, which are reported to harbor almost universal inactivating TP53 and RB1 mutations and a dominant tobacco smoke-related signature 4, uterine cervix SCCs rarely harbored mutations affecting these genes (2/9, 22% TP53; 0% RB1) and displayed a dominant aging (67%) or APOBEC mutational signature (17%), akin to HPV-driven cancers, including cervical adeno-and squamous cell carcinomas and head and neck squamous cell carcinomas. Taken together, in contrast to SCLCs, which are characterized by highly recurrent TP53 and RB1 alterations, uterine cervix SCCs were positive for HPV leading to inactivation of the suppressors p53 and RB, suggesting that these SCCs are convergent phenotypes.

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A novel nomogram and risk classification system for predicting lymph node metastasis of breast mucinous carcinoma: A SEER‐based study

Gai

et al. 2022

Cancer Medicine

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Background Mucinous breast cancer (MBC) is a rare disease, and patients with lymph node metastasis (LNM) have a poor prognosis. We aimed to explore the predictive factors of LNM and to construct a nomogram for predicting the risk of LNM and to identify the suitable axillary surgery for patients with diverse risks. Patients and Methods Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Chi‐square and rank‐sum tests were used to analyze the differences between groups. Survival analysis was performed with Kaplan–Meier curves and log‐rank tests. Independent factor identification and nomogram construction were performed with logistic regression analysis. The nomogram was qualified with a discrimination and calibration plot. Propensity score matching was performed to balance the disparities between groups. Results Patients with metastatic lymph nodes have a worse prognosis. Univariate and multivariate analyses indicated that tumor size, grade, and age were independent risk factors for LNM. The nomogram constructed with these three factors can predict the risk of LNM with high accuracy (AUC: 0.767, 95% CI: 0.697–0.838) and good calibration. Based on the nomogram, a risk classification system satisfactorily stratified the patients into 3 groups with diverse risks of LNM. In the low‐risk group, there were no significant differences between sentinel lymph node biopsy and no axillary surgery. In the middle‐ and high‐risk groups, both SLNB and axillary lymph node dissection were superior to no axillary surgery, with similar survival benefits. Conclusions The nomogram based on tumor size, grade, and age could conveniently and accurately predict the risk of LNM in MBC and assist clinicians in optimizing surgical strategies.

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The Genomic Landscape of Mucinous Breast Cancer

Cited by 68 publications

References 18 publications

Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma

Micropapillary variant of mucinous carcinoma of the breast shows genetic alterations intermediate between those of mucinous carcinoma and micropapillary carcinoma

Genomic characterization of small cell carcinomas of the uterine cervix

A novel nomogram and risk classification system for predicting lymph node metastasis of breast mucinous carcinoma: A SEER‐based study

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