MyMedR

Displaying all 4 publications

Abstract:

Sort:

Tumor Budding Detection System in Whole Slide Pathology Images

Fauzi MFA, Chen W, Knight D, Hampel H, Frankel WL, Gurcan MN

J Med Syst, 2019 Dec 18;44(2):38.
PMID: 31853654 DOI: 10.1007/s10916-019-1515-y

Tumor budding is defined as the presence of single tumor cells or small tumor clusters (less than five cells) that 'bud' from the invasive front of the main tumor. Tumor budding (TB) has recently emerged as an important adverse prognostic factor for many different cancer types. In colorectal carcinoma (CRC), tumor budding has been independently associated with lymph node metastasis and poor outcome. Pathologic assessment of tumor budding by light microscopy requires close evaluation of tumor invasive front on intermediate to high power magnification, entailing locating the 'hotspot' of tumor budding, counting all TB in one high power field, and generating a tumor budding score. By automating these time-consuming tasks, computer-assisted image analysis tools can be helpful for daily pathology practice, since tumor budding reporting is now recommended on select cases. In this paper, we report our work on the development of a tumor budding detection system in CRC from whole-slide Cytokeratin AE1/3 images, based on de novo computer algorithm that automates morphometric analysis of tumor budding.
Fulltext Association of ESR1 Germline Variants with TP53 Somatic Variants in Breast Tumors in a Genome-wide Study

Tjader NP, Beer AJ, Ramroop J, Tai MC, Ping J, Gandhi T, et al.

Cancer Res Commun, 2024 Jun 27;4(6):1597-1608.
PMID: 38836758 DOI: 10.1158/2767-9764.CRC-24-0026

In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors. A genome-wide association study was conducted in 2,850 women of European ancestry with breast cancer using TP53 and PIK3CA mutation status (positive or negative) as well as specific functional categories [e.g., TP53 gain-of-function (GOF) and loss-of-function, PIK3CA activating] as phenotypes. Germline variants showing evidence of association were selected for validation analyses and tested in multiple independent datasets. Discovery association analyses found five variants associated with TP53 mutation status with P values <1 × 10-6 and 33 variants with P values <1 × 10-5. Forty-four variants were associated with PIK3CA mutation status with P values <1 × 10-5. In validation analyses, only variants at the ESR1 locus were associated with TP53 mutation status after multiple comparisons corrections. Combined analyses in European and Malaysian populations found ESR1 locus variants rs9383938 and rs9479090 associated with the presence of TP53 mutations overall (P values 2 × 10-11 and 4.6 × 10-10, respectively). rs9383938 also showed association with TP53 GOF mutations (P value 6.1 × 10-7). rs9479090 showed suggestive evidence (P value 0.02) for association with TP53 mutation status in African ancestry populations. No other variants were significantly associated with TP53 or PIK3CA mutation status. Larger studies are needed to confirm these findings and determine if additional variants contribute to ancestry-specific differences in mutation frequency.
SIGNIFICANCE: Emerging data show ancestry-specific differences in TP53 and PIK3CA mutation frequency in breast tumors suggesting that germline variants may influence somatic mutational processes. This study identified variants near ESR1 associated with TP53 mutation status and identified additional loci with suggestive association which may provide biological insight into observed differences.
Fulltext Association of ESR1 germline variants with TP53 somatic variants in breast tumors in a genome-wide study

Tjader NP, Beer AJ, Ramroop J, Tai MC, Ping J, Gandhi T, et al.

medRxiv, 2023 Dec 06.
PMID: 38106140 DOI: 10.1101/2023.12.06.23299442

BACKGROUND: In breast tumors, somatic mutation frequencies in TP53 and PIK3CA vary by tumor subtype and ancestry. HER2 positive and triple negative breast cancers (TNBC) have a higher frequency of TP53 somatic mutations than other subtypes. PIK3CA mutations are more frequently observed in hormone receptor positive tumors. Emerging data suggest tumor mutation status is associated with germline variants and genetic ancestry. We aimed to identify germline variants that are associated with somatic TP53 or PIK3CA mutation status in breast tumors.
METHODS: A genome-wide association study was conducted using breast cancer mutation status of TP53 and PIK3CA and functional mutation categories including TP53 gain of function (GOF) and loss of function mutations and PIK3CA activating/hotspot mutations. The discovery analysis consisted of 2850 European ancestry women from three datasets. Germline variants showing evidence of association with somatic mutations were selected for validation analyses based on predicted function, allele frequency, and proximity to known cancer genes or risk loci. Candidate variants were assessed for association with mutation status in a multi-ancestry validation study, a Malaysian study, and a study of African American/Black women with TNBC.
RESULTS: The discovery Germline x Mutation (GxM) association study found five variants associated with one or more TP53 phenotypes with P values <1×10-6, 33 variants associated with one or more TP53 phenotypes with P values <1×10-5, and 44 variants associated with one or more PIK3CA phenotypes with P values <1×10-5. In the multi-ancestry and Malaysian validation studies, germline ESR1 locus variant, rs9383938, was associated with the presence of TP53 mutations overall (P values 6.8×10-5 and 9.8×10-8, respectively) and TP53 GOF mutations (P value 8.4×10-6). Multiple variants showed suggestive evidence of association with PIK3CA mutation status in the validation studies, but none were significant after correction for multiple comparisons.
CONCLUSIONS: We found evidence that germline variants were associated with TP53 and PIK3CA mutation status in breast cancers. Variants near the estrogen receptor alpha gene, ESR1, were significantly associated with overall TP53 mutations and GOF mutations. Larger multi-ancestry studies are needed to confirm these findings and determine if these variants contribute to ancestry-specific differences in mutation frequency.
Fulltext Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Martin RM, Lewis SJ, et al.

Nat Commun, 2020 01 30;11(1):597.
PMID: 32001714 DOI: 10.1038/s41467-020-14389-8

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.