Germline variant burden in cancer genes correlates with age at diagnosis and somatic mutation burden

Purpose Among Nigerian women, breast cancer is diagnosed at later stages, is more frequently triple-negative disease, and is far more frequently fatal than in Europe or the United States. We evaluated the contribution of an inherited predisposition to breast cancer in this population. Patients and Methods Cases were 1,136 women with invasive breast cancer (mean age at diagnosis, 47.5 ± 11.5 years) ascertained in Ibadan, Nigeria. Patients were selected regardless of age at diagnosis, family history, or prior genetic testing. Controls were 997 women without cancer (mean age at interview, 47.0 ± 12.4 years) from the same communities. BROCA panel sequencing was used to identify loss-of-function mutations in known and candidate breast cancer genes. Results Of 577 patients with information on tumor stage, 86.1% (497) were diagnosed at stage III (241) or IV (256). Of 290 patients with information on tumor hormone receptor status and human epidermal growth factor receptor 2, 45.9% (133) had triple-negative breast cancer. Among all cases, 14.7% (167 of 1,136) carried a loss-of-function mutation in a breast cancer gene: 7.0% in BRCA1, 4.1% in BRCA2, 1.0% in PALB2, 0.4% in TP53, and 2.1% in any of 10 other genes. Odds ratios were 23.4 (95% CI, 7.4 to 73.9) for BRCA1 and 10.3 (95% CI, 3.7 to 28.5) for BRCA2. Risks were also significantly associated with PALB2 (11 cases, zero controls; P = .002) and TP53 (five cases, zero controls; P = .036). Compared with other patients, BRCA1 mutation carriers were younger ( P < .001) and more likely to have triple-negative breast cancer ( P = .028). Conclusion Among Nigerian women, one in eight cases of invasive breast cancer is a result of inherited mutations in BRCA1, BRCA2, PALB2, or TP53, and breast cancer risks associated with these genes are extremely high. Given limited resources, prevention and early detection services should be especially focused on these highest-risk women.

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Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.195 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 195-195

Author(s):

Simon Yuen Fai Fu ◽

Elie Ritch ◽

Steven Yip ◽

Daniel Khalaf ◽

Sinja Taavitsainen ◽

...

Keyword(s):

Prostate Cancer ◽

Somatic Mutation ◽

Nonnegative Matrix ◽

Castration Resistant Prostate Cancer ◽

Control Cohort ◽

Castration Resistant ◽

Whole Exome ◽

Mutation Burden ◽

Selection For ◽

Poor Outcomes

195 Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% > 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had > 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9 – 11.4) vs. 18.2 m (95% CI 15.1 – 21.3), p = 0.001; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = < 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p < 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.

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Germline MC1R status influences somatic mutation burden in melanoma

Nature Communications ◽

10.1038/ncomms12064 ◽

2016 ◽

Vol 7 (1) ◽

Cited By ~ 70

Author(s):

Carla Daniela Robles-Espinoza ◽

Nicola D. Roberts ◽

Shuyang Chen ◽

Finbarr P. Leacy ◽

Ludmil B. Alexandrov ◽

...

Keyword(s):

Somatic Mutation ◽

Mutation Burden

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Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

10.1101/528182 ◽

2019 ◽

Cited By ~ 1

Author(s):

Gwendolen Lorch ◽

Karthigayini Sivaprakasam ◽

Victoria Zismann ◽

Nieves Perdigones ◽

Tania Contente-Cuomo ◽

...

Keyword(s):

Cell Lines ◽

Somatic Mutation ◽

Transmembrane Domain ◽

Human Cancer ◽

Copy Number Variants ◽

Point Mutations ◽

Lung Cancers ◽

Mutation Burden ◽

Never Smokers ◽

Primary Canine

ABSTRACTNaturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 88 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 38% of canine pulmonary adenocarcinomas (cPAC, 28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, PTEN was the most frequently mutated gene (18%) while one case each bore likely pathogenic HRAS, KRAS, EGFR, MET, TP53, or VHL somatic mutations. In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (13.5%), SMAD4 (5.4%), PTEN (4.1%), and VHL (2.7%). cPACs assessed by exome sequencing displayed a low somatic mutation burden (median 64 point mutations, 19 focal copy number variants, and 1 translocation). The majority (93%) of HER2 mutations were hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E correlated with constitutive phosphorylation of AKT in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines. These findings have translational and comparative relevance for lung cancer and HER2 inhibition.

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Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.5072 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 5072-5072

Author(s):

Simon Yuen Fai Fu ◽

Elie Ritch ◽

Cameron Herberts ◽

Steven Yip ◽

Daniel Khalaf ◽

...

Keyword(s):

Prostate Cancer ◽

Median Time ◽

Somatic Mutation ◽

Clinical Data ◽

Castration Resistant Prostate Cancer ◽

Control Cohort ◽

Mutational Signatures ◽

Whole Exome ◽

Mutation Burden ◽

Homozygous Deletions

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.

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Insights Into the Somatic Mutation Burden of Hepatoblastomas From Brazilian Patients

Frontiers in Oncology ◽

10.3389/fonc.2020.00556 ◽

2020 ◽

Vol 10 ◽

Author(s):

Talita Ferreira Marques Aguiar ◽

Maria Prates Rivas ◽

Silvia Costa ◽

Mariana Maschietto ◽

Tatiane Rodrigues ◽

...

Keyword(s):

Somatic Mutation ◽

Mutation Burden

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