Jian Carrot-Zhang

Broad Institute of MIT and Harvard · Cancer Program

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth a...

Several moderate- and high-risk breast cancer susceptibility genes have been discovered, but more are likely to exist. To discover new breast cancer susceptibility genes, we used 2 populations (from Poland and Quebec, Canada) and applied whole-exome sequencing in a discovery phase (n = 195), followed by validation. We identified rare recurrent RECQ...

We evaluated ancestry effects on mutation rates, DNA methylation, and mRNA and miRNA expression among 10,678 patients across 33 cancer types from The Cancer Genome Atlas. We demonstrated that cancer subtypes and ancestry-related technical artifacts are important confounders that have been insufficiently accounted for. Once accounted for, ancestry-a...

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, E...

The digitization of health records and growing availability of tumour DNA sequencing provide an opportunity to study the determinants of cancer outcomes with unprecedented richness. Patient data are often stored in unstructured text and siloed datasets. Here we combine natural language processing annotations1,2 with structured medication, patient-r...

Obesity is a risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. We examined the relationship between obesity and tumor genotype in two clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma and cancers of unknown primaries, ind...

PURPOSE In lung squamous cell carcinoma (LUSC), Black patients show significantly higher incidence and lower overall survival than White patients. Although socioeconomic factors likely contribute to this survival disparity, genomic factors have yet to be elucidated in LUSC. METHODS Using 416 LUSC tumor samples in the Cancer Genome Atlas (TCGA), we...

Genetic similarity of populations (or genetic ancestry) contributes to cancer driving alterations. We performed a meta-analysis leveraging two real-world cohorts of targeted gene panel sequencing, comprising 275,605 tumor samples, to investigate ancestry-associated somatic alterations across 14 common cancers. We focused on five continental ancestr...

A growing body of research highlighted a strong presence of continuums that describe human genomic diversity. Historical scholarship has also extensively investigated the use of discrete classification systems in human genomics further questioning their validity. To investigate the limiting effect of pre-defined stratification, we performed a wide...

Clinical data storage in unstructured notes and siloed datasets present a major challenge for large-scale cancer informatics. Whether natural language processing (NLP) combined with multimodal integration across datasets can produce a mineable resource and improve discovery of relationships between tumor genomics and clinical phenotypes is unknown....

Allostatic load (AL) is the cumulative burden of chronic stress and life events typically measured by lab and vital values routinely collected during standard care. AL has been associated with adverse socioenvironmental stressors and increased mortality rates including risk of cancer death. Despite modifications of AL as a result of progressing can...

Background Racial disparities in outcomes exist in endometrial cancer (EC). The contribution of ancestry‐based variations in germline pathogenic variants (gPVs) is unknown. Methods Germline assessment of ≥76 cancer predisposition genes was performed in patients with EC undergoing tumor‐normal Memorial Sloan Kettering Cancer Center Integrated Mutat...

Introduction Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. Methods A retrospective review of patients with renal cell car...

Background. Recent decades have witnessed a steady decrease in the use of race categories in genomic studies. While studies that still include race categories vary in goal and type, these categories already build on a history during which racial color lines have been enforced and adjusted in the service of social and political systems of power and...

People with different ancestries inherit different risks and encounter different environmental exposures resulting in different somatic profiles. A lack of knowledge about ancestry-specific alterations is a major barrier to implementing precision medicine, leading to inequities in genetic testing, targeted treatment and clinical trial design for ca...

Differential mRNA expression between ancestry groups can be explained by both genetic and environmental factors. We outline a computational workflow to determine the extent to which germline genetic variation explains cancer-specific molecular differences across ancestry groups. Using multi-omics datasets from The Cancer Genome Atlas (TCGA), we enu...

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation shapes the genomic landscape...

CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutati...

People with different ancestries inherit different risks and encounter different environmental exposures resulting in different somatic profiles. A lack of knowledge about ancestry-specific alterations is a major barrier to implementing precision medicine, leading to inequities in genetic testing, targeted treatment and clinical trial design for ca...

Immune checkpoint blockade (CPB) improves melanoma outcomes, but many patients still do not respond. Tumor mutational burden (TMB) and tumor-infiltrating T cells are associated with response, and integrative models improve survival prediction. However, integrating immune/tumor-intrinsic features using data from a single assay (DNA/RNA) remains unde...

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscap...

Inherited lung cancer risk, particularly in nonsmokers, is poorly understood. In particular, the frequency of somatic EGFR and KRAS mutations in lung cancer varies by ethnicity. Somatic EGFR mutation rates are higher in lung cancers from patients with East Asian ancestry and lower in patients with European or African ancestry. Somatic KRAS mutation...

CDC20 is a co-activator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/C CDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic muta...

Background Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1 , the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving S...

Cancer immunotherapy with checkpoint blockade (CPB) leads to improved outcomes in melanoma and other tumor types, but a majority of patients do not respond. High tumor mutation burden (TMB) and high levels of tumor-infiltrating T cells have been associated with response to immunotherapy, but integrative models to predict clinical benefit using DNA...

Cellular and molecular aberrations contribute to the disparity of human cancer incidence and etiology between ancestry groups. Multiomics profiling in The Cancer Genome Atlas (TCGA) allows for querying of the molecular underpinnings of ancestry-specific discrepancies in human cancer. Here, we provide a protocol for integrative associative analysis...

RTK/RAS/RAF pathway alterations (RPAs) are a hallmark of lung adenocarcinoma (LUAD). In this study, we use whole-genome sequencing (WGS) of 85 cases found to be RPA(−) by previous studies from The Cancer Genome Atlas (TCGA) to characterize the minority of LUADs lacking apparent alterations in this pathway. We show that WGS analysis uncovers RPA(+)...

Inherited lung cancer risk, particularly in non-smokers, is poorly understood. Genomic and ancestry analysis of 1153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden (TMB), and specific driver mutations in EGFR, KRAS, and STK11. A local Nat...

Inherited lung cancer risk, particularly in non-smokers, is poorly understood. Genomic and ancestry analysis of 1,153 lung cancers from Latin America revealed striking associations between Native American ancestry and their somatic landscape, including tumor mutational burden (TMB), and specific driver mutations in EGFR, KRAS , and STK11 . A local...

p>Cancer immunotherapy with checkpoint blockade has improved survival and outcomes in melanoma, but still a majority of patients do not respond. Both high tumor mutation burden (TMB) and high T cell infiltration have been associated with response, but integrative models based on DNA or RNA assays have not been comprehensively explored and validated...

Lung adenocarcinomas (LUAD) are typically characterized by genetic activation of the receptor tyrosine kinase (RTK)/RAS/RAF/MAP kinase (MAPK) pathway. A minority of LUAD cases (20-25%) lack apparent genetic alterations in this pathway, and thus are ineligible for most targeted therapies. These candidate “oncogene negative” LUADs may harbor novel cl...

Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic st...

Background: African American men have more than twice the age-adjusted mortality rate from prostate cancer than European American men. Lower rate of PSA screening, less aggressive treatment, and other socioeconomic factors have been raised as possible reasons for this disparity, but genetic differences between prostate cancers from African and Euro...

Background The frequency of targetable somatic genomic alterations is known to differ based on a patient's ancestry; for example, in lung adenocarcinoma EGFR mutations are more common in East Asians than Europeans. Accurately characterizing these differences will help to illuminate differences in the genetic etiology of cancer between populations....

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangeme...

In a differential cytotoxicity screen, we identified a novel small molecule modulator of phosphodiesterase 3A (PDE3A) that kills cancer cells expressing elevated levels of PDE3A and SLFN12 (de Waal, Nat Chem Biol, 2016). Treatment with this cell-selective cytotoxic small molecule, DNMDP, induces complex formation between PDE3A and SLFN12, resulting...

Introduction: Cdc20 is a co-activator recruited by the anaphase-promoting complex (APC), a large, multi-subunit complex that functions as an Ubiqutin ligase that targets key substrates for degradation to promote cell cycle progression. During mitosis the APC/Cdc20 complex is inhibited by the spindle assembly checkpoint (SAC) pathway, which ensures...

Precision medicine (PM) can be defined as a predictive, preventive, personalized, and participatory healthcare service delivery model. Recent developments in molecular biology and information technology make PM a reality today through the use of massive amounts of genetic, 'omics', clinical, environmental, and lifestyle data. With cancer being one...

Background: Dysembryoplastic neuroepithelial tumors (DNETs) are benign developmental brain tumors associated with intractable, drug-resistant epilepsy. Distinguishing this entity from other low-grade ganglioneuronal tumors is challenging for neuro-pathologists. We set out to identify the genetic causes of DNETs and to clarify the molecular mechanis...

Background: Osteonecrosis of the femoral head is a debilitating disease that involves impaired blood supply to the femoral head and leads to femoral head collapse. Methods: We use whole-exome sequencing and Sanger sequencing to analyse a family with inherited osteonecrosis of the femoral head and fluorescent Ca(2+) imaging to functionally charac...

Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNE...

We developed an efficient tool dedicated to call somatic variants from whole-exome sequencing (WES) data using tumor and its matched normal tissue, plus a user-defined control panel of non-cancer samples. Compared with other methods, we showed superior performance of LoLoPicker with significantly improved specificity. The algorithm of LoLoPicker is...

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy diagnosed in women under age 40. We and others recently determined that germline and/or somatic deleterious mutations in SMARCA4 characterize SCCOHT. Alterations in this gene, or the related SWI/SNF chromatin remodeling gene SMARCB1...

Introduction: Although several programs are designed to identify variants with low allelic-fraction, further improvement is needed, especially to push the detection limit of low allelic-faction variants in low-quality, "noisy" tumor samples. Results: We developed LoLoPicker, an efficient tool dedicated to calling somatic variants from next-gener...

Ovarian cancer remains a challenging condition to prevent, diagnose and treat. We have conducted several different studies that have attempted to advance knowledge in one or more of these areas. These projects are briefly summarized below. 1) Sequencing of samples from a BRCA1 mutation carrier with high grade serous carcinoma We performed whole exo...

Cole-Carpenter syndrome is a severe bone fragility disorder that is characterized by frequent fractures, craniosynostosis, ocular proptosis, hydrocephalus, and distinctive facial features. To identify the cause of Cole-Carpenter syndrome in the two individuals whose clinical results were presented in the original description of this disorder, we pe...

Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor and the most common type of undifferentiated ovarian malignancy presenting at less than 40 years of age. Its cause and histogenesis remain unknown. We sequenced the exomes of individuals from three familial cases of SCCOHT. Subsequently, we used whole exome sequen...

Here we provide compelling evidence that Next Generation Sequencing will revolutionise diagnostics. We reappraised a case from 1991, published in 1993, describing the unique occurrence of an ovarian immature teratoma arising in a young woman and a clonally distinct intracerebral immature teratoma developing in her daughter. We conducted whole exome...

Background Ovarian carcinoma is a common, and often deadly, gynecological cancer. Mutations in BRCA1 and BRCA2 genes are present in at least a fifth of patients. Uncovering other genes that become mutated subsequent to BRCA1/BRCA2 inactivation during cancer development will be helpful for more effective treatments. Methods We performed exome seque...

Insects in the field are exposed to multiple bouts of cold, and there is increasing evidence that the fitness consequences of repeated cold exposure differ from the impacts of a single cold exposure. We tested the hypothesis that different kinds of cold exposure (in this case, single short, prolonged and repeated cold exposure) would result in diff...