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Purpose: To explore the role of NBN as a pan-cancer susceptibility gene. Experimental Design: Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation. Results: We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation. Conclusions: Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.

Supplementary Figure 1. Electropherogram. Supplementary Figure 2. Ramachandran plot. Supplementary Figure 3. Modeling ERCC3 R109X via CRISPR/Cas9 genome editing. Supplementary Figure 4. Haplotype analyses from the TAGC heterozygote carriers. Supplementary Figure 5. ERCC3 mutations present in the cBioPortal (MSKCC) datasets. Supplementary Figure 6. ERCC3 transcript levels in patient derived whole blood. Supplementary Table 1. Family history and pathology information on R109X carriers. Supplementary Table 2. Identity of mutations in HMLE cell lines generated by CRISPR/Cas9.

Supplementary Figure S1. Germline and somatic data from The Cancer Genome Atlas (TCGA) project, representing 10,268 cancer patients with whole exome sequencing data.

Purpose:To explore the role of NBN as a pan-cancer susceptibility gene.Experimental Design:Matched germline and somatic DNA samples from 34,046 patients were sequenced using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets and presumed pathogenic germline variants (PGV) identified. Allele-specific and gene-centered analysis of enrichment was conducted and a validation cohort of 26,407 pan-cancer patients was analyzed. Functional studies utilized cellular models with analysis of protein expression, MRN complex formation/localization, and viability assessment following treatment with γ-irradiation.Results:We identified 83 carriers of 32 NBN PGVs (0.25% of the studied series), 40% of which (33/83) carried the Slavic founder p.K219fs. The frequency of PGVs varied across cancer types. Patients harboring NBN PGVs demonstrated increased loss of the wild-type allele in their tumors [OR = 2.7; confidence interval (CI): 1.4–5.5; P = 0.0024; pan-cancer], including lung and pancreatic tumors compared with breast and colorectal cancers. p.K219fs was enriched across all tumor types (OR = 2.22; CI: 1.3–3.6; P = 0.0018). Gene-centered analysis revealed enrichment of PGVs in cases compared with controls in the European population (OR = 1.9; CI: 1.3–2.7; P = 0.0004), a finding confirmed in the replication cohort (OR = 1.8; CI: 1.2–2.6; P = 0.003). Two novel truncating variants, p.L19* and p.N71fs, produced a 45 kDa fragment generated by alternative translation initiation that maintained binding to MRE11. Cells expressing these fragments showed higher sensitivity to γ-irradiation and lower levels of radiation-induced KAP1 phosphorylation.Conclusions:Burden analyses, biallelic inactivation, and functional evidence support the role of NBN as contributing to a broad cancer spectrum. Further studies in large pan-cancer series and the assessment of epistatic and environmental interactions are warranted to further define these associations.

Supplementary Tables S2-S5

Supplementary Methods, Supplementary Figures S1-S11, Supplementary Tables S1, S6, S8-11

Supplementary Table S7

Purpose:Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explored the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities.Experimental Design:We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wild-type and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs.Results:We found that putative damaging germline and somatic alterations in NER genes were present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard-of-care agent, cisplatin. Hypomorphic ERCC2/3-mutant cells had impaired ability to repair irofulven-induced DNA damage. Transcriptomic profiling of tumor tissues suggested codependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies.Conclusions:These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs.See related commentary by Jiang and Greenberg, p. 1833

The world is witnessing a rising number of preterm infants who are at significant risk of medical conditions. These infants require continuous care in Neonatal Intensive Care Units (NICU). Medical parameters are continuously monitored in premature infants in the NICU using a set of wired, sticky electrodes attached to the body. Medical adhesives used on the electrodes can be harmful to the baby, causing skin injuries, discomfort, and irritation. In addition, respiration rate (RR) monitoring in the NICU faces challenges of accuracy and clinical quality because RR is extracted from electrocardiogram (ECG). This research paper presents a design and validation of a smart textile pressure sensor system that addresses the existing challenges of medical monitoring in NICU. We designed two e-textile, piezoresistive pressure sensors made of Velostat for noninvasive RR monitoring; one was hand-stitched on a mattress topper material, and the other was embroidered on a denim fabric using an industrial embroidery machine. We developed a data acquisition system for validation experiments conducted on a high-fidelity, programmable NICU baby mannequin. We designed a signal processing pipeline to convert raw time-series signals into parameters including RR, rise and fall time, and comparison metrics. The results of the experiments showed that the relative accuracies of hand-stitched sensors were 98.68 (top sensor) and 98.07 (bottom sensor), while the accuracies of embroidered sensors were 99.37 (left sensor) and 99.39 (right sensor) for the 60 BrPM test case. The presented prototype system shows promising results and demands more research on textile design, human factors, and human experimentation.

PURPOSEDespite advances in DNA sequencing technology and expanded medical guidelines, the vast majority of individuals carrying pathogenic variants of common cancer susceptibility genes have yet to be identified. An alternative to population-wide genetic screening of healthy individuals would exploit the trend for genetic testing at the time of cancer diagnosis to guide therapy and prevention, combined with augmented familial diffusion or “cascade” of genomic risk information.METHODSUsing a multiple linear regression model, we derived the time interval to detect an estimated 3.9 million individuals in the United States with a pathogenic variant in 1 of 18 cancer susceptibility genes. We analyzed the impact of the proportion of incident patients sequenced, varying observed frequencies of pathogenic germline variants in patients with cancer, differential rates of diffusion of genetic information in families, and family size.RESULTSThe time to detect inherited cancer predisposing variants in the population is affected by the extent of cascade to first-, second-, and third-degree relatives (FDR, SDR, TDR, respectively), family size, prevalence of mutations in patients with cancer, and the proportion of patients with cancer sequenced. In a representative scenario, assuming a 7% prevalence of pathogenic variants across cancer types, an average family size of 3 per generation, and 15% of incident patients with cancer in the United States undergoing germline testing, the time to detect all 3.9 million individuals with pathogenic variants in 18 cancer susceptibility genes would be 46.2, 22.3, 13.6, and 9.9 years if 10%, 25%, 50%, and 70%, respectively, of all FDR, SDR, and TDR were tested for familial mutations.CONCLUSIONPeridiagnostic and cascade cancer genetic testing offers an alternative strategy to achieve population-wide identification of cancer susceptibility mutations.

INTRODUCTION AND OBJECTIVE:Prostate cancers with high microsatellite instability/deficient mismatch repair (MSI-H/dMMR) and high tumor mutational burden (TMB-H) are rare but recognized as molecular...

A rising number of preterm babies demands innovative solutions to monitor them in the Neonatal Intensive Care Unit (NICU) continuously. NICU monitors various kinds of vital signs. Among them, there is a strong demand for an accurate and sophisticated technology to monitor respiration rate (RR) and detect critical events such as apnea. Existing solutions for RR monitoring either rely on the indirect measurements from thoracic impedance or other invasive techniques posing discomfort and risk of infections to babies. Also, multiple wire loops lying around babies hinder the delivery of parental and clinical care. Motivated by this need, we have designed an Internet-of-Things (IoT) based smart textile chest belt called "Baby-Guard" to monitor RR and detect apnea. The Baby-Guard is a neonatal wearable system consisting of a sensor belt, a wearable embedded system, and an edge computing device. The sensor belt consists of textile-based pressure sensors and an Inertial Measurement Unit (IMU). The wearable system consists of a microcontroller equipped with wireless connectivity and power management. The edge computing device (ECD) connects with the wearable system through an MQTT networking architecture. ECD hosts signal processing and computing services to extract RR and detect apnea. We conducted simulation experiments using a high-fidelity, programmable NICU baby mannequin. We found an average error of 0.89 BrPM in breathing rate and ~97 percent accuracy in apnea detection. Computation and communication latencies were found to be ~66 and 22 ms, respectively. The Baby-Guard showed potential to be a wireless infant monitoring system in the NICU settings.

Background: Cancer survivors are developing more subsequent tumors. We sought to characterize patients with multiple (≥2) primary cancers (MPC) to assess associations and genetic mechanisms. Methods: Patients were prospectively consented (01/2013–02/2019) to tumor-normal sequencing via a custom targeted panel (MSK-IMPACT). A subset consented to return of results of ≥76 cancer predisposition genes. International Agency for Research on Cancer (IARC) 2004 rules for defining MPC were applied. Tumor pairs were created to assess relationships between cancers. Age-adjusted, sex-specific, standardized incidence ratios (SIR) for first to second cancer event combinations were calculated using SEER rates, adjusting for confounders and time of ascertainment. Associations were made with germline and somatic variants. Results: Of 24,241 patients, 4,340 had MPC (18%); 20% were synchronous. Most (80%) had two primaries; however, 4% had ≥4 cancers. SIR analysis found lymphoma–lung, lymphoma–uterine, breast–brain, and melanoma–lung pairs in women and prostate–mesothelioma, prostate–sarcoma, melanoma–stomach, and prostate–brain pairs in men in excess of expected after accounting for synchronous tumors, known inherited cancer syndromes, and environmental exposures. Of 1,580 (36%) patients who received germline results, 324 (21%) had 361 pathogenic/likely pathogenic variants (PV), 159 (44%) in high penetrance genes. Of tumor samples analyzed, 55% exhibited loss of heterozygosity at the germline variant. In those with negative germline findings, melanoma, prostate, and breast cancers were common. Conclusions: We identified tumor pairs without known predisposing mutations that merit confirmation and will require novel strategies to elucidate genetic mechanisms of shared susceptibilities. Impact: If verified, patients with MPC with novel phenotypes may benefit from targeted cancer surveillance.

5035 Background: Germline genomic alterations and/or environmental factors are proposed as critical to GCT development given the significant rates of bilateral and familial cases. A number of low-moderate risk loci for GCT have been identified (Litchfield, Eur Urol 2018 & Pluta, Nat Comm 2021), predominantly by analysing unilateral GCT, with a polygenic heritability model proffered. We postulate bilateral GCT represents an extreme phenotype with higher frequency of loss of function germline genomic alterations and/or pre-disposing environmental exposures. Methods: Bilateral GCT pts who consented to a prospective clinically annotated GCT DNA registry were included for analysis. The registry integrates self-reported questionnaires on environmental exposures, relevant medical history and germline whole exome sequencing (WES). Pathogenicity of variants identified by WES were classified using the algorithm Pathogenicity of Mutation Analyzer (PathoMAN) [Ravichandran, Genet Med 2019]. Aggregated WES results were curated to identify disruptive or deleterious variants affecting the same genes as the most significant individual variants in the Litchfield series. A < 1% minor allele frequency threshold was set for candidate variants, likely benign/benign variants were excluded . Results: Of 43 bilateral cases with germline WES results, median age at first diagnosis was 32.1 years (range 18-73), 9 tumors were synchronous and 34 metachronous with median interval between diagnosis of 76.4 months for metachronous cases. Tumor histology was seminoma in 52 and nonseminoma in 34. 39 of 43 (91%) pts completed questionnaires with 35 (90%) reporting White race, 2 Hispanic/Latino, 1 Asian, and 1 Peruvian. 13 (33%) reported prior smoking, 21 (54%) prior marijuana use, and 6 (15%) other illicit drug use. 6 (15%) pts reported undescended testis and 1 (3%) hypospadias. 24/43 (45%) patients harbored ≥1 variant within 15 Litchfield genes (60%). 43 distinct variants were identified: 33 (77%) nonsynonymous missense alterations, 7 (16%) intron variants, 1 inframe deletion in STH3TC1, and 1 initiator and 1 stop codon variant in DEFB132, which plays a role in binding spermatozoa. Multiple bilateral patients harbored variants in MPDZ (n = 7), EHBP1L1 (n = 6), SKIV2L (n = 5), FAM160A2 (n = 3), ADAMTS18 (n = 3), JMJD4 (n = 3), ABCC4 (n = 3), R3HCC1 (n = 2), MLXIP (n = 2) and VPS16 (n = 2). Conclusions: In this bilateral GCT cohort, we identified several alterations in candidate susceptibility genes from the Litchfield series, whereas no convincing causative recurrent environmental exposures were observed. Our results support a polygenic model of GCT pathogenesis and show that analyzing enriched cohorts such as bilateral GCT may aid understanding of GCT pathogenesis. Additional analysis of the specific variants is required to further assess pathogenicity, elucidate their role and association with bilateral GCT.

5007 Background: Epidemiologic studies on germ cell tumors (GCT) in men have shown GCT has a high heritability. Yet, the genetic mechanisms underlying development of GCT in men remain unknown. We sought to determine the prevalence of pathogenic or likely pathogenic (P/LP) germline variants in cancer predisposition genes in men with GCT and identify clinical and pathologic factors associated with the presence of P/LP variants. Methods: We retrospectively identified men with testicular (T) or mediastinal (M) GCT who underwent matched tumor--germline sequencing of ≥ 310 genes as part of an institutional genomic profiling initiative from 04/2015 to 12/2020. Presence of germline variants in clinically actionable genes associated with hereditary cancer syndromes were analyzed. Clinicopathologic characteristics, including primary site, histology and family history were assessed by the presence of P/LP variants and compared using Fisher’s exact test. Results: The study included 480 men, 70 (15%) with M-GCT and 410 (85%) with T-GCT. The median age of diagnosis was 30 years (interquartile range 24 – 39). A total of 81% had non-seminoma; 5% had localized disease; 46%, 14%, and 34% had good, intermediate, and poor risk advanced disease, respectively; 6% had family history of GCT. Among men with T-GCT, 4% had bilateral T-GCT. P/LP variants in clinically actionable genes were identified in 58 (12%) men in the entire cohort. Men with M-GCT had higher frequency of P/LP variants compared to those with T-GCT (15/70 [21%] vs 43/410 [10%], p = 0.02). A total of 7 (10%) men with M-GCT and 20 (5%) with T-GCT had P/LP variants in moderate or high penetrance cancer predisposition genes (p = 0.09). Most P/LP variants in both M-GCT (11/15, 73%) and T-GCT (33/43, 77%) were in genes involved in DNA damage repair pathways. The spectrum of moderate or high penetrance DNA damage repair genes identified is shown in the Table 1. Family history and histology (seminoma vs. non-seminoma) were not associated with the presence of a P/LP variants in the overall cohort (p = 0.8 and 0.7, respectively). Bilateral disease was not associated with the presence of P/LP variants in men with T-GCT (p = 0.4). Conclusions: Approximately 1 in 5 men with M-GCT carried a P/LP variant in a clinically actionable cancer susceptibility gene and 10% had a P/LP variant in a high-risk gene such as TP53 and PMS2. As men with GCT tend to develop disease in early adulthood, identification of germline P/LP variant has significant implications for enhanced cancer screening and surveillance, cascade testing for at-risk family members, and potential preconception genetic counseling. [Table: see text]

This book chapter is a tutorial-driven hands-on guide on data analytics for wearable sensor signals. The chapter takes an example of smart gloves integrated with flex/bend sensors on fingers measuring the angular movement of the knuckles. The gloves are designed to measure the motor symptoms of Parkinson’s disease. The movements of the fingers are converted into time-series signals that hold information regarding the impact and progress of Parkinson’s disease. The beginning sections of the chapter take a traditional approach of signal processing. All the materials including signal/data files and MATLAB codes are open source and freely available on GitHub. Each section provides the MATLAB script to perform signal processing task taking the conditioned signal to the next step in the process. At last, the chapter ends with machine learning classification of different activities of the hand and fingers. This chapter is designed for students who are new to the fields of time-series signals, digital signal processing, and machine learning that are important for handling and analysis of wearable sensor signals. This chapter can also be useful for labs and class assignments targeting wearable sensor data analytics.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10 -6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL ( P = 1.0) or MZL ( P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10 -5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

Purpose: Nucleotide excision repair (NER) gene alterations constitute potential cancer therapeutic targets. We explored the prevalence of NER gene alterations across cancers and putative therapeutic strategies targeting these vulnerabilities. Experimental Design: We interrogated our institutional dataset with mutational data from more than 40,000 patients with cancer to assess the frequency of putative deleterious alterations in four key NER genes. Gene-edited isogenic pairs of wild-type and mutant ERCC2 or ERCC3 cell lines were created and used to assess response to several candidate drugs. Results: We found that putative damaging germline and somatic alterations in NER genes were present with frequencies up to 10% across multiple cancer types. Both in vitro and in vivo studies showed significantly enhanced sensitivity to the sesquiterpene irofulven in cells harboring specific clinically observed heterozygous mutations in ERCC2 or ERCC3. Sensitivity of NER mutants to irofulven was greater than to a current standard-of-care agent, cisplatin. Hypomorphic ERCC2/3-mutant cells had impaired ability to repair irofulven-induced DNA damage. Transcriptomic profiling of tumor tissues suggested codependencies between DNA repair pathways, indicating a potential benefit of combination therapies, which were confirmed by in vitro studies. Conclusions: These findings provide novel insights into a synthetic lethal relationship between clinically observed NER gene deficiencies and sensitivity to irofulven and its potential synergistic combination with other drugs. See related commentary by Jiang and Greenberg, p. 1833

PURPOSE Mutations in DNA mismatch repair genes and PTEN, diagnostic of Lynch and Cowden syndromes, respectively, represent the only established inherited predisposition genes in endometrial cancer to date. The prevalence of other cancer predisposition genes remains unclear. We determined the prevalence of pathogenic germline variants in unselected patients with endometrial cancer scheduled for surgical consultation. PATIENTS AND METHODS Patients prospectively consented (April 2016 to May 2017) to an institutional review board–approved protocol of tumor-normal sequencing via a custom next-generation sequencing panel—the Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets—that yielded germline results for more than 75 cancer predisposition genes. Tumors were assessed for microsatellite instability. Per institutional standards, all tumors underwent Lynch syndrome screening via immunohistochemistry (IHC) for mismatch repair proteins. RESULTS Of 156 patients who consented to germline genetic testing, 118 (76%) had stage I disease. In 104 patients (67%), tumors were endometrioid, and 60 (58%) of those tumors were grade 1. Twenty-four pathogenic germline variants were identified in 22 patients (14%): seven (4.5%) had highly penetrant cancer syndromes and 15 (9.6%) had variants in low-penetrance, moderate-penetrance, or recessive genes. Of these, five (21%) were in Lynch syndrome genes (two MSH6, two PMS2, and one MLH1). All five tumors had concordant IHC staining; two (40%) were definitively microsatellite instability–high by next-generation sequencing. One patient had a known BRCA1 mutation, and one had an SMARCA4 deletion. The remaining 17 variants (71%) were incremental findings in low- and moderate-penetrance variants or genes associated with recessive disease. CONCLUSION In unselected patients with predominantly low-risk, early-stage endometrial cancer, germline multigene panel testing identified cancer predisposition gene variants in 14%. This finding may have implications for future cancer screening and risk-reduction recommendations. Universal IHC screening for Lynch syndrome successfully identifies the majority (71%) of high-penetrance germline mutations.

PURPOSE Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown. PATIENTS AND METHODS We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]). RESULTS Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [ P = .02] and 7.1% v 4.2% [ P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non–breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC. CONCLUSION Mutation rates are at least 7% in all patients with BRCA1/2 mutation–negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

Photoplethysmogram (PPG) is increasingly used to provide monitoring of the cardiovascular system under ambulatory conditions. Wearable devices like smartwatches use PPG to allow long term unobtrusive monitoring of heart rate in free living conditions. PPG based heart rate measurement is unfortunately highly susceptible to motion artifacts, particularly when measured from the wrist. Traditional machine learning and deep learning approaches rely on tri-axial accelerometer data along with PPG to perform heart rate estimation. The conventional learning based approaches have not addressed the need for device-specific modeling due to differences in hardware design among PPG devices. In this paper, we propose a novel end to end deep learning model to perform heart rate estimation using 8 second length input PPG signal. We evaluate the proposed model on the IEEE SPC 2015 dataset, achieving a mean absolute error of 3.36+-4.1BPM for HR estimation on 12 subjects without requiring patient specific training. We also studied the feasibility of applying transfer learning along with sparse retraining from a comprehensive in house PPG dataset for heart rate estimation across PPG devices with different hardware design., Under review in EMBC 2019