Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline.

PURPOSE: To guide use of multigene panels for germline genetic testing for patients with cancer. METHODS: An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing. RESULTS: Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4. RECOMMENDATIONS: Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing.Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines.

Breast and colorectal cancer risks among over 6,000 CHEK2 pathogenic variant carriers: A comparison of missense versus truncating variants.

BACKGROUND AND AIMS: Heterozygous truncating pathogenic variants (PVs) in CHEK2 confer a 1.5 to 3-fold increased risk for breast cancer and may elevate colorectal cancer risks. Less is known regarding missense variants. Here we compared the cancer associations with truncating and missense PVs in CHEK2 across breast and colorectal cancer. METHODS: This was a retrospective analysis of 705,797 patients who received single laboratory multigene panel testing between 2013 and 2020. Multivariable logistic regression models determined cancer risk associated with CHEK2 variants as odds ratios (ORs) and 95% confidence intervals (CIs) after adjusting for age at diagnosis, cancer history, and ancestry. Breast and colorectal cancer analyses were performed using 6255 CHEK2 PVs, including truncating PVs (N = 4505) and missense PVs (N = 1750). RESULTS: CHEK2 PVs were associated with an increased risk of ductal invasive breast cancer (p < 0.001) and ductal carcinoma in situ (DCIS) (p < 0.001), with no statistically significant differences when truncating PVs (p < 0.001) and missense PVs (p < 0.001) were evaluated separately. All CHEK2 variants assessed conferred little to no risk of colorectal cancer. CONCLUSIONS: In our large cohort, CHEK2 truncating and missense PVs conferred similar risks for breast cancer and did not seem to elevate risk for colorectal cancer.

Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.

PURPOSE: New guidelines recommend considering germline genetic testing for all patients with colorectal cancer (CRC). However, there is a lack of data on stakeholders' perspectives on the advantages and barriers of implementing universal germline testing (UGT). This study assessed the perspectives of members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) regarding the implementation of UGT for patients with CRC, including readiness, logistics, and barriers. METHODS: A cross-sectional survey was sent to 317 active members of CGA-IGC. The survey included sections on demographics, clinical practice specialty, established institutional practices for testing, and questions pertaining to support of and barriers to implementing UGT for patients with CRC. RESULTS: Eighty CGA-IGC members (25%) participated, including 42 genetic counselors (53%) and 14 gastroenterologists (18%). Forty-seven (59%) reported an academic medical center as their primary work setting, and most participants (56%) had more than 10 years of clinical practice. Although most participants (73%) supported UGT, 54% indicated that changes in practice would be required before adopting UGT, and 39% indicated that these changes would be challenging to implement. There was support for both genetics and nongenetics providers to order genetic testing, and a majority (57%) supported a standardized multigene panel rather than a customized gene panel. Key barriers to UGT implementation included limited genetics knowledge among nongenetics providers, time-consuming processes for obtaining consent, ordering tests, disclosing results, and lack of insurance coverage. CONCLUSION: This study demonstrates wide support among hereditary GI cancer experts for implementation of UGT for patients with CRC. However, alternative service delivery models using nongenetics providers should be considered to address the logistical barriers to UGT implementation, particularly the growing demand for genetic testing.

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Conclusion: Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

Clinical implications of conflicting variant interpretations in the cancer genetics clinic.

PURPOSE: The aim of this study was to describe the clinical impact of commercial laboratories issuing conflicting classifications of genetic variants. METHODS: Results from 2000 patients undergoing a multigene hereditary cancer panel by a single laboratory were analyzed. Clinically significant discrepancies between the laboratory-provided test reports and other major commercial laboratories were identified, including differences between pathogenic/likely pathogenic and variant of uncertain significance (VUS) classifications, via review of ClinVar archives. For patients carrying a VUS, clinical documentation was assessed for evidence of provider awareness of the conflict. RESULTS: Fifty of 975 (5.1%) patients with non-negative results carried a variant with a clinically significant conflict, 19 with a pathogenic/likely pathogenic variant reported in APC or MUTYH, and 31 with a VUS reported in CDKN2A, CHEK2, MLH1, MSH2, MUTYH, RAD51C, or TP53. Only 10 of 28 (36%) patients with a VUS with a clinically significant conflict had a documented discussion by a provider about the conflict. Discrepant counseling strategies were used for different patients with the same variant. Among patients with a CDKN2A variant or a monoallelic MUTYH variant, providers were significantly more likely to make recommendations based on the laboratory-reported classification. CONCLUSION: Our findings highlight the frequency of variant interpretation discrepancies and importance of clinician awareness. Guidance is needed on managing patients with discrepant variants to support accurate risk assessment.

Priorities to Promote Participant Engagement in the Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network.

BACKGROUND: Engaging diverse populations in cancer genomics research is of critical importance and is a fundamental goal of the NCI Participant Engagement and Cancer Genome Sequencing (PE-CGS) Network. Established as part of the Cancer Moonshot, PE-CGS is a consortium of stakeholders including clinicians, scientists, genetic counselors, and representatives of potential study participants and their communities. Participant engagement is an ongoing, bidirectional, and mutually beneficial interaction between study participants and researchers. PE-CGS sought to set priorities in participant engagement for conducting the network's research. METHODS: PE-CGS deliberatively engaged its stakeholders in the following four-phase process to set the network's research priorities in participant engagement: (i) a brainstorming exercise to elicit potential priorities; (ii) a 2-day virtual meeting to discuss priorities; (iii) recommendations from the PE-CGS External Advisory Panel to refine priorities; and (iv) a virtual meeting to set priorities. RESULTS: Nearly 150 PE-CGS stakeholders engaged in the process. Five priorities were set: (i) tailor education and communication materials for participants throughout the research process; (ii) identify measures of participant engagement; (iii) identify optimal participant engagement strategies; (iv) understand cancer disparities in the context of cancer genomics research; and (v) personalize the return of genomics findings to participants. CONCLUSIONS: PE-CGS is pursuing these priorities to meaningfully engage diverse and underrepresented patients with cancer and posttreatment cancer survivors as participants in cancer genomics research and, subsequently, generate new discoveries. IMPACT: Data from PE-CGS will be shared with the broader scientific community in a manner consistent with participant informed consent and community agreement.

Whole exome sequencing and replication for breast cancer among Hispanic/Latino women identifies FANCM as a susceptibility gene for estrogen-receptor-negative breast cancer.

Introduction: Breast cancer (BC) is one of the most common cancers globally. Genetic testing can facilitate screening and risk-reducing recommendations, and inform use of targeted treatments. However, genes included in testing panels are from studies of European-ancestry participants. We sequenced Hispanic/Latina (H/L) women to identify BC susceptibility genes. Methods: We conducted a pooled BC case-control analysis in H/L women from the San Francisco Bay area, Los Angeles County, and Mexico (4,178 cases and 4,344 controls). Whole exome sequencing was conducted on 1,043 cases and 1,188 controls and a targeted 857-gene panel on the remaining samples. Using ancestry-adjusted SKAT-O analyses, we tested the association of loss of function (LoF) variants with overall, estrogen receptor (ER)-positive, and ER-negative BC risk. We calculated odds ratios (OR) for BC using ancestry-adjusted logistic regression models. We also tested the association of single variants with BC risk. Results: We saw a strong association of LoF variants in FANCM with ER-negative BC (p=4.1×10-7, OR [CI]: 6.7 [2.9-15.6]) and a nominal association with overall BC risk. Among known susceptibility genes, BRCA1 (p=2.3×10-10, OR [CI]: 24.9 [6.1-102.5]), BRCA2 (p=8.4×10-10, OR [CI]: 7.0 [3.5-14.0]), and PALB2 (p=1.8×10-8, OR [CI]: 6.5 [3.2-13.1]) were strongly associated with BC. There were nominally significant associations with CHEK2, RAD51D, and TP53. Conclusion: In H/L women, LoF variants in FANCM were strongly associated with ER-negative breast cancer risk. It previously was proposed as a possible susceptibility gene for ER-negative BC, but is not routinely tested in clinical practice. Our results demonstrate that FANCM should be added to BC gene panels.

Behavioral beliefs about genetic counseling among high-risk Latina breast cancer survivors in Florida and Puerto Rico.

Compared with non-Hispanic White women, Latina women are less likely to receive genetic counseling (GC) and testing (GT) following BC diagnosis. This study used secondary data analysis to explore beliefs about GC among Latina BC survivors in and outside the US mainland. GC/GT-naïve, high-risk, Spanish-preferring Latina BC survivors (n = 52) in FL and PR completed the Behavioral Beliefs about GC scale. Participants reported high positive beliefs about GC (M = 4.19, SD = 0.92); the majority agreed that GC was beneficial to understand cancer risk (90%) and promote discussion (87%) in their family. Participants reported low-to-moderate scores for barriers (Ms = 1.53-3.40; SDs = 0.59-0.90). The most frequently endorsed barriers were desire for additional GC information (M = 3.44; SD = 0.90), and GC logistic concerns (M = 2.71; SD = 0.80). No statistically significant differences for barriers and benefits scales were identified by place of residence (all ps ≥ 0.12). These findings highlight the importance of delivering culturally sensitive GC information to high-risk Latina BC survivors.

Perspectives on Spanish language concordant cancer genetic counseling sessions from the Spanish-speaking population.

Genetic counselors (GCs) provide risk assessment, education, and counseling about the genetic contribution to disease. To do so, they must effectively communicate, build rapport, and help patients make the best decisions for themselves and their families. Language barriers add a complex layer to this patient-provider dynamic. While interpreters serve as a primary solution when a patient and GC speak different languages, issues have been documented with these sessions, such as misinterpreted genetic terminology (Gutierrez et al., 2017). Having a GC with concordant language skills may help address these barriers. The purpose of this study was to assess Spanish-speaking patients' perspectives on communication, decision-making, and the interpersonal relationship developed with a bilingual GC in language concordant cancer genetic counseling sessions. Spanish-speaking patients, ages 18 or older, seen by a Spanish-speaking GC at a California public, safety-net hospital were eligible to participate in this study. Nine participants were interviewed via telephone by the bilingual researcher using a semi-structured interview guide to assess three domains: communication, decision-making, and interpersonal relationship. Analyses of interview transcripts identified themes within these three areas of focus: (1) participants felt all explanations were clear and they were not afraid to ask questions in the session, (2) participants experienced preference-concordant decision making, and (3) participants felt empowered and supported by the GC. Participants suggested that GCs working with Spanish-speaking patients in the future should consider group counseling sessions, engaging in outreach efforts to educate the Spanish-speaking community about genetics, and increasing the number of GCs who speak Spanish. These results demonstrate the positive experiences of Spanish-speaking patients in language concordant cancer genetic counseling sessions and further support the need for recruitment of Spanish-speaking individuals into the profession. Future research should further assess the experience of Spanish-speaking patients in language concordant sessions and address the role of cultural concordance in sessions.

Integration of Universal Germline Genetic Testing for All New Breast Cancer Patients.

BACKGROUND: The American Society of Breast Surgeons recommends genetic testing (GT) for all women with breast cancer (BC), but implementation and uptake of GT has not been well-described. METHODS: A retrospective chart review was performed for newly diagnosed BC patients or patients with a newly identified recurrence of BC seen in a multidisciplinary clinic (MDBC) who were offered genetic counseling (GC) and GT. RESULTS: The 138 women attending the MDBC had a median age of 54 years and comprised non-Hispanic whites (46%), Asians (28%), Hispanics (17%), blacks (4%), and other (5%). Of the 105 (76%) patients without prior GT, 100 (95%) accepted GC, with 93 (93%) of these 100 patients undergoing GT. The patients meeting the National Comprehensive Cancer Network (NCCN) guidelines for GT were more likely to undergo GT. Testing was performed with a 67- to 84-gene panel, together with an 8- to 9-gene STAT panel if needed. Among 120 patients with reports available, including 33 patients previously tested, 15 (12%) were positive (1 BLM, 1 BRCA1, 3 BRCA2, 1 BRIP1, 1 CFTR, 1 CHEK2, 1 MUTYH, 1 PALB2, 1 PRSS1, 1 RAD50, 1 RET, and 2 TP53), 44 (37%) were negative, and 61 (51%) had an uncertain variant. The median time to STAT results (n = 50) was 8 days. The STAT results were available before surgery for 47 (98%) of the 48 STAT patients undergoing surgery. CONCLUSIONS: New BC patients attending the MDBC demonstrated high rates of acceptance of GC and GT. The combination of GC and GT can offer timely information critical to patient risk assessment and treatment planning.

Provider discussion of genetic counseling among high-risk Spanish-preferring Latina breast cancer survivors.

Among high-risk breast cancer (BC) survivors, genetic counseling (GC) and genetic testing (GT) may inform cascade testing and risk management. Compared to non-Hispanic White BC survivors, Spanish-preferring Latina BC survivors are less likely to report discussing GC with a healthcare provider. However, few studies have examined Latinas' experiences with GC/GT, particularly outside of the mainland USA. This study aimed to compare frequency of provider discussion of GC between Spanish-preferring Latina BC survivors living in Florida (FL) and Puerto Rico (PR). We conducted secondary data analysis of baseline assessments from a randomized pilot of an educational intervention for Spanish-preferring Latina BC survivors. Participants (N = 52) were GC/GT-naive, but met clinical criteria for GC/GT referral. Participants self-reported sociodemographic, clinical, and cultural variables, including previous provider discussion of GC. Descriptive statistics characterized frequency of GC discussion. Logistic regression examined the relationships between sociodemographic, clinical, and cultural characteristics and GC discussion. Only 31% of participants reported previous GC discussion. More participants from PR reported having GC discussions (43% vs. 21% in the mainland USA). In multivariable analyses, greater likelihood of GC discussion was associated with PR (vs. mainland USA) residence (odds ratio [OR] = 6.00, p = .03), older age at baseline (OR = 1.19, p = .04), and younger age at BC diagnosis (OR = 0.80, p = .03). Few high-risk Spanish-preferring Latina BC survivors in the mainland USA and PR had discussed GC with their providers. These results highlight a gap in the implementation of evidence-based genetics guidelines. Provider-directed interventions may be needed to increase uptake of GC/GT among Latina BC survivors.

Some families have changes in the BRCA genes that increase their risk for developing breast cancer compared to those who do not have these gene changes. Through genetic testing, we can identify breast cancer survivors who have these gene changes so their families can take action to prevent future cancers. Breast cancer survivors who are diagnosed at a young age, or who have a strong family history of breast and ovarian cancer, are eligible for genetic counseling and BRCA testing. Yet, compared to women from other racial and ethnic groups, fewer Latina breast cancer survivors have genetic counseling and testing. This study explored frequency of healthcare providers' discussion about genetic counseling among Spanish-preferring Latina breast cancer survivors living in Florida and Puerto Rico. Although all participants were eligible, only 3 out of 10 indicated that a provider previously discussed genetic counseling with them. Participants who were living in Puerto Rico, older at study entry, or younger at the time of their breast cancer diagnosis were more likely to have discussed genetic counseling with a healthcare provider. Healthcare providers are important for identifying and referring high-risk Spanish-preferring Latinas for genetic counseling in and outside the mainland USA.

Risk-reducing mastectomy decisions among women with mutations in high- and moderate- penetrance breast cancer susceptibility genes.

BACKGROUND: Women harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high-risk screening or risk-reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making. METHODS: We performed a retrospective study assessing RRM decisions for 279 women. RESULTS: Women with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age. CONCLUSION: Although national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision-making in this population.

Transcriptome analysis provides critical answers to the "variants of uncertain significance" conundrum.

While whole-genome and exome sequencing have transformed our collective understanding of genetics' role in disease pathogenesis, there are certain conditions and populations for whom DNA-level data fails to identify the underlying genetic etiology. Specifically, patients of non-White race and non-European ancestry are disproportionately affected by "variants of unknown/uncertain significance" (VUS), limiting the scope of precision medicine for minority patients and perpetuating health disparities. VUS often include deep intronic and splicing variants which are difficult to interpret from DNA data alone. RNA analysis can illuminate the consequences of VUS, thereby allowing for their reclassification as pathogenic versus benign. Here we review the critical role transcriptome analysis plays in clarifying VUS in both neoplastic and non-neoplastic diseases.

Development and pilot testing of a training for bilingual community education professionals about hereditary breast and ovarian cancer among Latinas: ÁRBOLES Familiares.

Cancer health disparities remain a significant problem in the USA, compounded by lack of access to care, language barriers and systemic biases in health care. These disparities are particularly evident in areas such as genetics/genomics. For example, Latinas at high risk for hereditary breast and ovarian cancer (HBOC) have extremely low rates of genetic counseling/testing. Long-standing barriers and inequities in access to services such as genetic counseling and testing require innovative solutions. One solution can involve training community outreach and education professionals (CORE-Ps) to bridge the gap between underserved communities and genetic specialists. We sought to develop and pilot test a training program for English-Spanish bilingual CORE-Ps to reduce disparities in access to and uptake of genetic services among Latino populations. Guided by Adult Learning Theory and with input from multiple stakeholders, we developed ÁRBOLES Familiares (Family Trees), an in-person and online training program for bilingual CORE-Ps to facilitate identification, referral, and navigation of Latinas to genetic counseling/testing. We conducted a pilot test of 24 CORE-Ps recruited from across the United States and assessed knowledge, genetic literacy, and self-efficacy at baseline and follow-up. At follow-up, participants in the pilot with complete baseline and follow-up data (N = 15) demonstrated significant improvements in HBOC knowledge, genetic literacy, self-efficacy and reports of fewer barriers to identify/navigate Latinas (ps < .05). Qualitative assessment identified ways to improve the training curriculum. Pilot results suggest ÁRBOLES is a promising approach for training CORE-Ps to identify and refer high-risk Latinas to genetic services. Next steps involve further refinement of ÁRBOLES, development of an online toolkit, and adaptation for virtual delivery.

Latinas at high risk for hereditary breast and ovarian cancer (HBOC) have low rates of genetic counseling and testing. Latinas may not have ready access to services like genetic counseling and testing, which need special solutions. One solution can involve training community health workers to bridge the gap between Latinas and genetic specialists. We developed an online and in person training program (ÁRBOLES Familiares or Family Trees) for English-Spanish bilingual community health workers that teaches them how to help Latinas get access to genetic services. We tested this program with a small group of community health workers. After the program, their HBOC knowledge, genetic literacy, and confidence to help Latinas get access to genetic services had improved. Trainees also made suggestions to improve the program, which will be used to help future trainees expand their knowledge and skills to work with Latinas at risk of HBOC.

A Case Series of Multiple Primary Malignancies Among Patients With Advanced Melanoma.

Multiple primary malignancies (MPM) are described as two or more primary tumors within the same individual. The impact of MPM on the tumor microenvironment among patients with melanoma is poorly understood. Here, we describe this unique group of patients who have both advanced melanoma and at least one other primary malignancy and report their survival outcomes. In this study, patients with advanced melanoma and a second primary malignancy were identified. Medical records were reviewed for cancer treatment history. Kaplan-Meier methods were used to derive survival curves and estimate overall survival (OS), and log-rank tests were used to compare OS. Among 11 MPM patients, the most common non-melanoma cancers were breast (n = 3) and thyroid (n = 3). Median OS was 153.5 months for all patients. Median OS for synchronous MPM (sMPM) and metachronous MPM (mMPM) were 83.1 and 196.7 months, respectively (p= 0.10). Median OS was not reached when melanoma was diagnosed first, and 153.5 months when diagnosed second (p= 0.45). For six patients receiving immunotherapy for melanoma, there was a 100% complete response rate. In conclusion, patients with melanoma are at risk of secondary malignancies, including breast and thyroid cancer. The timing of secondary malignancies may impact prognosis. Further study of the impact of immunotherapy on MPM is warranted.

Increased burden of familial-associated early-onset cancer risk among minority Americans compared to non-Latino Whites.

Background: The role of race/ethnicity in genetic predisposition of early-onset cancers can be estimated by comparing family-based cancer concordance rates among ethnic groups. Methods: We used linked California health registries to evaluate the relative cancer risks for first-degree relatives of patients diagnosed between ages 0 and 26, and the relative risks of developing distinct second primary malignancies (SPMs). From 1989 to 2015, we identified 29,631 cancer patients and 62,863 healthy family members. We calculated the standardized incident ratios (SIRs) of early-onset primary cancers diagnosed in proband siblings and mothers, as well as SPMs detected among early-onset patients. Analyses were stratified by self-identified race/ethnicity. Results: Given probands with cancer, there were increased relative risks of any cancer for siblings and mothers (SIR = 3.32; 95% confidence interval [CI]: 2.85-3.85) and of SPMs (SIR = 7.27; 95% CI: 6.56-8.03). Given a proband with solid cancer, both Latinos (SIR = 4.98; 95% CI: 3.82-6.39) and non-Latino Blacks (SIR = 7.35; 95% CI: 3.36-13.95) exhibited significantly higher relative risk of any cancer in siblings and mothers when compared to non-Latino White subjects (SIR = 3.02; 95% CI: 2.12-4.16). For hematologic cancers, higher familial risk was evident for Asian/Pacific Islanders (SIR = 7.56; 95% CI: 3.26-14.90) compared to non-Latino whites (SIR = 2.69; 95% CI: 1.62-4.20). Conclusions: The data support a need for increased attention to the genetics of early-onset cancer predisposition and environmental factors in race/ethnic minority families in the United States. Funding: This work was supported by the V Foundation for funding this work (Grant FP067172).