Application of the ACMG/NSGC genetic referral guidelines for hereditary renal cell carcinoma at the University of Miami, from 2014 to 2017.

Identifying hereditary syndromes among patients with renal cell carcinoma (RCC) is essential for surveillance of affected individuals and their at-risk family members and for treatment optimization. We conducted a chart review to determine the percentage of patients with RCC who were seen at the University of Miami Health System (UHealth), and met the American College of Medical Genetics (ACMG) and the National Society of Genetic Counselors (NSGC) genetic referral criteria at the University of Miami. Subsequently, we determined the percentage of those who went on to receive genetic evaluation. Patients selected by International Classification of Diseases (ICD) 9/10 codes corresponding to kidney cancer who were at least 18 years of age at the time of diagnosis were included in the study. We included a total of 1443 patients in the final analysis, and after exclusion of charts with incorrect ICD codes, insufficient clinical data, unknown pathology, and patients who were not seen. We used chi-square analysis, ANOVA, and t-test. Of 1443 charts reviewed, 65.7% were male and 34.3% were female. 47.7% self-identified as White, 39.2% as Hispanic, 9.1% as Black, and 4.0% as "other." The mean age of RCC diagnosis was 60.0 ± 12.4 years old. In total, 47.0% of patients met ACMG/NSGC referral criteria for genetic evaluation. Of those, only 4.2% had documented genetic assessment. This study showed a low adherence to ACMG/NSGC genetic referral guidelines at our institution and a need for increasing patients' and practitioners' awareness about the significance of genetic assessment for RCC patients and their family members.

Mutation analysis of PALB2 in BRCA1 and BRCA2-negative breast and/or ovarian cancer families from Eastern Ontario, Canada.

BACKGROUND: PALB2 has emerged as a breast cancer susceptibility gene. Mutations in PALB2 have been identified in almost all breast cancer populations studied to date, but the rarity of these mutations and lack of information regarding their penetrance makes genetic counseling for these families challenging. We studied BRCA1/2 -negative breast and/or ovarian cancer families to a) assess the contribution of PALB2 mutations in this series and b) identify clinical, pathological and family history characteristics that might make PALB2 screening more efficient. METHODS: The coding region of the PALB2 gene was analyzed in 175 probands with family histories of breast and/or ovarian cancer ascertained from a single Canadian institution in Eastern Ontario. RESULTS: We identified 2 probands with PALB2 mutations that are known or strongly considered to be pathogenic and 3 probands with missense mutations that are possibly pathogenic. One of the identified truncating mutations [c.3113G > A (p.Gly1000_Trp1038del - major product)], has been previously described while the other four mutations [c.3507_3508delTC (p.H1170Ffs*19), c.1846G > C (p.D616H), c.3418 T > G (p.W1140G), c.3287A > G (p.N1096S)] have not been previously reported. Loss of heterozygosity was detected in two breast tumors from one c.3507_3508delTC mutation carrier but not in other available tumors from that family or in tumors from carriers of other mutations. CONCLUSIONS: PALB2 mutation screening identifies a small, but significant number of mutations in BRCA1/2 -negative breast and/or ovarian cancer families. We show that mutations are more likely to be found in families with three or more breast cancers as well as other BRCA2-related cancers. In our cohort, both clearly pathogenic mutations were identified in premenopausal breast cancer cases (2/77, 2.6%). Testing should be preferentially offered to affected women from such families.

Triple Primary Cancers: An Analysis of Genetic and Environmental Factors.

The occurrence of multiple primary cancers (MPC) is thought to reflect increased cancer susceptibility in patients due to a combination of genetic and environmental factors. Here we conducted a retrospective review of 2,894 consecutive patients evaluated at a single institution and identified 31 (1.14%) individuals with a history of three or more primary cancers, then analyzed the genetic and environmental influences associated with their propensity for developing malignancies. We found that 35.5% of patients had a hereditary cancer syndrome (HCS), with high penetrance HCS in 72.7% of cases, suggesting that monogenic causes underly a significant proportion of triple primary cancer risk. Analysis of cancer frequencies found that the diagnosis of breast cancer was associated with a significantly lower likelihood of HCS, while the diagnosis of colorectal, prostate, and pancreas cancer was associated with a significantly higher likelihood of HCS. Comparison of HCS-positive and HCS-negative patients revealed similar demographic characteristics, mean age at first diagnosis, and family history of cancer. Moreover, no significant differences in lifestyle behaviors, occupational exposures, chronic health conditions, or treatment with chemotherapy and radiation were observed between HCS-positive and -negative groups, though outliers in tobacco smoking, as well as systemic treatment after both first and second primary cancers were observed. These findings indicate a robust contribution of HCS to cancer susceptibility among patients with triple primary cancers while environmental influences were less evident. This emphasizes the need for larger MPC cohorts incorporating additional genetic and environmental factors to more comprehensively characterize drivers of cancer risk. PREVENTION RELEVANCE: In patients with three or more primary cancers, genetic predisposition explained a significant proportion of cases; however, treatment history, lifestyle habits, and other exposures appeared to play a less significant role. This highlights the value of early genetic screening and the need to develop more sensitive markers of cancer susceptibility. See related Spotlight, p. 193.

Atypical ATMs: Broadening the phenotypic spectrum of ATM-associated hereditary cancer.

Heterozygous, loss-of-function germline variants in ATM have been associated with an increased lifetime risk of breast, pancreas, prostate, stomach, ovarian, colorectal, and melanoma cancers. We conducted a retrospective review of thirty-one unrelated patients found to be heterozygous for a germline pathogenic variant in ATM and identified a significant proportion of patients in this cohort with cancers not currently associated with the ATM hereditary cancer syndrome, including carcinomas of the gallbladder, uterus, duodenum, kidney, and lung as well as a vascular sarcoma. A comprehensive review of the literature found 25 relevant studies where 171 individuals with a germline deleterious ATM variant have been diagnosed with the same or similar cancers. The combined data from these studies were then used to estimate the prevalence of germline ATM pathogenic variants in these cancers, which ranged between 0.45% and 2.2%. Analysis of tumor sequencing performed in large cohorts demonstrated that the frequency of deleterious somatic ATM alterations in these atypical cancers equaled or exceeded the alteration frequency in breast cancer and occurred at a significantly higher rate than in other DNA-damage response tumor suppressors, namely BRCA1 and CHEK2. Furthermore, multi-gene analysis of somatic alterations in these atypical cancers demonstrated significant co-occurrence of pathogenic alterations in ATM with BRCA1 and CHEK2, while there was significant mutual exclusivity between pathogenic alterations in ATM and TP53. This indicates that germline ATM pathogenic variants may play a role in cancer initiation and progression in these atypical ATM malignancies, potentially influencing these cancers to be driven toward DNA-damage repair deficiency and away from loss of TP53. As such, these findings provide evidence for broadening of the ATM-cancer susceptibility syndrome phenotype to improve the recognition of affected patients and provide more efficacious, germline-directed therapies.

DNA damage repair deficiency as a predictive biomarker for FOLFIRINOX efficacy in metastatic pancreatic cancer.

Patients with pathogenic germline and somatic variants in DNA damage repair (DDR) genes may derive greater benefit with platinum-based chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC). This study investigates the role of DDR genes as a predictive biomarker for response to first-line platinum chemotherapy with FOLFIRINOX in metastatic PDAC patients. Demographic, clinical, and pathologic variables were collected for patients with metastatic PDAC who received FOLFIRINOX as frontline treatment and who had germline and somatic genetic testing. Kaplan-Meier analysis of overall survival (OS) and progression free survival (PFS) were correlated to the presence of DDR pathogenic variants. Forty patients with metastatic PDAC met inclusion criteria. Germline genetic testing revealed germline pathogenic variants in DDR genes in 5 patients (12%), and somatic pathogenic variants in DDR genes in 4 patients (10%). Median PFS was significantly longer in patients with any (germline or somatic) pathogenic variant in DDR genes than in those without alterations 18.5 vs. 6.9 months (log-rank P=0.003). When restricted to the presence or absence of germline pathogenic variants in DDR genes, the median PFS was 18.5 vs. 7.4 months (log-rank P=0.005). The median OS for the entire cohort was 11.5 months was not statistically different between the two groups, however there were no deaths in the subgroup with germline pathogenic variants in DDR genes treated with frontline FOLFIRINOX. A subset of patients with metastatic PDAC and germline or somatic pathogenic variants in DDR genes have a statistically superior PFS when treated with the platinum containing regimen FOLFIRINOX. The role of DDR gene alterations as a predictive biomarker for FOLFIRINOX benefit should be further evaluated in prospective trials.

Co-occurrence of Lynch syndrome and juvenile polyposis syndrome confirmed by multigene panel testing.

Through germline multigene panel testing, we discovered the co-occurrence of Lynch syndrome due to a PMS2 mutation and juvenile polyposis syndrome due to a BMPR1A mutation in a young man with synchronous bladder and colorectal cancers and a family history of colorectal polyps. To our knowledge, this is the first report of an individual having these two hereditary colorectal cancer syndromes. This discovery highlights the benefit of multigene testing over traditional stepwise genetic testing, particularly when a clinical presentation suggests more than one underlying genetic cause. This report adds to the growing body of literature of individuals with multiple inherited cancer gene defects being identified thanks to the increasing implementation of multigene panels with next generation sequencing technologies.

Exceptional response to FOLFIRINOX in a patient with pancreatic cancer and a germline RAD51C mutation.

Pancreatic cancer is projected to become the second leading cause of cancer death in the United States by 2030. Deleterious germline mutations can contribute to pancreatic cancer susceptibility. Herein we report a case of a patient with metastatic pancreatic adenocarcinoma to the lung and liver who was found to have a deleterious germline mutation in RAD51C who had a remarkable response to chemotherapy with FOLFIRINOX, a platinum-containing regimen.

Primary Peritoneal Carcinoma in a BRCA1/2-negative, PALB2-positive patient.

•First reported case of PPC after BSO in a BRCA1/2-negative, PALB2-positive patient•The PALB2 mutation and genetic counseling is discussed•Multi-gene panel testing can benefit prognostic factors and targeted therapy.

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.

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 affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.