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Loss of heterozygosity data from familial tumors suggest that BRCA1, a gene that confers susceptibility to ovarian and early-onset breast cancer, encodes a tumor suppressor. The BRCA1 region is also subject to allelic loss in sporadic breast and ovarian cancers, an indication that BRCA1 mutations may occur somatically in these tumors. The BRCA1 coding region was examined for mutations in primary breast and ovarian tumors that show allele loss at the BRCA1 locus. Mutations were detected in 3 of 32 breast and 1 of 12 ovarian carcinomas; all four mutations were germline alterations and occurred in early-onset cancers. These results suggest that mutation of BRCA1 may not be critical in the development of the majority of breast and ovarian cancers that arise in the absence of a mutant germline allele.

It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).

To clarify the relationships among TML, MMR, and immune checkpoint expression, we profiled the frequency of shared biomarker phenotypes. On the basis of a variety of potential biomarkers of response to immune checkpoints, only small subsets of glioma patients are likely to benefit from monotherapy immune checkpoint inhibition.

The lifetime risk of breast cancer may approach 80-90% in women who have germline mutations of either of two genes, BRCA1 or BRCA2. A single BRCA1 mutation, 185delAG, has been noted in approximately 20% of Ashkenazi Jewish women with early onset breast cancer and in 0.9% of the Ashkenazi population. We recently detected a 6174delT frameshift mutation in BRCA2 in an hereditary breast cancer kindred of Ashkenazi Jewish ancestry. Here, we investigated the frequency of this mutation in 200 women with early-onset breast cancer. Six of 80 Ashkenazi Jewish women (8%) diagnosed with breast cancer before the age of 42, wer heterozygous for the 6174delT mutation, compared to none of 93 non-Jewish women diagnosed with breast cancer at the same age (P = .005). These cases were ascertained without regard to family history. Two of 27 (7%) additional Jewish families in which the proband was diagnosed with breast cancer at age 42 to 50 and had a family history of breast or ovarian cancer had germline 6174delT mutations. The results of this report suggest that a recurrent mutation of BRCA1 and a recurrent mutation BRCA2 together may account for over a quarter of all early-onset breast cancer in the setting of a personal or family history of ovarian cancer in Ashkenazi Jewish women.

Using a multiplex testing approach, 28% of CUP carried one or more predictive biomarkers (MSI-H, PD-L1 and/or TML-H) to the immune checkpoint blockade, providing a novel option for treatment in patients with CUP.

BRCA1 is a breast and ovarian cancer susceptibility gene. An inferred germline regulatory mutation was previously reported in the BRCA1-linked kindred K2035, based on the absence of transcripts from the BRCA1 allele associated with the cancer susceptibility haplotype. In this study, the promoter region of BRCA1 was examined in individuals from K2035 for evidence of a mutation which could halt transcription. Evaluation of a polymorphism located within intron 2 of BRCA1 gave results consistent with the presence of a large deletion in K2035 mutation carriers. Southern blot analysis identified unique restriction fragments which occurred as a result of a 14 kb deletion that removed both of BRCA1's transcription start sites (exons 1a and 1b) as well as exon 2. Sequencing indicated that unequal crossover between Alu repeats was the likely cause of the deletion. Similar deletions may be responsible for other reported inferred regulatory mutations, as well as unidentified mutations in families linked to BRCA1.

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