Breast invasive lobular carcinoma (ILC) is the second most common type of breast cancer, making up approximately 10% of all invasive breast cancers. Breast ILC is characterized by loss of e-cadherin protein expression (CDH1), which is usually caused by loss of function mutations in the CDH1 gene. A subset of breast ILC cases have no identifiable CDH1 mutation, but presumably inactivate CDH1 through currently unknown mechanisms.

Tumors from more than 150,000 unique patients including more than 15,000 breast cancers were examined by comprehensive genomic profiling to detect base substitutions, indels, copy number alterations, and genomic rearrangements in the full coding regions of up to 465 genes. Statistical significance of the disease distributions was calculated using Fisher's exact test with false discovery rate multiple hypothesis testing correction.

Of 760 breast ILC cases, 583 (76.7%) had a known loss-of-function mutation in the CDH1 gene. To identify previously unknown mutations that result in or substitute for CDH1 loss-of-function we performed statistical analysis on all mutations, in any gene, occurring more than once in the 177 ILC cases without an identifiable CDH1 mutation. The most statistically significant mutation was very near to a splice site of CDH1 (chr16:68863554 c.2296-3A>G), occurring in 7 CDH1 negative ILC cases as well as 9 other cases in cancer types that frequently harbor CDH1 mutations (7 breast, 2 gastroesophageal junction) and 1 colorectal cancer. Based on tumor-only test based zygosity modeling, this mutation is only observed as somatic and usually homozygous in the tumor. Four other positions near to splice sites of CDH1 (chr16:68844247 c.832+3A>G, chr16:68849667 c.1565+5G>A, chr16:68856133 c.1936+5G>A, chr16:68857532 c.2164+3A>C), mutated in 13 CDH1 negative ILC cases, were also statically significant, somatic, and usually homozygous. No statistically significant mutations were found in genes other than CDH1.

Previously unappreciated somatic, non-canonical splice site mutations in CDH1 occur in ~10% (20/177) of breast ILC cases with no known CDH1 mutation. These mutations occur almost exclusively in tumor types known to harbor frequent CDH1 mutations and are usually homozygous in the tumor, strongly indicating that they are CDH1 loss-of-function mutations.

Citation Format: Garrett M. Frampton, Ryan Hartmaier, Ethan Sokol, Anika Gupta, Joel Greenbowe, Steven Roels, Laurie Gay, Philip J. Stephens. Novel CDH1 mutations in breast invasive lobular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2363.