High prevalence of the MLH1 V384D germline mutation in patients with HER2-positive luminal B breast cancer

Abstract

HER2-positive luminal B breast cancer (BC), a subset of the luminal B subtype, is ER-positive and HER2-positive BC which is approximately 10% of all BC. However, HER2-positive luminal B BC has received less attention and is less represented in previous molecular analyses than other subtypes. Hence, it is important to elucidate the molecular biology of HER2-positive luminal B BC to stratify patients in a way that allows them to receive their respective optimal treatment. We performed molecular profiling using targeted next-generation sequencing on 94 HER2-positive luminal B BC to identify its molecular characteristics. A total of 134 somatic nonsynonymous mutations, including 131 nonsynonymous single nucleotide variants and three coding insertions/deletions were identified in 30 genes of 75 samples. PIK3CA was most frequently mutated (38/94, 40.4%), followed by TP53 (31/94, 33.0%), and others were detected at lower frequencies. Recurrent germline mutations of MLH1 V384D were found in 13.8% (13/94), with a significantly high TP53 mutations rate. The frequency of MLH1 V384D germline mutation in individuals with HER2-positive luminal B BC was significantly higher than that observed in the controls. All 13 cases were classified as microsatellite stable tumors. Tumor mutation burdens (TMB) were not significantly different between MLH1 V384D carrier and wild type. The concordant results of microsatellite instability (MSI) and TMB suggest that the haploinsufficiency of MLH1 plays a role as a tumor predisposition factor rather than a direct oncogenic driver. Our study identified, for the first time, that MLH1 V384D germline variant is frequently detected in HER2-positive luminal B BC. MLH1 V384D germline variant may not only contribute to gastrointestinal cancer predisposition but may also contribute to BC in East Asians.

Mismatch repair protein loss in breast cancer: clinicopathological associations in a large British Columbia cohort

“…In addition, another study that sequenced MMR genes in 12,019 cancers comprising 32 cancer types reported less than 2% frequency of MMR deficiency in breast cancer [36]. Furthermore, a recent study in 94 HER2-positive luminal B breast cancer patients showed that, although 13.5% of cases had a germline mutation (V384D) in the MLH1 gene, only 3 cases (3.2%) were MLH1-deficient by IHC [37]. In contrast, a recently published cohort from Italy reported a ten-times higher frequency (17%, 75 out of 444 cases) of homogenous MMR loss by immunohistochemistry [30]; although when further investigated by microsatellite instability assay, all but seven of these were negative (meaning only 1.6% of cases overall were MSI positive).…”

“…Overall survival (c) and breast cancer diseasespecific survival (d) in ER-positive, tamoxifen-treated patients of higher specificity achieved through curated genomic methods versus a higher sensitivity using protein expression detected through IHC methods [19]. We opted for IHC because MMR deficiency in breast cancer patients is very rarely hereditary [37,43]. Additionally, IHC is wellestablished in colorectal cancer and endometrial cancer, inexpensive and readily available [40,44].…”

The pan-cancer landscape of prognostic germline variants in 10,582 patients

“…In line with the heritability of some cancers, several germline variants predict a patient's risk for developing cancer and are useful for individualizing cancer screening guidelines [4][5][6][7][8][9][10][11][12][13]. Germline variation can affect drug sensitivity, predict drug toxicity, and could help select therapy to minimize side-effects [14][15][16][17][18][19][20][21][22][23][24][25][26].…”

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

“…Genomic scars in the MMR system are relatively rare in breast cancer, being reported in~2% of cases [49]. However, this subject is controversial in literature given the lack of companion diagnostics and/or tumor-specific guidelines for MMR analysis [47,[49][50][51][52][53][54]. Unlike in endometrial and colorectal cancers, MSI is restricted to a minority of breast cancers showing MMR protein loss [54].…”